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Review

Table of Contents

CuAAC: An Efficient Click Chemistry Reaction on Solid Phase

# Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology 08028-Barcelona, Spain
⊥ CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, 08028-Barcelona, Spain
◊ Department of Organic Chemistry, University of Barcelona, 08028-Barcelona, Spain
§ School of Chemistry, Yachay Tech, Yachay City of Knowledge, Urcuqui, Ecuador
∥ School of Chemistry & Physics, University of KwaZulu-Natal, 4001-Durban, South Africa
ACS Comb. Sci., 2016, 18 (1), pp 1–14
DOI: 10.1021/acscombsci.5b00087
Publication Date (Web): December 11, 2015
Copyright © 2015 American Chemical Society
Cite this:ACS Comb. Sci.  18, 1, 1-14

Abstract

Abstract Image

Click chemistry is an approach that uses efficient and reliable reactions, such as Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC), to bind two molecular building blocks. CuAAC has broad applications in medicinal chemistry and other fields of chemistry. This review describes the general features and applications of CuAAC in solid-phase synthesis (CuAAC-SP), highlighting the suitability of this kind of reaction for peptides, nucleotides, small molecules, supramolecular structures, and polymers, among others. This versatile reaction is expected to become pivotal for meeting future challenges in solid-phase chemistry.

Keywords:

alkyne; azide; Click Chemistry; CuAAC; solid-phase;

1 Introduction

In 1963, Merrifield(1) introduced the concept of solid-phase peptide synthesis (SPPS), reporting the first efficient production of a tetrapeptide on a solid matrix, wherein the peptide chain was grown by covalent attachment of one end to the functionalized support. Thanks to Merrifield’s pioneering work, this concept has become a fully established method in peptide synthesis; however, many other known organic reactions have also been applied on solid phase (SP) supports to address synthetic problems and generate new molecular entities.(2, 3)
Click chemistry(4, 5) promotes the use of organic reactions that allow the connection of two molecular building blocks in a facile, selective, high-yield reaction under mild conditions with few or no byproducts.(4, 5) Diels–Alder, Michael addition, pyridyl sulfide reaction, oxyme, thiolene, strain-promoted azide–alkyne cycloaaddition (SPAAC), and Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) have all been reported as Click reactions.(6-24)
In the past decade, the CuAAC(25-27) has emerged as an efficient alternative in SP to replace amide bonds in peptides(28) and to generate amino acid triazole derivatives,(29) cyclic peptides,(30) nucleotides,(31-33) and new resins.(34, 35) Furthermore, this chemistry has the capacity to promote bioconjugation and peptide ligation, stemming from the properties of the triazole linkage as a peptide mimetic.
This Review describes the general features and applications of CuAAC on SP (CuAAC-SP) and reveals the suitability of this kind of reaction for the modification of peptides,(36-38) nucleotides,(31-33) small molecules,(39) supramolecular structures,(40, 41) and polymers.(42)

2 General Considerations Regarding Cu(I)-Catalyzed Azide–Alkyne Cycloaddition on Solid Phase (CuAAC-SP)

CuAAC is a type of Huisgen1,3-dipolar cycloaddition based on the formation of 1,4-disubstituted [1,2,3]-triazoles between a terminal alkyne and an aliphatic azide in the presence of copper(43, 44) and is classified as a Click Chemistry reaction.(5) Click Chemistry was defined by Sharpless et al.(4, 5) as any chemical reaction that allows high yields, generates no side-products or ones that are easily removed, is stereospecific, gives physiologically stable products, exhibits a large thermodynamic driving force, and has simple reaction conditions. Research into the synthesis of biomolecules via CuAAC-SP has emerged because of the stability of triazole scaffolds against metabolic degradation.(4, 5) In this Review, we use the terms CuAAC and Click Chemistry interchangeably.
In 2001, Meldal et al.(25, 26) developed a method for preparing 1,4-disubtituted 1,2,3-triazoles using Cu(I) salts as a catalyst for the 1,3-dipolar cycloaddition of terminal alkynes to azides on SP at room temperature using organic solvents such as ACN, THF, DCM, toluene, and DMF. Shortly after and using protic polar solvents such as t-butyl alcohol, ethanol or water, Sharpless et al.(27) independently reported the same reaction in solution, naming it CuAAC (Scheme 1).
figure
Scheme 1. Cu(I)-Catalyzed Azide–Alkyne Cycloaddition (CuAAC)a

aFor CuAAC-SP, either the alkyne or azide are attached to a solid-phase support.

The CuAAC reaction was a breakthrough in triazole chemistry. The reactions of organic azides with terminal alkynes were shown to be accelerated by copper ions and to proceed regioselectively under these conditions, giving the 1,4-disubstituted 1,2,3-triazole regioisomer exclusively. The formation of the 1,4-disubtituted 1,2,3-triazole ring occurs rapidly in the presence of Cu(I). The cycloaddition product is chemically inert and stable toward redox reactions and it has strong dipole moment of ∼5 D, as shown by experimental studies,(5) hydrogen bond accepting capacity, and aromatic character.(45)
Table 1 summarizes the main features of the reaction. In general, several resins with a broad range of hydrophobicity have been used to prepare compounds such as peptides, peptoids, PNA, and nucleotides. Most of these reactions were carried out using a Cu(I) source and polar solvents. CuI, CuBr, CuCl, CuBr(PPh3)3, and [Cu(CH3CN)4]PF6 are the most widely used copper sources, whereas DMF, ACN, THF, DCM, H2O, tBuOH, NMP, DMSO, CHCl3, and MeOH are the most frequently used polar solvents. In some cases, a Cu(II) salt, such as CuSO4·5H2O, is used instead of Cu(I) salt, and the addition of a reductive reagent such as sodium ascorbate is required to reduce Cu(II) to Cu(I). These reactions can be carried out with or without a base, with reaction times ranging between 4 and 63 h. The application of microwave radiations between 40 and 60 °C decreases the reaction time considerably. The yield of CuAAC-SP is often reported as quantitative. In many cases, the process has been monitored by IR spectroscopy, tracking the disappearance of the characteristic azide band in the IR spectrum. The broad range of reaction conditions has allowed the production of a great variety of final products via CuAAC-SP (Table 1), thereby revealing the versatility of this kind of reaction and its huge potential.
Table 1. General Conditions of CuAAC-SPa
resinCu(I) cat.Cu (equiv)basetR (h)final productref
Tenta GelCuSO4·5H2Ob0.2DIEA16cpeptide46
12′2-bypiridine2cpeptide47
  4glycooligomer48
CuBrb1DIEA, 2,6-lutidine16–48resin, peptide, PNA34, 35, 49, 50
0.1–2.5DIEA24–72peptide, PNA51−54
0.3TBTA2glycodendrimer, nucleotide55, 56
CuIb DIEA, 2,6-lutidine PNA57
[Cu(CH3CN)4]PF60.1TBTA16–48PNA, resin58, 59
PEGA 800CuI1–0.5DIEA16–72peptide, PNA50, 60−62
AMCMCuBrb1DIEA, 2,6-lutidine16resin34, 35
2-CTCCuSO4·5H2Ob0.2–0.5DIEA16–48peptoid46, 63, 64
CuBrb PMDTA peptide65
CuBrb1DIEA, 2,6-lutidine6peptide30
CuIb DIEA16peptoid66
WangCuI2DIEA2–48peptide, peptoid67−70
CuI1.5DIEA, HBTU24small molecule71
CuBr  20oligomer72
PAMCuSO4·5H2Ob0.2–0.5TBTA1–18coligomer60
CuIb0.52,6-lutidine16peptide73
Rink-amideCuSO4·5H2Ob0.1–0.5TBTA–242cpeptide74−77
CuBra1.5DIEA, 2,6-lutidine peptide78
[Cu(CH3CN)4]PF6 DIEA peptide79
1TBTA, 2,6-lutidine peptide80
CuIb 2,6-lutidine12peptide81
5 24peptoid82
MBHACuBrb1DIEA, 2,6-lutidine16resin34, 35
CuIb5piperidine5–16peptide83, 84
CuSO4·5H2Ob5 1cpeptide85
MerrifieldCuSO4·5H2O2TEA small molec.86
CuI0.05DIEA10–63csmall molec., S.S.87−97
CuBr(PPh3)3  16–36csmall molec., S.S.98, 99
CPGCuSO4·5H2Ob0.4–0.5 0.2–16nucleotide100−108
CuSO4·5H2Ob TBTA0.5–5cnucleotide109−112
CuSO4·5H2O5 0.5–4cnucleotide113, 114
CuI1DIEA16PNA115
CuCl1 16PNA116
a

Polar solvents were used in the most reactions.

b

Sodium ascorbate was used as Cu(I) stabilizer.

c

Temperature between 40 and 60 °C or microwave reaction conditions. S.S.: Supramolecular structure.

The main variables in CuAAC-SP are the choice of resin, copper catalyst, solvent, and the presence or absence of a base; Table 1 provides an indication of the variables in each category. Both hydrophobic and hydrophilic resins can be used; however, in all cases a polar solvent has been utilized to obtain quantitative results. The copper catalyst is indispensable, and a Cu(I) stabilizer is widely used. Finally, although a base (i.e., DIEA, piperidine, and others) is not imperative, it has been used in most cases to improve performance.
To better understand CuAAC-SP, we describe the current understanding of its mechanism and outline various methods used to synthesizing azide reaction partners. Preparation of the terminal alkyne is not included in this review because this group is usually introduced through conventional SP coupling procedures.(48)
2.1Cu(I)-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) Mechanism
The last generally accepted mechanism of the CuAAC reaction is shown in Scheme 2.(-117, 118)
While the involvement of two Cu(I) ions in the reaction has been appreciated for some time, a detailed mechanism of this reaction has remained elusive. Worrell et al. recently showed that two Cu(I) atoms of the catalytic complex become equivalent and can scramble,(119) but the mode of binding of the azide to the Cu(I) π-complexes has not been demonstrated experimentally.
figure
Scheme 2. Cu(I)-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) Mechanism
2.2Azide Formation
Azides for the CuAAC-SP can be prepared by various methods,(120, 121) substitution or diazo-transfer being those most commonly used. Aliphatic azides are readily accessible by SN2-type substitution with the highly nucleophilic azide ion.(121) These azide derivatives have long been appreciated as an important class of compounds (Table 2).(122) Sodium azide (Na+·N– = N+ = N–) is the most widely used azide source.(123)
The diazo-transfer reaction allows the synthesis of organic azides from primary amines using a diazo-transfer reagent (Scheme 3). The most widely used diazo-transfer reagents are shown in Table 2. The procedure is well suited to SP, since side reactions involving the sensitive aliphatic diazonium ions can be circumvented. As an example, Barral et al.(124) performed a particularly efficient conversion of aromatic amines into azides on SP, using trimethylsilyl azide as diazo-transfer reagent (Table 2, entry 1).
figure
Scheme 3. Diazo-Transfer Reaction from Amine to Azide
Wong et al.(125-129) studied the diazo-transfer of aliphatic amines using Cu (II), Ni (II), Zn (II), tetrabutylammonium hydrogen sulfate, or 18-crown-6 as catalysts or additives, and trifluoromethanesulfonyl azide (triflyl azide) as diazo-transfer reagent. In most cases, the latter is prepared in situ by reaction of trifluoromethanesulfonic anhydride and sodium azide (Table 2, entry 2). Diversely substituted [1,2,3]-triazoles were achieved by treating resin-bound 3-amino-2-butenoic acid amides with tosyl azide in the presence of DMF and DIPEA(130) (Table 2, entry 3).
In 2010, Katritzky et al.(131) synthesized the crystalline benzotriazole-1-yl-sulfonyl azide (Table 2, entry 4) as a new stable and widely available diazo-transfer reagent that efficiently provides N-(α-azidoacyl) benzotriazoles with CuSO4·5H2O as copper source. Crystalline 2-ethylimidazole-1-sulfonyl azide (Table 2, entry 5) was designed by Schottenberger et al.(132) as a convenient reagent to improve thermal stability for the azidation of electrophilic carbanions.
Similarly, Goddard et al.(133, 134) developed imidazole-1-sulfonyl azide hydrochloride (Table 2, entry 6), an affordable and effective diazo-transfer reagent using K2CO3 and MeOH in the presence of CuSO4·5H2O as copper catalyst source.(133) This reagent has proven to equal triflyl azide in its capacity as a “diazo donor” to promote the conversion of primary amines into azides and of activated methylene substrates into diazo compounds.
Table 2. Azide Formation Reagents
However, there are some safety concerns regarding the potential risk of explosion of this reagent. To identify safer-to-handle forms of this compound, several types of imidazole-1-sulfonyl azide salts (Table 2, entry 6) were prepared, and their sensitivity to heat, impact, friction, and electrostatic discharge were quantitatively determined. A number of these salts exhibited improved properties and can be considered safer than the aforementioned hydrochloride.(134) In addition, Wang et al.(135) reported a facile approach to synthesize this diazo-transfer reagent by optimizing the procedure to diminish potential risk of explosion. Some reports support the use of this reagent to prompt efficient diazo-transfer reactions, always using polar solvents or aqueous media.(136-139)
The introduction of azide groups on SP has been accomplished mainly through direct nucleophilic displacement of chloromethyl-derivatized solid supports by the azide ion.(87, 88, 140) Some of these methods are sluggish under the harsh conditions used and they lack reproducibility. To overcome these limitations, a diazo-transfer reaction using trifyl azide (TfN3) was developed to convert amines into azides on SP, allowing the synthesis of azido peptides,(141, 142) oligonucletides,(55) and glycodendrimers.(56) However, TfN3 is unstable and potentially explosive and it requires in situ preparation. To avoid this problem, Hansen et al.(143) used imidazole-1-sulfonyl azide hydrochloride (ISA.HCl) as a diazo-transfer reagent for the efficient preparation of azido peptides on SP. With the aim to generate azide resins, we recently described the application of the ISA·HCl-based diazo-transfer method to a set of four resins covering a broad range of hydrophobicity.(35)

3 Cu(I)-Catalyzed Azide–Alkyne Cycloaddition on Solid-Phase (CuAAC-SP)

3.1History
In 1996, Zaragoza et al.(130) published the first synthesis of diversely substituted [1,2,3]-triazoles on a solid support through a cyclization. This synthesis was achieved by treating resin-bound 3-amino-2-butenoic acid amides with tosyl azide in the presence of a tertiary amine. A few years later, in 2002, Meldal et al.(26) reported the first mild, efficient, and regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes into azides on SP, using hydrophilic PEGA 800 and SPOCC resins to obtain diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains.
Given that CuAAC-SP has been successfully introduced in many fields of science, and to gain a better understanding of this topic, we have classified its use with regard to peptides,(36-38) nucleotides,(31-33) small molecules,(39) supramolecular structures,(40, 41) and polymers,(42) thus demonstrating its potential in SP synthesis over the last ten years.
3.2Peptides
Peptides as drug candidates have some limitations that are related to their aqueous solubility, lipophilicity, H-bond formation, chemical stability, and metabolic stability (proteolytic or enzymatic degradation). Many strategies, including as the introduction of non-natural amino acids, terminal protection, cyclization, and backbone modifications,(37, 144) have been used to increase the stability of drug candidate peptides
The 1,2,3-triazole has attracted increasing attention as a bioisostere of the amide bond of peptides. Tron et al.(28) reported the physicochemical properties of 1,2,3-triazole and compared them with the amide bond. The 1,4-disubstituted triazole scaffold shows similarity to a Z-amide bond (Figure 1). This similarity is appreciated by the following features: the distances between substituents; R to R′ are 3.9 Å in amide and 5.0 Å in 1,4-disubstituted 1,2,3-triazole; the lone pair of 3-nitrogen mimics that of the carbonyl oxygen of the amide bond (Figure 1, blue remarked); the polarized C(5)-H bond can act as a hydrogen bonding donor, just like the amide N–H bond (Figure 1, red remarked); and the electrophilic and polarized 4-carbon is electronically similar to the carbonyl carbon (Figure 1, green remarked). The overall dipolar moment of the triazole system is larger than that of the amide bond: amide ∼4 D, 1,4-disubstituted1,2,3-triazole ∼5 D, and its hydrogen bonding donor and acceptor properties are more marked than those of an amide bond, improve the properties of peptide mimicry.(28, 145)
figure

Figure 1. Structural similarities between Z-amide bond and the 1,4-disubstitued 1,2,3-triazole scaffold.

For instance, SP synthesis of 1,4-disubstituted 1,2,3-triazole via Click Chemistry has been used to replace the amide bond by 1,4-disubstituted 1,2,3-triazoles to form peptidotriazoles,(60) peptide mimics,(146) cyclic peptides,(30) and amino acid modifications.(29) Additionally, it has also been applied in radiotracer conjugation,(147) peptide ligation,(52) and bioconjugation.(68) Most of these uses promote the introduction of contact groups to enhance affinity or the formation of glycopeptides,(148) PEGylated peptides,(82) and peptide nucleic acids(64) (Figure 2).
The replacement of amide bonds by 1,4-disubstituted 1,2,3-triazoles on resin was reported in analog formation of peptidomimetics, such as Leu-enkephalin.(146) Furthermore, RGD-based peptidomimetics with high activity and selectivity toward αvβ3 and α5β1,(149) a matriptase inhibitor mimic and(46) a small peptide mimic of the Grb2-SH2 domain respectively,(67) were also reported.
Furthermore, the formation of 1,2,3-triazoles as a substitute of 3-oxoalkanoic acids on Wang resin,(130) the preparation of N-substituted histidine and tripeptide analogs from propargylglycine to form peptidotriazoles on PEGA 800 and SPOCC resins,(26) and the formation of triazolamer (Figure 2, 2a) under different conditions of CuAAC were established.(60)
figure

Figure 2. CuAAC on Solid-Phase Peptide Synthesis (SPPS).

A triazole scan of a biologically relevant peptide and its utility for the identification of novel peptidomimetics with improved properties was also achieved via a CuAAC strategy.(79) Also, on-resin “Click” construction of peptide diphenyl phosphonates has been reported as a valuable method for the rapid diversification of serine protease activity-based probes (ABPs).(74)
CuAAC-SP has been used as a macrocyclization tool for the formation of triazole scaffold by substituting an amide bond via Click Chemistry. This reaction yielded the following: cyclic peptide mimetic model to optimize PEG based resins,(62) cyclic tetra-, penta-, hexa-, and hepta-peptides (Figure 2, 2b),(30) as a new family of cyclopeptide cyclo[-Arg-Gly-Asp-Ψ(triazole)-Gly-Xaa-] analogs;(150) new cyclic RGD and NGR peptide analogs;(78) two asymmetrical cyclopeptides (CP1 and CP2);(65) side chain to side chain macrocyclization for the synthesis of a series of 21 amino acid helical peptides;(49) cyclic peptide C2BL3C based on membrane penetration C2B loop 3 of Syt1;(80) cyclic peptidotriazoles derived from the antimicrobial cyclic peptide c(Lys-Lys-Leu-Lys-Lys-Phe-Lys-Lys-Leu-Gln) (BPC194);(83) and a cyclic peptidosteroid via convergent peptide ligation and macrocyclation.(47)
Head-to-tail oligopeptide cyclodimerization was also reported when precursors containing azide and alkyne groups were exposed to Cu(I) ions on polystyrene supports.(73, 81) Cyclic lipopeptidotriazoles, which has proven to be a useful approach to improve the antibacterial activity of the parent peptides, as well as to endow them with antifungal properties, were also prepared using CuAAC-SP.(84)
CuAAC was also used on azidoproline (Azp) (Figure 2, 2c)(29) and on Azp-containing collagen model peptides (CMPs) to study their functionality and conformational properties.(75, 76) Click chemistry was also applied to attach [18F]fluoroalkynes to peptides functionalized with 3-azidopropionic acid (Figure 2, 2d),(147) and also to introduce hydrophilic carbohydrate linker moieties into the stabilized BBS (7–14) sequence previously synthesized on Rink-amide resin bearing the (NαHis) Ac-chelator labeled with 99mTc using the tricarbonyl technique.(151)
Several peptide sequences, which contained modified amino-acid propargylglicine (Pra), were attached to red-fluorescent tetramethylrhodamine azide (TAMRA) via CuAAC-SP, in order to generate wide range of fluorescent substances,(12) thus allowing the identification of cyclic peptidyl inhibitors against the calcineurin/NFAT interaction through high-throughput screening of one-bead-one-compound libraries.(152, 153)
In addition, this Click Chemistry has been used to produce assembled and scaffolded peptides from peptide and scaffold precursors N-terminally modified with azido and alkyne moieties, respectively, using 2-CTC resin.(52) An efficient self-purifying N-to-C iterative triazole ligation strategy was also applied to the synthesis of a polypeptide with 160 residues on ChemMatrix, PEGA800 and PEGA1900 resins, achieving high purity without the need of chromatographic purification.(154)
CuAAC-SP was also used as the key step to obtain valuable aminoacyl-(peptidyl)-penicillins, and this reaction showed general applicability and excellent regioselectivity using Wang resin as solid support (Figure 2, 2e).(69) Two biotin linkers of different lengths bearing the activated p-(N-propynoylamino) toluic acid (PATA) were incorporated in biotinylated oligopeptides and C-myc peptide both in solution and on a solid support, achieving excellent yields of conversion.(68)
In this regard, peptides labeled with short-lived positron emitters were synthesized by CuAAC-SP for later use in molecular imaging by positron emission tomography.(85) Another example is peptides loaded with a dendron via CuAAC-SP; these peptide mimotopes are promising candidates as multivalent ligands for antibody B13-DE1 recognition.(155)
Resins modified by CuAAC-SP for the purpose of peptide synthesis and another applications have been published. We reported on the CuAAC reaction for the preparation of a novel OH-BTL resin (Figure 2, 2i) to circumvent the disadvantages generated by the use of Wang resin in SPPS.(34, 35) Another modified resin prepared via CuAAC-SP to solid phase organic synthesis (SPOS) was reported, with an outgoing linker after treatment of DBU in the presence of NaI.(156)
3.3Peptoids
Peptoids have become an important class of peptide mimics because of their structural and functional properties.(157) Examples of peptoids formed via CuAAC-SP include glycosylated peptoids by global on-resin Click glycoconjugation of alkynyl substituted peptoids (Figure 2, 2f).(148) Other highly functionalized peptoid oligomers were generated by sequential CuAAC-SP.(158) Also, modular synthesis of glycosylated peptoids and polyamines,(63) or amphiphilic peptoid transporters used for cell-penetration(66) were performed using Rink-amide resin.
A focused dipeptide conjugated azidothymidine (AZT) library has been synthesized, and a convenient and efficient CuAAC-SP has been described using Wang resin as solid support.(70) Versatile approaches for the efficient synthesis of PEGylated lipo-peptides via CuAAC “Click” conjugation between alkyne-bearing solid-supported lipopeptides and azido-functionalized PEGs was described using polystyrene or TentaGel resins (Figure 2, 2h).(82) Most of the studies cited demonstrated the potential of CuAAC in chemical ligation strategies. Other examples of peptoids were described by Zabrodski et al.,(157) reporting a fast and efficient incorporation of the pyridine ligands derivatives into N-substituted glycine peptoid oligomers via CuAAC-SP.
3.4Peptide Nucleic Acid
Concerning peptide nucleic acids (PNAs), organometallic PNA oligomers were synthesized by Click Chemistry on SP through the insertion of ferrocene into PNA oligomers via 1,2,3-triazole formation on PEGA800 resin.(159) Azidoferrocene, ethynylferrocene, and DEPA-ferrocene derivatives were introduced into TentaGel resin via Click Chemistry by reaction with PNA trimer conjugates.(50) Other organometallic compounds, such as azidomethyl-ruthenocene, and their application via Click Chemistry with PNA oligomers immmobilized on TentaGel resin have also been reported.(57) Furthermore, a new azido derivative of 2,2′-dipicolylamine (Dpa) was successfully coupled on SP to a PNA oligomer (H-4-pentynoic acid–spacer–spacer–tgca–tgca–tgca–Lys–NH2; spacer (−NH–(CH2)2–O–(CH2)2–O–CH2–CO−) using CuAAC-SP to give Dpa-PNA oligomer.(53) Finally, a fluorescent rhenium-containing PNA bioconjugate (Re-PNA) was prepared by means of conjugation of rhenium tricarbonyl complex of a bis(quinoline)-derived ligand (2-azido-N,N-bis((quinolin-2-yl)methyl)ethanamine, L–N3), namely, ([Re(CO)3(L–N3)]Br), to a PNA oligomer via CuAAC-SP (TentaGel resin).(54)
The synthesis of PNA bearing a triazole in place of the amide bond assembled via CuAAC-SP (Rink-amide resin) has been achieved (Figure 2, 2g).(64) Click attachment of peptide to oligonucleotides on solid support (Wang resin) was also reported.(116) Several peptide-siRNA conjugates were also obtained by a CuAAC-SP strategy, using an alkynyl nucleoside analog “clicked” onto a peptide-derivatized CPG (controlled pore glass) as solid support.(115) Finally, fluorescent molecules were attached to pyrrolidinyl peptide nucleic acid bearing a D-prolyl-2-aminocyclopentane carboxylic acid backbone (acpcPNA) as a base surrogate via a triazole linker and using a CuAAC strategy on TentaGel resin as solid support.(51, 58)
3.5Nucleotides
The structural diversity of active nucleosides proves that nucleoside analogs do not need to resemble their natural counterpart, and these new structures are worth exploring. In this regard, researchers have moved their attention to the possible benefits of innovative and new synthetic approaches, such as CuAAC-SP, for the synthesis of modified nucleosides,(31) in which the phosphodiester linkage is replaced by 1,2,3-triazole moiety. This moiety is able to form cyclic nucleotides or assists in bioconjugation, such as in the case of glyconucleotides, glycoclusters,(32) and contact groups (Figure 3).
To discover new derivatives with potential biological activity, CuAAC-SP has been applied to the loading of alkyne-functionalized leader nucleoside monomers suitable for SP oligonucleotide synthetic applications (Figure 3, 3a).(55, 160) In relation to the replacement of phosphodiester linkage by 1,2,3-triazole moiety, Isobe et al. designed and synthesized a new triazole-linked analog of DNA on TentaGel resin (Figure 3, 3b).(100) On the other hand, Morvan et al. designed an azido linker to prepare a DNA oligonucleotide, bearing both 3′-azide and 5′alkyne functions on CPG resin. Cycloadditions were performed (Figure 3, 3c).(101)
CuAAC-SP has also been applied to the synthesis of new nucleoside bioconjugates(31) and to the generation of small libraries of nucleoside derivatives on resin.(161) Indeed, the efficiency and simplicity of this reaction make it an attractive choice for the covalent linkage of two molecular entities to provide biomolecules with novel properties, such as biological activity, altered hydrophobicity, increased bioaffinity, or the capacity to carry metal ions.(31) For instance, glyconucleotides were synthesized by 1,3-dipolar cycloaddition not only of T12trispropargylphosphoramidate oligonucleotide with galactosyl azide on SP (CPG resin)(102) but also of manose and galactose-alkyne for the preparation of oligonucleotide conjugates.(103)
Glycocluster synthesis is carried out using the CPG resin as solid support.(104-106) DNA-based glycoclusters can be fucosylated pentaerythityl phosphodiester oligomers (PePOs) (Figure 3, 3d),(104) phosphodiester galactosyl clusters,(105) or carbohydrate-centered galactosyl clusters.(106)
figure

Figure 3. CuAAC-SP for the synthesis of nucleotides.

Mannose and galactose oligonucleotide conjugates have been prepared by bi-Click Chemistry (two successive CuAACs-SP).(109) The efficient synthesis of RNA conjugates with non-nucleoside building blocks has been described by Click Chemistry on CPG resin (Figure 3, 3e).(110, 111, 113, 162-164) The introduction of contact groups for recognition was also assisted by Click Chemistry. Biotin linker (p-N-propynoylaminotoluic acid, PATA) was conjugated to oligonucleotides.(68) The site-specific incorporation of diamondoids on DNA via CuAAC on CPG resin was achieved (Figure 3, 3f).(165) Facile one-step SP synthesis of multitopic organic-DNA hybrids on GPC beads was performed via CuAAC.(112)
Another example is the use of CuAAC-SP to prepare fluorescent DNA probes containing internal xanthenes and cyanine dyes.(114) Meyer et al.(107) described the synthesis of heteroglyco 5′-oligonucleotide conjugates via CuAAC-SP with the formation of phosphoramidite derivatives bearing orthogonal function alkyne/thioacetyl, and an azide-bearing carbohydrate. Tähtinen et al.(108) reported the synthesis of Neomycin-conjugated homopyrimidine oligo 2′-deoxyribonucleotides on SP using Click Chemistry as these compounds are potential therapeutic agents since they recognize the DNA and the double helical RNA.
3.6Small Molecules
The combinatorial synthesis of libraries based on the so-called small molecules as bioactive entities has led to increased pressure on chemical synthesis to enhance throughput. SPOS has become an area of huge interest in organic and medicinal chemistry; the application of SPOS comprises a broad variety of organic reactions. For instance, CuAAC is a specific reaction that has been successfully applied on SP for small molecules (Figure 4).
Initially, Gmeiner et al.(87-92, 166) developed an efficient 1,3-dipolar cycloaddition of alkynyl-substituted handles with azidomethyl polystyrene that allowed the preparation of the formylaryloxymethyltriazole (FAMT) handle and the formylindolylmethyltriazole linker (FIMT) as backbone amide linker (BAL) analog for the parallel synthesis of pharmacologically tested compounds (Figure 4, 4a), with affinity for selective dopamine D4 receptor ligands.(87) The same concept of resin, in this case known as regenerative Michael acceptor (REM) resin, was developed for the synthesis of tertiary amines (Figure 4, 4b).(88)
figure

Figure 4. CuAAC-SP for the synthesis of small molecules.

Dopamine receptor ligands,(89) N-benyltriazolescarboxamides as superpotent G-protein-coupled receptor ligands,(90) dopaminergic phenylacetylenes,(91) dopamine D4 selective positron emission tomography (PET) ligand candidate (Figure 4, 4c),(92) and a potent dopaminergic N-phenyltriazole carboxamides(166) were synthesized by CuAAC on SP using polystyrene resin.
Moses et al.(93) prepared ethynyldiisopropyldilyl as a new silyl-based reagent for “catch and release” immobilization, combining Click Chemistry with silyl protection (Figure 4, 4d). In this case, the traditional “all carbon” attachment to solid supports in a silyl-type linker was substituted by a stable triazole, which was easily assembled using the CuAAC reaction on polystyrene resin.(93) Nielsen et al.(61) developed the synthesis of NH-1,2,3-triazoles, which were prepared by a Click strategy using an acid-labile azido linker supported on PEGA800, polystyrene, TentaGel, ChemMatrix, or Wang resins.
An efficient method for the preparation of 1,4-disubstituted 1,2,3-triazole compounds was also described using polymeric quaternary ammonium salts with azide or alkyne functionality to remove unreacted excess starting molecules (azide/alkyne).(86) Click Chemistry was used to build a polyheterocyclicbenzopyran library(98) and also to develop a useful kit for the detection of a molecule of interest.(167)
Furthermore, the synthesis of triazole-based dansylfluorophore for selective and sensitive ratiometric detection of Hg2+ was developed by Lee et al. (Figure 4, 4e)(77) on Rink-amide resin. Gothelf et al.(168) developed the synthesis of dopamine and serotonin synthesized with short PEG ethers, which were azide-functionalized to promote coupling onto alkyne-modified magnetic beads (Dynabeads M-270) via Click Chemistry on SP.(168) Also, Pericàs et al.(94) used the Click strategy to immobilize MacMillan organocatalyst onto polymers and magnetic nanoparticles.(94) Portnoy et al. studied one-pot esterification–Click reactions for the functionalization of Wang resin via CuAAC.(71) Recently, the SPOS of 1-vinyl and 1-allyl substituted 1,2,3-triazoles was achieved on a selenium linker on solid support via Click Chemistry.(95)
3.7Supramolecular Structures and Polymers
CuAAC-SP has been successfully applied to supramolecular structures, polymers, and affinity chromatography fields (Figure 5). The synthesis of lysine-based glycodendrimers as antagonists against Escherichia coli (Figure 5, 5a) using Click Chemistry was carried out by means of azide-functionalized Rink resin and propargyl α-d-mannopiryranoside.(56) Moreover, Hartmann et al.(48) developed heteromultivalent glycooligomers by CuAAC for application in several fields such as antiviral drugs, vaccines and biosensors.(48) The synthesis of molecularly encoded oligomers using a chemoselective CuAAC-SP was also carried out.(72) Furthermore, the design and synthesis of a series of solid-tethered rotaxanes utilizing crown ether-naphthalene diimide or crown ether-bipyridinium host guest interactions were described (Figure 5, 5b).(59) TentaGel polystyrene resins were initially modified into azide-functionalized beads in a two-stage procedure before the target supramolecular architectures were attached.(59)
The modification of polymers after the successful achievement of polymerization is a central task in macromolecular science.(10) CuAAC-SP has been applied to polymeric synthesis. Haddleton et al.(99, 169) developed the living radical polymerization of methyl methacrylate (MMA) and a fluorescent comonomer with 2-bromo-2-methylpropionic acid 3-azidopropyl ester and 2-bromo-2-methylhept-6-yn-3-ester as initiators. These initiators have been successfully used in the synthesis of fluorescently tagged azide- and alkyne-terminated poly(methyl methacrylate) (PMMA) with average number of molar mass (Mn) close to that predicted, PDI < 1.20, and good first order kinetics, as expected for a living polymerization.
Cho et al.(96) prepared multiwalled carbon nanotubes (MWCNTs) functionalized with poly(styrene-b-(ethylene-co-butylene)-b-styrene) triblock copolymer (SEBS) using Click Chemistry. In this case, various compositions of SEBS-functionalized MWCNTs were obtained from the reaction of azide moiety-containing SEBS on styrene units with alkyne-decorated MWCNTs (Figure 5, 5c). Girard et al.(97) developed the polystyrene-supported triazoles via CuAAC on Merrifield resin.
figure

Figure 5. CuAAC-SP supramolecular structures and polymer applications.

Affinity chromatography is crucial for separating or analyzing specific target compounds in samples and for studying biological interactions. The immobilization of biomolecules is a mainstay in biological fields and related areas, with many potential applications such as the characterization of their functions and their interaction with other biomolecules, the analysis and purification of mixtures of biomolecules, and the design of SP-based assays or bioactive implant surfaces. The CuAAC has been used on silica supports and the modified supports have been successfully applied in affinity chromatography.
For instance, the covalent immobilization of suitable alkyne/azide carbohydrate derivatives on complementarily functionalized azide/alkyne silica was performed by Click ligation through CuAAC reaction of such compounds. New glyco-silicas have shown to be efficient and valuable bioselective affinity chromatographic supports for the purification of lectins, as well as for the one-pot fluorescent labeling of these proteins.(170) Yang et al.(171) developed a method, namely hydrophilic interaction chromatography (HILIC), which used a support prepared by clicking aspartic acid onto silica gel (termed as Click AA). This material was used as SP extraction sorbent for selective enrichment of glycopeptides.(171) Another example reported was the building of 2-oxoglutaric acid receptor attached to resin via CuAAC-SP. This scaffold showed high affinity and specificity to separate the established 2-OG binding protein NtcA.(172)

4 Conclusions

CuAAC has made a significant contribution to Click Chemistry but has also been greatly extended to SP in recent years. This review reveals the potential of this kind of Click reaction for the rapid construction of several molecules. We focused on CuAAC-SP, taking to account the capacity of this method to prepare a wide range of molecular entities, such as peptides, nucleotides, small molecules, supramolecular structures, and polymers. CuAAC-SP has been performed in the presence of the alkyne and the azide (one of them attached to the SP), a Cu(I) source, and the adequate solvent under basic conditions. In most reports either CuI, DIEA, and DMF or CuSO4·5H2O, Asc, and water/tBuOH were the reagents used as copper source, base, and solvent, respectively. CuAAC-SP allowed the replacement of amide bonds in peptides, thus facilitating the synthesis of cyclic or mimetic peptides. In addition to its application in bioconjugation, this reaction has also been used to generate new resins and amino acid-triazole derivatives. Favorable conditions to carry out the CuAAC-SP open up new avenues to tackle future synthetic challenges.
Funding Information

The work was carried out in the authors’ laboratories. The study was partially funded by the CICYT (CTQ2012-30930), the Generalitat de Catalunya (2014 SGR 137), and the Institute for Research in Biomedicine Barcelona (IRB Barcelona).

The authors declare no competing financial interest.

Abbreviations
DMF

dimethylformamide

ACN

acetonitrile

THF

tetrahydrofuran

DCM

dichloromethane

NMP

N-methylpyrrolidone

DMSO

dimethyl sulfoxide

DIEA

N,N-diisopropylethylamine

TEA

triethylamine

TBTA

tris (benzyltriazolylmethyl)amine

PMDTA

N,N,N′,N′,N″-pentamethyldiethylenetriamine

CuAAC

Cu(I)-catalyzed azide–alkyne cycloaddition

SPOCC

(solid-phase organic and combinatorial chemistry) resin

PEGA

poly(ethylene glycol) amide backbone resin

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    Catalytic azide-alkyne cycloaddition: reactivity and applications
    Wu, Peng; Fokin, Valery V.
    Aldrichimica Acta (2007), 40 (1), 7-17CODEN: ALACBI; ISSN:0002-5100. (Aldrich Chemical Co.)
    A review which is not intended to be a comprehensive survey of the title subject; it will focus instead on the fundamental aspects of the transformation, highlighting the advantage, potential, and limitations of copper-catalyzed azide-alkyne cycloaddn. by using several representative examples.
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  19. 19.
    Majumder, N. Click Chemistry in Nano Drug Delivery System and Its Applications in Biology Int. J. Res. Pharm. Chem. 2015, 5, 95– 105
    [CAS]
    19.
    Click chemistry in nano drug delivery system and its applications in biology
    Majumder, Nairrita
    International Journal of Research in Pharmacy and Chemistry (2015), 5 (1), 95-105, 11 pp.CODEN: IJRPFG; ISSN:2231-2781. (Catchway Technologies)
    Since the introduction of the click concept by Sharpless and coworkers in 2001, numerous examples of click reactions have been reported for the prepn. and functionalization of polymeric micelles and nanoparticles, liposomes and polymersomes, capsules, microspheres, metal and silica nanoparticles, carbon nanotubes and fullerenes, or bionanoparticles. Among these click processes, Cu(I)-catalyzedazide-alkyne cycloaddn. (CuAAC) has attracted most attention based on its high orthogonality, reliability, and exptl. simplicity for non-specialists. The alkyne- azidecycloaddn., popularly known as the "click" reaction, has been extensively exploited in mol./macromol. build-up, and has offered tremendous potential in the design of nanomaterials for applications in a diverse range of disciplines, including biol. Some advantageous characteristics of this coupling include high efficiency, and adaptability to the environment in which the desired covalent linking of the alkyne and azide terminated moieties needs to be carried out. The efficient delivery of active pharmaceutical agents to specific organelles like mitochondria and lipid bodies, employing nanocarriers developed through the use of "click" chem., constitutes a continuing topical area of research. In this review, we highlight important contributions click chem. in the nanosized drug delivery system and its future aspects.
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  20. 20.
    Paris, C.; Brun, O.; Pedroso, E.; Grandas, A. Exploiting Protected Maleimides to Modify Oligonucleotides, Peptides and Peptide Nucleic Acids Molecules 2015, 20, 6389– 6408 DOI: 10.3390/molecules20046389
    [Crossref], [PubMed], [CAS]
    20.
    Exploiting protected maleimides to modify oligonucleotides, peptides and peptide nucleic acids
    Paris, Clement; Brun, Omar; Pedroso, Enrique; Grandas, Anna
    Molecules (2015), 20 (4), 6389-6408CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    A review. This work reviews the possibilities offered by 2,5-dimethylfuran-protected maleimides. Suitably derivatized building blocks incorporating the exo Diels-Alder cycloadduct can be introduced at any position of oligonucleotides, peptide nucleic acids, peptides and peptoids, making use of std. solid-phase procedures. Maleimide deprotection takes place upon heating, which can be followed by either Michael-type or Diels-Alder click conjugation reactions. However, the one-pot procedure in which maleimide deprotection and conjugation are simultaneously carried out provides the target conjugate more quickly and, more importantly, in better yield. This procedure is compatible with conjugates involving oligonucleotides, peptides and peptide nucleic acids. A variety of cyclic peptides and oligonucleotides can be obtained from peptide and oligonucleotide precursors incorporating protected maleimides and thiols.
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  21. 21.
    Dar, M. A.; Shrivastava, S.; Iqbal, P. F. Click Chemistry and Anticancer Propierties of 1,2,3-Triazoles World J. Pharm. Res. 2015, 4, 1949– 1975
    [CAS]
    21.
    Click chemistry and anticancer properties of 1,2,3-triazoles
    Dar, Mukhtar Ahmad; Shrivastava, Sarita; Iqbal, Prince Firdoos
    World Journal of Pharmaceutical Research (2015), 4 (1), 1949-1975, 27 pp.CODEN: WJPRAP; ISSN:2277-7105. (World Journal of Pharmaceutical Research)
    A review. This review summarizes anti-cancer activities of 1,2,3-triazole derivs. developed mainly through click chem. approach.
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  22. 22.
    Totobenazara, J.; Burke, A. J. New Click-Chemistry Methods for 1,2,3-Triazoles Synthesis: Recent Advances and Applications Tetrahedron Lett. 2015, 56, 2853– 2859 DOI: 10.1016/j.tetlet.2015.03.136
    [Crossref], [CAS]
    22.
    New click-chemistry methods for 1,2,3-triazoles synthesis: recent advances and applications
    Totobenazara, Jane; Burke, Anthony J.
    Tetrahedron Letters (2015), 56 (22), 2853-2859CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    A review. 1,2,3-Triazoles find applications in several major technol. areas, and esp. in drug discovery. The click-chem. approaches based on Huisgen's cycloaddn. reaction are particularly attractive and have received enormous attention over the last decade and a half, due to their utility in prepg. compds. with diverse applications, from drugs to linkers for bioconjugation.
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  23. 23.
    Tornøe, C. W.; Meldal, M. Dipolar Cycloaddition Reactions in Peptide Chemistry. In Organic Azides: Syntheses and Applications; Bräse, S.; Banert, K., Eds.; John Wiley & Sons, Ltd.: Chichester, United Kingdom, 2010; pp 285– 310.
    There is no corresponding record for this reference.
  24. 24.
    Benjamin, R. B.; Heaney, H. Mechanistic Investigations of Copper(I)-Catalysed Alkyne–Azide Cycloaddition Reactions. In Click Triazoles; Košmrlj, J., Ed.; Springer Verlag: Berlin, 2012; pp 1– 29.
    There is no corresponding record for this reference.
  25. 25.
    Tornøe, C. W.; Meldal, M. The Wave of the Future; Lebl, M.; Houghten, R. A., Eds.; American Petide Society and Kluwer Academic: San Diego, CA, 2001; pp 263– 264.
    There is no corresponding record for this reference.
  26. 26.
    Tornøe, C. W.; Christensen, C.; Meldal, M. Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(i)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides J. Org. Chem. 2002, 67, 3057– 3064 DOI: 10.1021/jo011148j
    [ACS Full Text ACS Full Text], [CAS]
    26.
    Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides
    Tornoe, Christian W.; Christensen, Caspar; Meldal, Morten
    Journal of Organic Chemistry (2002), 67 (9), 3057-3064CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    The cycloaddn. of azides to alkynes is one of the most important synthetic routes to 1H-[1,2,3]-triazoles. This work reports a novel regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddn. of terminal alkynes to azides on solid-phase. Primary, secondary, and tertiary alkyl azides, aryl azides, and an azido sugar were used successfully in the copper(I)-catalyzed cycloaddn. producing diversely 1,4-substituted [1,2,3]-triazoles in peptide backbones or side chains. The reaction conditions were fully compatible with solid-phase peptide synthesis on polar supports. The copper(I) catalysis is mild and efficient (>95% conversion and purity in most cases) and furthermore, the x-ray structure of 2-azido-2-methylpropanoic acid has been solved, to yield structural information on the 1,3-dipoles entering the reaction. Novel Fmoc-protected amino azides were prepd. from Fmoc-amino alcs. by Mitsunobu reaction.
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  27. 27.
    Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. A Stepwise Huisgen Cycloaddition Process: copper(I)-Catalyzed Regioselective “Ligation” of Azides and Terminal Alkynes Angew. Chem., Int. Ed. 2002, 41, 2596– 2599 DOI: 10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4
    [Crossref], [PubMed], [CAS]
    27.
    A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes
    Rostovtsev, Vsevolod V.; Green, Luke G.; Fokin, Valery V.; Sharpless, K. Barry
    Angewandte Chemie, International Edition (2002), 41 (14), 2596-2599CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH)
    1,4-Disubstituted 1,2,3-triazoles I (R1 = PhCH2, PhCH2OCH2, 1-adamantyl, etc.; R2 = HO2C, Ph, PhOCH2, Et2NCH2, etc.) were readily and cleanly prepd. via highly efficient and regioselective copper(I)-catalyzed cycloaddn. of azides R1N3 with terminal alkynes R2C≡CH in 82-93% yields.
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  28. 28.
    Tron, G. C.; Pirali, T.; Billington, R. A.; Canonico, P. L.; Sorba, G.; Genazzani, A. A. Click Chemistry Reactions in Medicinal Chemistry: Applications of the 1, 3-Dipolar Cycloaddition Between Azides and Alkynes Med. Res. Rev. 2008, 28, 278– 308 DOI: 10.1002/med.20107
    [Crossref], [PubMed], [CAS]
    28.
    Click chemistry reactions in medicinal chemistry: applications of the 1,3-dipolar cycloaddition between azides and alkynes
    Tron, Gian Cesare; Pirali, Tracey; Billington, Richard A.; Canonico, Pier Luigi; Sorba, Giovanni; Genazzani, Armando A.
    Medicinal Research Reviews (2008), 28 (2), 278-308CODEN: MRREDD; ISSN:0198-6325. (John Wiley & Sons, Inc.)
    A review. In recent years, there has been an ever-increasing need for rapid reactions that meet the three main criteria of an ideal synthesis: efficiency, versatility, and selectivity. Such reactions would allow medicinal chem. to keep pace with the multitude of information derived from modern biol. screening techniques. The present review describes one of these reactions, the 1,3-dipolar cycloaddn. ("click-reaction") between azides and alkynes catalyzed by copper (I) salts. The simplicity of this reaction and the ease of purifn. of the resulting products have opened new opportunities in generating vast arrays of compds. with biol. potential. The present review will outline the accomplishments of this strategy achieved so far and outline some of medicinal chem. applications in which click-chem. might be relevant in the future.
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  29. 29.
    Gopi, H. N.; Tirupula, K. C.; Baxter, S.; Ajith, S.; Chaiken, I. M. Click Chemistry on Azidoproline: High-Affinity Dual Antagonist for HIV-1 Envelope Glycoprotein gp120 ChemMedChem 2006, 1, 54– 57 DOI: 10.1002/cmdc.200500037
    [Crossref], [PubMed], [CAS]
    29.
    Click chemistry on azidoproline: high-affinity dual antagonist for HIV-1 envelope glycoprotein gp120
    Gopi, Hosahudya N.; Tirupula, Kalyan C.; Baxter, Sabine; Ajith, Sandya; Chaiken, Irwin M.
    ChemMedChem (2006), 1 (1), 54-57CODEN: CHEMGX; ISSN:1860-7179. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The envelope glycoprotein gp120 of HIV-1 mediates the first steps of viral entry into the host cell. An azidoproline-based peptide conjugate blocks the interaction of gp120 with both the CD4 cell-surface receptor and 17b (an antibody surrogate of the CCR5 co-receptor). It represents a potentially effective approach in preventing HIV infection.
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  30. 30.
    Turner, R. A.; Oliver, A. G.; Lokey, R. S. Click Chemistry as a Macrocyclization Tool in the Solid-Phase Synthesis of Small Cyclic Peptides Org. Lett. 2007, 9, 5011– 5014 DOI: 10.1021/ol702228u
    [ACS Full Text ACS Full Text], [CAS]
    30.
    Click Chemistry as a Macrocyclization Tool in the Solid-Phase Synthesis of Small Cyclic Peptides
    Turner, Rushia A.; Oliver, Allen G.; Lokey, R. Scott
    Organic Letters (2007), 9 (24), 5011-5014CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    1,2,3-Triazole-contg. macrocyclic peptides I {X = [(S)-COCH(CH2CHMe2)NH]n; n = 2-5} are prepd. chemoselectively by macrocyclization of resin-bound oligoleucine peptides attached to a resin via an L-propargylglycine ester and contg. N-terminal L-azidoleucine residues followed by cleavage from the resin. Macrocyclization reactions on resin using stoichiometric copper (I) bromide and L-ascorbic acid occur within 6 h at ambient temp., while the use of substoichiometric amts. of copper gives a mixt. of macrocycles and oligomers; mixts. of macrocyclic monomers contg. one triazole ring and macrocyclic dimers contg. two triazole rings are generated, in most cases favoring the monomeric macrocycles with chemoselectivities of >3:1. The structure of I (n = 3) is detd. by X-ray crystallog.; two crystallog. distinct mols. in the unit cell exist as type-I' and type-II' β-turn conformers, resp.
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  31. 31.
    Amblard, F.; Cho, J. H.; Schinazi, R. F. Cu(I)-Catalyzed Huisgen Azide-Alkyne 1,3-Dipolar Cycloaddition Reaction in Nucleoside, Nucleotide, and Oligonucleotide Chemistry Chem. Rev. 2009, 109, 4207– 4220 DOI: 10.1021/cr9001462
    [ACS Full Text ACS Full Text], [CAS]
    31.
    Cu(I)-Catalyzed Huisgen Azide-Alkyne 1,3-Dipolar Cycloaddition Reaction in Nucleoside, Nucleotide, and Oligonucleotide Chemistry
    Amblard, Franck; Cho, Jong Hyun; Schinazi, Raymond F.
    Chemical Reviews (Washington, DC, United States) (2009), 109 (9), 4207-4220CODEN: CHREAY; ISSN:0009-2665. (American Chemical Society)
    A review with refs. on. The Cu(I)-catalyzed 1,3-dipolar cycloaddn. reaction between alkynes and azides has been suitable for the synthesis of a large no. of modified nucleosides and oligonucleotides with a broad range of applications. The possibilities opened by this reaction have been attractive not only for the formation of 1,2,3-triazoles as bio-isosteres, or active moieties, but also for the use of 1,2,3-triazoles as a linker to a solid support or to form probes and bio-conjugates.
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  32. 32.
    Morvan, F.; Vidal, S.; Souteyrand, E.; Chevolot, Y.; Vasseur, J.-J. DNA Glycoclusters and DNA-Based Carbohydrate Microarrays: From Design to Applications RSC Adv. 2012, 2, 12043– 12068 DOI: 10.1039/c2ra21550k
    [Crossref], [CAS]
    32.
    DNA glycoclusters and DNA-based carbohydrate microarrays: From design to applications
    Morvan, Francois; Vidal, Sebastien; Souteyrand, Eliane; Chevolot, Yann; Vasseur, Jean-Jacques
    RSC Advances (2012), 2 (32), 12043-12068CODEN: RSCACL; ISSN:2046-2069. (Royal Society of Chemistry)
    A review. Our goal was to design carbohydrate mimetics capable of preventing cell adhesion of pathogens by targeting lectins. The original synthesis of these mimetics combines the automated chem. of DNA and "click" chem. From simple building blocks (i.e. phosphoramidites, solid supports and carbohydrates such as alkyne or azide derivs.), a "Lego" approach provides complex and varied decoys exhibiting various topologies and no. of carbohydrate residues. The resulting glycomimetics tagged with a specific DNA sequence are efficiently immobilized on a DNA microarray by double strand formation. This glycoarray allows the study of the interactions between carbohydrate mimics and lectins using a minute amt. of material. This micro system using DNA arrays is much more effective than conventional carbohydrate microarrays. The studies allowed the identification of the important structural parameters for a customized construction of high-affinity carbohydrate mimics.
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  33. 33.
    Abramova, T. Frontiers and Approaches to Chemical Synthesis of Oligodeoxyribonucleotides Molecules 2013, 18, 1063– 1075 DOI: 10.3390/molecules18011063
    [Crossref], [PubMed], [CAS]
    33.
    Frontiers and approaches to chemical synthesis of oligodeoxyribonucleotides
    Abramova, Tatyana
    Molecules (2013), 18 (), 1063-1075CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    This review presents the advantages and disadvantages of existing approaches to the synthesis of oligodeoxyribonucleotides (ODN) are discussed focusing on large-scale methods. The liq. phase and solid supported synthesis and the synthesis on sol. polymers are discussed. Different problems concerning the methods and implementation of the ODN synthesis are outlined depending on goals of using target oligomers.
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  34. 34.
    Castro, V.; Rodriguez, H.; Albericio, F. Wang Linker Free of Side Reactions Org. Lett. 2013, 15, 246– 249 DOI: 10.1021/ol303367s
    [ACS Full Text ACS Full Text], [CAS]
    34.
    Wang Linker Free of Side Reactions
    Castro, Vida; Rodriguez, Hortensia; Albericio, Fernando
    Organic Letters (2013), 15 (2), 246-249CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A new resin for the solid-phase synthesis of peptide acids was developed. It was based on a linker with two unique features: methoxy groups as the only activating groups of the Ph ring and a copper(I)-catalyzed click chem. reaction to anchor it to the solid support. The efficiency of this new resin in solid phase peptide synthesis was compared with that of Wang resin.
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  35. 35.
    Castro, V.; Blanco-Canosa, J. B.; Rodriguez, H.; Albericio, F. Imidazole-1-Sulfonyl Azide-Based Diazo-Transfer Reaction for the Preparation of Azido Solid Supports for Solid-Phase Synthesis ACS Comb. Sci. 2013, 15, 331– 334 DOI: 10.1021/co4000437
    [ACS Full Text ACS Full Text], [CAS]
    35.
    Imidazole-1-sulfonyl Azide-Based Diazo-Transfer Reaction for the Preparation of Azido Solid Supports for Solid-Phase Synthesis
    Castro, Vida; Blanco-Canosa, Juan B.; Rodriguez, Hortensia; Albericio, Fernando
    ACS Combinatorial Science (2013), 15 (7), 331-334CODEN: ACSCCC; ISSN:2156-8944. (American Chemical Society)
    Aminomethylated polystyrene and Rink amide MBHA resin, a poly(ethylene glycol)-polystyrene resin (Tentagel S NH2), and a poly(ethylene glycol) (aminomethyl-ChemMatrix) resin with differing hydrophobicities underwent diazo-transfer reactions with imidazole-1-sulfonyl azide hydrochloride in the presence of diisopropylethylamine and in the absence of a copper catalyst to give the corresponding azide-functionalized resins. Imidazole-1-sulfonyl azide hydrochloride is easily prepd. or com. available and is stable to storage at 4 °C, making it preferable to triflyl azide for diazo-transfer reactions to amine-functionalized resins. Cycloaddn. of azide-functionalized resins with an ethynyldimethoxybenzaldehyde yielded TFA-labile formylphenyltriazole-substituted resins potentially useful for solid-phase synthesis.
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  36. 36.
    Meldal, M.; Tornøe, C. W.; Nielsen, T. E.; Diness, F.; Le Quement, S. T.; Christensen, C. a; Jensen, J. F.; Worm-Leonhard, K.; Groth, T.; Bouakaz, L.; Wu, B.; Hagel, G.; Keinicke, L. Ralph F. Hirschmann Award Address 2009: Merger of Organic Chemistry with Peptide Diversity Biopolymers 2010, 94, 161– 182 DOI: 10.1002/bip.21344
    [Crossref], [PubMed], [CAS]
    36.
    Ralph F. Hirschmann award address 2009: Merger of organic chemistry with peptide diversity
    Meldal, Morten; Tornoee, Christian W.; Nielsen, Thomas E.; Diness, Frederik; Le Quement, Sebastian T.; Christensen, Christian A.; Jensen, Jakob Feldthusen; Worm-Leonhard, Kasper; Groth, Thomas; Bouakaz, Lamine; Wu, Boqian; Hagel, Grith; Keinicke, Lise
    Biopolymers (2010), 94 (2), 161-182CODEN: BIPMAA; ISSN:0006-3525. (John Wiley & Sons, Inc.)
    A review. A huge unleashed potential lies hidden in the large and diverse pool of encoded and particularly nonencoded chiral α-, β-, and γ-amino acids available today. Although these have been extensively exploited in peptide science, the community of org. chem. has only used this source of diversity in a quite focused and targeted manner. The properties and behavior of peptides as functional mols. in biol. are well documented and based on the ability of peptides to adapt a range of discrete conformers at a minimal entropic penalty and therefore ideally fitting their endogenous targets. The development of new org. reactions and chemistries that in a general and quant. way transform peptides into new functional mols., preferably on solid support, is a source of completely new classes of mols. with important and advantageous functional properties. The peptide diversity and the ability to perform chem. on solid support add tremendously to the combinatorial scope of such reactions in pharmaceutical and materials screening scenario. In recent years, the need for "click" reactions to shape complex mol. architecture has been realized mainly with a basis in the world of peptides and DNA, and in polymer chem. where connection of highly functionalized biol. active substances or property bearing fragments are assembled as mol. LEGO using quant. and orthogonal click chemistries. In this article, three such new reactions originating in the Carlsberg Lab. over the last decade taking advantage of org. transformations in the peptide framework is presented. Initially, the click reaction between azide and terminal alkynes catalyzed by Cu(1) (CuAAC-reaction) is described. This CuAAC "click" reaction was obsd. first at Carlsberg Lab. in reactions of azido acid chlorides with alkynes on solid support. Second, the Electrophilic Arom. Substitution Cyclization-Intramol. Click-Cascade (EASCy-ICC) reaction will be presented. This quant. stereo-selective cascade reaction provides a highly diverse set of interesting novel scaffolds from peptides. Finally, we describe the prepn. of solid phase peptide phosphine- and carbene-based green catalysts (organozymes), which upon complex formation with transition metal perform with high turnovers under aq. conditions. These catalysts thrive from the peptide folding and diversity, while phosphines and carbenes in the backbone provide for bidental complex formation with transition metals in a format providing an excellent entry into combinatorial catalyst chem. © 2010 Wiley Periodicals, Inc.Biopolymers (Pept Sci) 94: 161-182, 2010.
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  37. 37.
    Li, H.; Aneja, R.; Chaiken, I. Click Chemistry in Peptide-Based Drug Design Molecules 2013, 18, 9797– 9817 DOI: 10.3390/molecules18089797
    [Crossref], [PubMed], [CAS]
    37.
    Click chemistry in peptide-based drug design
    Li, Huiyuan; Aneja, Rachna; Chaiken, Irwin
    Molecules (2013), 18 (), 9797-9817CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    A review. Click chem. is an efficient and chemoselective synthetic method for coupling mol. fragments under mild reaction conditions. Since the advent in 2001 of methods to improve stereochem. conservation, the click chem. approach has been broadly used to construct diverse chemotypes in both chem. and biol. fields. In this review, we discuss the application of click chem. in peptide-based drug design. We highlight how triazoles formed by click reactions have been used for mimicking peptide and disulfide bonds, building secondary structural components of peptides, linking functional groups together, and bioconjugation. The progress made in this field opens the way for synthetic approaches to convert peptides with promising functional leads into structure-minimized and more stable forms.
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  38. 38.
    Chandrudu, S.; Simerska, P.; Toth, I. Chemical Methods for Peptide and Protein Production Molecules 2013, 18, 4373– 4388 DOI: 10.3390/molecules18044373
    [Crossref], [PubMed], [CAS]
    38.
    Chemical methods for peptide and protein production
    Chandrudu, Saranya; Simerska, Pavla; Toth, Istvan
    Molecules (2013), 18 (), 4373-4388CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    This review describes the advances in peptide chem. including the variety of synthetic peptide methods currently available and the broad application of peptides in medicinal chem. Since the invention of solid phase synthetic methods by Merrifield in 1963, the no. of research groups focusing on peptide synthesis has grown exponentially. However, the original step-by-step synthesis had limitations: the purity of the final product decreased with the no. of coupling steps. After the development of Boc and Fmoc protecting groups, novel amino acid protecting groups and new techniques were introduced to provide high quality and quantity peptide products. Fragment condensation was a popular method for peptide prodn. in the 1980s, but unfortunately the rate of racemization and reaction difficulties proved less than ideal. Kent and co-workers revolutionized peptide coupling by introducing the chemoselective reaction of unprotected peptides, called native chem. ligation. Subsequently, research has focused on the development of novel ligating techniques including the famous click reaction, ligation of peptide hydrazides and the recently reported α-keto acid-hydroxylamine ligations with 5-oxaproline. Several companies were formed all over the world to prep. high quality GMP peptide products on a multi-kilogram scale.
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  39. 39.
    Millward, S. W.; Agnew, H. D.; Lai, B.; Lee, S. S.; Lim, J.; Nag, A.; Pitram, S.; Rohde, R.; Heath, J. R. In Situ Click Chemistry: From Small Molecule Discovery to Synthetic Antibodies Integr. Biol. 2013, 5, 87– 95 DOI: 10.1039/C2IB20110K
    [Crossref], [CAS]
    39.
    In situ click chemistry: from small molecule discovery to synthetic antibodies
    Millward, Steven W.; Agnew, Heather D.; Lai, Bert; Lee, Su Seong; Lim, Jaehong; Nag, Arundhati; Pitram, Suresh; Rohde, Rosemary; Heath, James R.
    Integrative Biology (2013), 5 (1), 87-95CODEN: IBNIFL; ISSN:1757-9694. (Royal Society of Chemistry)
    A review. Advances in the fields of proteomics, mol. imaging, and therapeutics are closely linked to the availability of affinity reagents that selectively recognize their biol. targets. Here we present a review of Iterative Peptide In Situ Click Chem. (IPISC), a novel screening technol. for designing peptide multiligands with high affinity and specificity. This technol. builds upon in situ click chem., a kinetic target-guided synthesis approach where the protein target catalyzes the conjugation of two small mols., typically through the azide-alkyne Huisgen cycloaddn. Integrating this methodol. with solid phase peptide libraries enables the assembly of linear and branched peptide multiligands we refer to as Protein Catalyzed Capture Agents (PCC Agents). The resulting structures can be thought of as analogous to the antigen recognition site of antibodies and serve as antibody replacements in biochem. and cell-based applications. In this review, we discuss the recent progress in ligand design through IPISC and related approaches, focusing on the improvements in affinity and specificity as multiligands are assembled by target-catalyzed peptide conjugation. We compare the IPISC process to small mol. in situ click chem. with particular emphasis on the advantages and tech. challenges of constructing antibody-like PCC Agents.
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  40. 40.
    Avti, P. K.; Maysinger, D.; Kakkar, A. Alkyne-Azide “Click” Chemistry in Designing Nanocarriers for Applications in Biology Molecules 2013, 18, 9531– 9549 DOI: 10.3390/molecules18089531
    [Crossref], [PubMed], [CAS]
    40.
    Alkyne-Azide "click" chemistry in designing nanocarriers for applications in biology
    Avti, Pramod K.; Maysinger, Dusica; Kakkar, Ashok
    Molecules (2013), 18 (), 9531-9549CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    A review. The alkyne-azide cycloaddn., popularly known as the "click" reaction, has been extensively exploited in mol./macromol. build-up, and has offered tremendous potential in the design of nanomaterials for applications in a diverse range of disciplines, including biol. Some advantageous characteristics of this coupling include high efficiency, and adaptability to the environment in which the desired covalent linking of the alkyne and azide terminated moieties needs to be carried out. The efficient delivery of active pharmaceutical agents to specific organelles, employing nanocarriers developed through the use of "click" chem., constitutes a continuing topical area of research. In this review, we highlight important contributions "click" chem. has made in the design of macromol.-based nanomaterials for therapeutic intervention in mitochondria and lipid droplets.
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  41. 41.
    Pasini, D. The Click Reaction as an Efficient Tool for the Construction of Macrocyclic Structures Molecules 2013, 18, 9512– 9530 DOI: 10.3390/molecules18089512
    [Crossref], [PubMed], [CAS]
    41.
    The click reaction as an efficient tool for the construction of macrocyclic structures
    Pasini, Dario
    Molecules (2013), 18 (), 9512-9530CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    A review. The Cu(I)-catalyzed azide-alkyne cycloaddn. (CuAAC, known as the click reaction) is an established tool used for the construction of complex mol. architectures. Given its efficiency it has been widely applied for bioconjugation, polymer and dendrimer synthesis. More recently, this reaction has been utilized for the efficient formation of rigid or shape-persistent, preorganized macrocyclic species. This strategy also allows the installment of useful functionalities, in the form of polar and function-rich 1,2,3-triazole moieties, directly embedded in the macrocyclic structures. This review analyzes the state of the art in this context, and provides some elements of perspective for future applications.
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  42. 42.
    Wong, C.-H.; Zimmerman, S. C. Orthogonality in Organic, Polymer, and Supramolecular Chemistry: From Merrifield to Click Chemistry Chem. Commun. (Cambridge, U. K.) 2013, 49, 1679– 1695 DOI: 10.1039/c2cc37316e
    [Crossref], [PubMed], [CAS]
    42.
    Orthogonality in organic, polymer, and supramolecular chemistry: from Merrifield to click chemistry
    Wong, Chun-Ho; Zimmerman, Steven C.
    Chemical Communications (Cambridge, United Kingdom) (2013), 49 (17), 1679-1695CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    A review. The concept of orthogonality was applied to many areas of chem., ranging from wave functions to chromatog. But it was Barany and Merrifield's orthogonal protecting group strategy that paved the way for solid phase peptide syntheses, other important classes of biomaterials such as oligosaccharides and oligonucleotides, and ultimately to a term in widespread usage that is focused on chem. reactivity and binding selectivity. The orthogonal protection strategy was extended to the development of orthogonal activation, and recently the click reaction, for streamlining org. synthesis. The click reaction and its variants are considered orthogonal as the components react together in high yield and in the presence of many other functional groups. Likewise, supramol. building blocks can also be orthogonal, thereby enabling programmed self-assembly, a superb strategy to create complex architectures. Overall, orthogonal reactions and supramol. interactions have dramatically improved the syntheses, the prepn. of functional materials, and the self-assembly of nanoscale structures.
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  43. 43.
    Huisgen, R. 1,3-Dipolar Cycloadditions. Past and Future Angew. Chem., Int. Ed. Engl. 1963, 2, 565– 598 DOI: 10.1002/anie.196305651
    [Crossref]
    There is no corresponding record for this reference.
  44. 44.
    Sustmann, R. Rolf Huisgen’s Contribution to Organic Chemistry, Emphasis 1,3-Dipolar Cycloadditions Heterocycles 1995, 40, 1– 18 DOI: 10.3987/1995-01-0001
    [Crossref], [CAS]
    44.
    Rolf Huisgen's contribution to organic chemistry, emphasizing 1,3-dipolar cycloadditions
    Sustmann, Reiner
    Heterocycles (1995), 40 (1), 1-18CODEN: HTCYAM; ISSN:0385-5414. (Japan Institute of Heterocyclic Chemistry)
    A review with 59 refs. Huisgen's investigations on 1,3-dipolar cycloaddns. have led to novel methods for the synthesis of heterocyclic compds.
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  45. 45.
    Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.; Fokin, V. V. Copper(I)-Catalyzed Synthesis of Azoles. DFT Study Predicts Unprecedented Reactivity and Intermediates J. Am. Chem. Soc. 2005, 127, 210– 216 DOI: 10.1021/ja0471525
    [ACS Full Text ACS Full Text], [CAS]
    45.
    Copper(I)-Catalyzed Synthesis of Azoles. DFT Study Predicts Unprecedented Reactivity and Intermediates
    Himo, Fahmi; Lovell, Timothy; Hilgraf, Robert; Rostovtsev, Vsevolod V.; Noodleman, Louis; Sharpless, K. Barry; Fokin, Valery V.
    Journal of the American Chemical Society (2005), 127 (1), 210-216CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Huisgen's 1,3-dipolar cycloaddns. become nonconcerted when copper(I) acetylides react with azides and nitrile oxides, providing ready access to 1,4-disubstituted 1,2,3-triazoles and 3,4-disubstituted isoxazoles, resp. The process is highly reliable and exhibits an unusually wide scope with respect to both components. Computational studies revealed a stepwise mechanism involving unprecedented metallacycle intermediates, which appear to be common for a variety of dipoles.
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  46. 46.
    Fittler, H.; Avrutina, O.; Glotzbach, B.; Empting, M.; Kolmar, H. Combinatorial Tuning of Peptidic Drug Candidates: High-Affinity Matriptase Inhibitors through Incremental Structure-Guided Optimization Org. Biomol. Chem. 2013, 11, 1848– 1857 DOI: 10.1039/c3ob27469a
    [Crossref], [PubMed], [CAS]
    46.
    Combinatorial tuning of peptidic drug candidates: high-affinity matriptase inhibitors through incremental structure-guided optimization
    Fittler, Heiko; Avrutina, Olga; Glotzbach, Bernhard; Empting, Martin; Kolmar, Harald
    Organic & Biomolecular Chemistry (2013), 11 (11), 1848-1857CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    Herein we report a convenient strategy for the development of novel, highly-potent peptidic inhibitors of the trypsin-like serine protease matriptase based on the monocyclic variant of the sunflower trypsin inhibitor-1 (SFTI-1[1,14]). We screened SFTI-1[1,14] variants possessing incremental modifications of the parent peptide for beneficial binding properties. This compd. library comprising 6 peptides and 16 triazole-contg. peptidomimetics was established via structure-guided rational design and synthesized using a divergent strategy employing "copper-click" chem. The most favorable amino acid substitutions were combined in one framework yielding potent SFTI-1-derived matriptase inhibitor-1 (SDMI-1) [H-Gly-Arg-c(Cys-Thr-Lys-Ser-Ile-Pro-Pro-Arg-Cys)-His-Pro-Asp-OH] and the truncated dodecapeptide variant (SDMI-2) [H-Gly-Arg-c(Cys-Thr-Lys-Ser-Ile-Pro-Pro-Arg-Cys)-His-NH2] with single-digit nanomolar inhibition consts. In silico studies indicated that the improved matriptase affinity compared to the parent peptide is caused by the successful establishment of addnl. favorable proton donor-acceptor interactions between basic inhibitor side chains and acidic residues on the surface of the target enzyme. SDMI-1 and 2 are potent inhibitors of the pharmaceutically relevant protease matriptase at a near physiol. pH and, thus, may find applications in therapy or diagnostics.
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  47. 47.
    Clemmen, A.; Boutton, C.; Vanlandschoot, P.; Wittelsberger, A.; Borghmans, I.; Coppens, A.; Casteels, P.; Madder, A. Straightforward Synthesis of Cholic Acid Stabilized Loop Mimetics Tetrahedron Lett. 2014, 55, 423– 429 DOI: 10.1016/j.tetlet.2013.11.046
    [Crossref], [CAS]
    47.
    Straightforward synthesis of cholic acid stabilized loop mimetics
    Clemmen, An; Boutton, Carlo; Vanlandschoot, Peter; Wittelsberger, Angela; Borghmans, Inge; Coppens, Astrid; Casteels, Peter; Madder, Annemieke
    Tetrahedron Letters (2014), 55 (2), 423-429CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    We here report on a new straightforward strategy for the synthesis of cyclic cholic acid-peptide conjugates. A solid-phase synthesis method is presented in which a selected anti-lysozyme CDR3 fragment, Asp-Ser-Thr-Ile-Tyr-Ala-Ser-Tyr-Tyr-Glu-Ser, is immobilized onto a steroidal cholic acid derived scaffold in order to yield a loop-like structure. Therefore, part of the desired sequence, i.e., Ser-Tyr-Tyr-Glu-Ser, is introduced, at the C12 position of the scaffold. Subsequently, the remainder of the envisaged sequence is introduced at C3 via a Cu-catalyzed cyclo-addn. reaction. Finally, amide bond formation delivers the desired cyclic peptidosteroid. This new synthetic strategy offers an easy and short access to cyclic peptidosteroids via convergent peptide ligation and macrocyclization.
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  48. 48.
    Ponader, D.; Maffre, P.; Aretz, J.; Pussak, D.; Ninnemann, N. M.; Schmidt, S.; Seeberger, P. H.; Rademacher, C.; Nienhaus, G. U.; Hartmann, L. Carbohydrate-Lectin Recognition of Sequence-Defined Heteromultivalent Glycooligomers J. Am. Chem. Soc. 2014, 136, 2008– 2016 DOI: 10.1021/ja411582t
    [ACS Full Text ACS Full Text], [CAS]
    48.
    Carbohydrate-Lectin Recognition of Sequence-Defined Heteromultivalent Glycooligomers
    Ponader, Daniela; Maffre, Pauline; Aretz, Jonas; Pussak, Daniel; Ninnemann, Nina M.; Schmidt, Stephan; Seeberger, Peter H.; Rademacher, Christoph; Nienhaus, G. Ulrich; Hartmann, Laura
    Journal of the American Chemical Society (2014), 136 (5), 2008-2016CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Multivalency as a key principle in nature has been successfully adopted for the design and synthesis of artificial glycoligands by attaching multiple copies of monosaccharides to a synthetic scaffold. Besides their potential in various applied areas, e.g. as antiviral drugs, for the vaccine development and as novel biosensors, such glycomimetics also allow for a deeper understanding of the fundamental aspects of multivalent binding of both artificial and natural ligands. However, most glycomimetics so far neglect the purposeful arranged heterogeneity of their natural counterparts, thus limiting more detailed insights into the design and synthesis of novel glycomimetics. Therefore, this work presents the synthesis of monodisperse glycooligomers carrying different sugar ligands at well-defined positions along the backbone using for the first time sequential click chem. and stepwise assembly of functional building blocks on solid support. This approach allows for straightforward access to sequence-defined, multivalent glycooligomers with full control over no., spacing, position, and type of sugar ligand. We demonstrate the synthesis of a set of heteromultivalent oligomers presenting mannose, galactose, and glucose residues. All heteromultivalent structures show surprisingly high affinities toward Con A lectin receptor in comparison to their homomultivalent analogs presenting the same no. of binding ligands. Detailed studies of the ligand/receptor interaction using STD-NMR and 2fFCS indeed indicate a change in binding mechanism for trivalent glycooligomers presenting mannose or combinations of mannose and galactose residues. We find that galactose residues do not participate in the binding to the receptor, but they promote steric shielding of the heteromultivalent glycoligands and thus result in an overall increase in affinity. Furthermore, the introduction of nonbinding ligands seems to suppress receptor clustering of multivalent ligands. Overall these results support the importance of heteromultivalency specifically for the design of novel glycoligands and help to promote a fundamental understanding of multivalent binding modes.
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  49. 49.
    Ingale, S.; Dawson, P. E. On Resin Side-Chain Cyclization of Complex Peptides Using CuAAC Org. Lett. 2011, 13, 2822– 2825 DOI: 10.1021/ol200775h
    [ACS Full Text ACS Full Text], [CAS]
    49.
    On resin side-chain cyclization of complex peptides using CuAAC
    Ingale, Sampat; Dawson, Philip E.
    Organic Letters (2011), 13 (11), 2822-2825CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    Triazole tethers have been explored for stabilization of secondary structures in peptides. Despite the utility of this approach, cyclization efficiency in complex peptides remains a significant challenge. A robust, on-resin protocol for side chain to side chain macrocyclization by CuAAC (copper-assist azide-alkyne cycloaddn.) is described. This protocol was applied to the synthesis of a series of 21 helical peptides presenting a binding dipeptide motif from the membrane proximal external region (MPER) of HIV-1 gp41.
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  50. 50.
    Hüsken, N.; Gasser, G.; Köster, S. D.; Metzler-Nolte, N. Four-Potential” Ferrocene Labeling of PNA Oligomers via Click Chemistry Bioconjugate Chem. 2009, 20, 1578– 1586 DOI: 10.1021/bc9001272
    [ACS Full Text ACS Full Text], [CAS]
    50.
    "Four-Potential" Ferrocene Labeling of PNA Oligomers via Click Chemistry
    Husken, Nina; Gasser, Gilles; Koster, S. David; Metzler-Nolte, Nils
    Bioconjugate Chemistry (2009), 20 (8), 1578-1586CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    The scope of the Cu(I)-catalyzed [2 + 3] azide/alkyne cycloaddn. (CuAAC, click chem.) as a key reaction for the conjugation of ferrocene derivs. to N-terminal functionalized PNA oligomers is explored herein (PNA: peptide nucleic acid). The facile solid-phase synthesis of N-terminal azide or alkyne-functionalized PNA oligomer precursors and their cycloaddn. with azidoferrocene, ethynylferrocene, and N-(3-ethylpent-1-yn-3-yl)ferrocene-carboxamide (DEPA-ferrocene) on the solid phase are presented. While the click reaction with azidomethylferrocene worked equally well, the ferrocenylmethyl group is lost from the conjugate upon acid cleavage. However, the desired product was obtained via a post-SPPS conversion of the alkyne-PNA oligomer with azidomethylferrocene in soln. The synthesis of all ferrocene-PNA conjugates (trimer t3-PNA, 3, 4, 5, 6; 12mer PNA, 10 - t c t a c a a g a c t c, 11 - t c t a c c g t a c t c) succeeded with excellent yields and purities, as detd. by mass spectrometry and HPLC. Electrochem. studies of the trimer Fc-PNA conjugates 3, 4, 5, and 6 with four different ferrocene moieties revealed quasi-reversible redox processes of the ferrocenyl redox couple Fc0/+ and electrochem. half-wave potentials in a range of E1/2 = -20 mV to +270 mV vs FcH0/+ (Fc: ferrocenyl, C10H9Fe). The obsd. potential differences ΔE1/2min are always greater than 60 mV for any given pair of Fc-PNA conjugates, thus allowing a reliable differentiation with sensitive electrochem. methods like e.g. square wave voltammetry (SWV). This is the electrochem. equiv. of "four-color" detection and is hence denoted "four-potential" labeling. Prepn. and electrochem. investigation of the set of four structurally different and electrochem. distinguishable ferrocenyl groups conjugated to PNA oligomers, as exemplified by the conjugates 3, 4, 5, and 6, demonstrates the scope of the azide/alkyne cycloaddn. for the labeling of PNA with electrochem. active ferrocenyl groups. Furthermore, it provides a PNA-based system for the electrochem. detection of single-nucleotide polymorphism (SNP) in DNA/RNA.
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  51. 51.
    Mansawat, W.; Boonlua, C.; Siriwong, K.; Vilaivan, T. Clicked Polycyclic Aromatic Hydrocarbon as a Hybridization-Responsive Fluorescent Artificial Nucleobase in Pyrrolidinyl Peptide Nucleic Acids Tetrahedron 2012, 68, 3988– 3995 DOI: 10.1016/j.tet.2012.03.062
    [Crossref], [CAS]
    51.
    Clicked polycyclic aromatic hydrocarbon as a hybridization-responsive fluorescent artificial nucleobase in pyrrolidinyl peptide nucleic acids
    Mansawat, Woraluk; Boonlua, Chalothorn; Siriwong, Khatcharin; Vilaivan, Tirayut
    Tetrahedron (2012), 68 (21), 3988-3995CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
    Pyrene as well as other arom. hydrocarbons could be successfully incorporated into pyrrolidinyl peptide nucleic acid bearing a d-prolyl-2-aminocyclopentane carboxylic acid backbone (acpcPNA) as a base surrogate via a triazole linker employing Cu-catalyzed alkyne-azide cycloaddn. (click chem.). The labeling can be performed via a pre-clicked pyrene monomer or by post-synthetic modification of azide-contg. acpcPNA on solid support. Thermal denaturation expts. suggested that the pyrene-triazole unit can behave as a universal base in the acpcPNA system. The mode of base-pairing has been proposed based on mol. dynamics simulations. Importantly, the fluorescence spectra of the pyrene-labeled single stranded acpcPNA and its hybrid with DNA are quite different. The ratio of emissions at 380 and 460 nm changed significantly (up to a factor of 7) upon hybrid formation with complementary DNA.
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  52. 52.
    Franke, R.; Doll, C.; Eichler, J. Peptide Ligation through Click Chemistry for the Generation of Assembled and Scaffolded Peptides Tetrahedron Lett. 2005, 46, 4479– 4482 DOI: 10.1016/j.tetlet.2005.04.107
    [Crossref], [CAS]
    52.
    Peptide ligation through click chemistry for the generation of assembled and scaffolded peptides
    Franke, Raimo; Doll, Christian; Eichler, Jutta
    Tetrahedron Letters (2005), 46 (26), 4479-4482CODEN: TELEAY; ISSN:0040-4039. (Elsevier B.V.)
    The synthesis of [1,2,3]-triazoles through copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddn. was examd. for its utility to generate assembled and scaffolded peptides from peptide and scaffold precursors, which were N-terminally modified with azido and alkyne moieties, resp. Thus, triazolyl peptides I [X = C, D, E, G, H, M, N, Q, R, S, T, W, Y (one-letter amino acid symbols)] were prepd. by ligating a protected azido peptide to resin-bound alkynes HC≡CCO-XAFK-resin.
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  53. 53.
    Gasser, G.; Jäger, K.; Zenker, M.; Bergmann, R.; Steinbach, J.; Stephan, H.; Metzler-Nolte, N. Preparation, 99mTc-Labeling and Biodistribution Studies of a PNA Oligomer Containing a New Ligand Derivative of 2,2′-Dipicolylamine J. Inorg. Biochem. 2010, 104, 1133– 1140 DOI: 10.1016/j.jinorgbio.2010.06.011
    [Crossref], [PubMed], [CAS]
    53.
    Preparation, 99mTc-labeling and biodistribution studies of a PNA oligomer containing a new ligand derivative of 2,2'-dipicolylamine
    Gasser, Gilles; Jaeger, Katrin; Zenker, Martin; Bergmann, Ralf; Steinbach, Joerg; Stephan, Holger; Metzler-Nolte, Nils
    Journal of Inorganic Biochemistry (2010), 104 (11), 1133-1140CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
    A new azido deriv. of 2,2'-dipicolylamine (Dpa), 2-azido-N,N-bis((pyridin-2-yl)methyl)ethanamine, (Dpa-N3) was readily prepd. from the known 2-(bis(pyridin-2-ylmethyl)amino)ethanol (Dpa-OH). It was demonstrated that Dpa-N3 could be efficiently labeled with both [Re(CO)3(H2O)3]Br and [99mTc(H2O)3(CO)3]+ to give [Re(CO)3(Dpa-N3)]Br and [99mTc(CO)3(Dpa-N3)]+, resp. Furthermore, Dpa-N3 was successfully coupled, on the solid phase, to a Peptide Nucleic Acid (PNA) oligomer (H-4-pentynoic acid-spacer-spacer-tgca-tgca-tgca-Lys-NH2; spacer = -NH-(CH2)2-O-(CH2)2-O-CH2-CO-) using the Cu(I)-catalyzed [2 + 3] azide/alkyne cycloaddn. (Cu-AAC, often referred to as the prototypical "click" reaction) to give the Dpa-PNA oligomer. Subsequent labeling of Dpa-PNA with [99mTc(H2O)3(CO)3]+ afforded [99mTc(CO)3(Dpa-PNA)] in radiochem. yields > 90%. Partitioning expts. in a 1-octanol/water system were carried out to get more insight on the lipophilicity of [99mTc(CO)3(Dpa-N3)]+ and [99mTc(CO)3(Dpa-PNA)]. Both compds. were found rather hydrophilic (log Do/w values at pH = 7.4 are -0.50: [99mTc(CO)3(Dpa-N3)]+ and -0.85: [99mTc(CO)3(Dpa-PNA)]. Biodistribution studies of [99mTc(CO)3(Dpa-PNA)] in Wistar rats showed a very fast blood clearance (0.26 ± 0.1 SUV, 1 h p.i.) and modest accumulation in the kidneys (5.45 ± 0.45 SUV, 1 h p.i.). There was no significant activity in the thyroid and the stomach, demonstrating a high in vivo stability of the 99mTc-labeled Dpa-PNA conjugate.
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  54. 54.
    Gasser, G.; Pinto, A.; Neumann, S.; Sosniak, A. M.; Seitz, M.; Merz, K.; Heumann, R.; Metzler-Nolte, N. Synthesis, Characterisation and Bioimaging of a Fluorescent Rhenium-Containing PNA Bioconjugate Dalt. Trans. 2012, 41, 2304– 2313 DOI: 10.1039/C2DT12114J
    [Crossref], [PubMed], [CAS]
    54.
    Synthesis, characterisation and bioimaging of a fluorescent rhenium-containing PNA bioconjugate
    Gasser, Gilles; Pinto, Antonio; Neumann, Sebastian; Sosniak, Anna M.; Seitz, Michael; Merz, Klaus; Heumann, Rolf; Metzler-Nolte, Nils
    Dalton Transactions (2012), 41 (8), 2304-2313CODEN: DTARAF; ISSN:1477-9226. (Royal Society of Chemistry)
    A new rhenium tricarbonyl complex of a bis(quinoline)-derived ligand (2-azido-N,N-bis((quinolin-2-yl)methyl)ethanamine, L-N3), namely [Re(CO)3(L-N3)]Br was synthesized and characterized in-depth, including by x-ray crystallog. [Re(CO)3(L-N3)]Br exhibits a strong UV absorbance in the range 300-400 nm with a max. at 322 nm, and upon photoexcitation, shows two distinct emission bands at about 430 and 560 nm in various solvents (water, ethylene glycol). [Re(CO)3(L-N3)]Br could be conjugated, on a solid phase, to a peptide nucleic acid (PNA) oligomer using the copper(I)-catalyzed azide-alkyne cycloaddn. reaction (Cu-AAC, "click" chem.) and an alkyne-contg. PNA building block to give Re-PNA. It was demonstrated that upon hybridization with a complementary DNA strand (DNA), the position of the maxima and emission intensity for the hybrid Re-PNA·DNA remained mainly unchanged compared to those of the single strand Re-PNA. The rhenium-contg. PNA oligomer Re-PNA could be then mediated in living cells where they have been shown to be nontoxic contrary to the general notion that organometallic compds. are usually unstable under physiol. conditions and/or cytotoxic. Furthermore, Re-PNA could be detected in living cells using fluorescent microscopy.
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  55. 55.
    Oyelere, A. K.; Chen, P. C.; Yao, L. P.; Boguslavsky, N. Heterogeneous Diazo-Transfer Reaction: A Facile Unmasking of Azide Groups on Amine-Functionalized Insoluble Supports for Solid-Phase Synthesis J. Org. Chem. 2006, 71, 9791– 9796 DOI: 10.1021/jo0618122
    [ACS Full Text ACS Full Text], [CAS]
    55.
    Heterogeneous Diazo-Transfer Reaction: A Facile Unmasking of Azide Groups on Amine-Functionalized Insoluble Supports for Solid-Phase Synthesis
    Oyelere, A. K.; Chen, P. C.; Yao, L. P.; Boguslavsky, N.
    Journal of Organic Chemistry (2006), 71 (26), 9791-9796CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Solid-supported azides are commonly generated through direct nucleophilic displacement of appropriately activated supports by the azide ion. This reaction usually proceeds rather sluggishly under harsh conditions. Here, we report that triflyl azide rapidly reacts with a series of amine-functionalized solid supports to generate azide-coated supports under mild conditions. Further, we demonstrate that the "azide coat" allows facile loading of alkyne-functionalized leader nucleoside monomers by click chem. Finally, we show that the nucleoside-functionalized supports are suitable for solid-phase oligonucleotide synthetic applications. The approach herein described extends the scope of the amine-azide conversion reaction and may be adaptable for the introduction of azide to diverse amine-terminated solid supports that are not easily accessible by the conventional nucleophilic displacement method.
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  56. 56.
    Papadopoulos, A.; Shiao, T. C.; Roy, R. Diazo Transfer and Click Chemistry in the Solid Phase Syntheses of Lysine-Based Glycodendrimers as Antagonists against Escherichia Coli FimH Mol. Pharmaceutics 2012, 9, 394– 403 DOI: 10.1021/mp200490b
    [ACS Full Text ACS Full Text], [CAS]
    56.
    Diazo transfer and Click chemistry in the solid phase syntheses of lysine-based glycodendrimers as antagonists against Escherichia coli FimH
    Papadopoulos, Alex; Shiao, Tze Chieh; Roy, Rene
    Molecular Pharmaceutics (2012), 9 (3), 394-403CODEN: MPOHBP; ISSN:1543-8384. (American Chemical Society)
    Uropathogenic Escherichia coli infections, ultimately leading to cystitis and pyelonephritis, are initially mediated by the adhesion of the bacterial FimH to the transmembrane glycoprotein uroplakin-1a present at the surface of urothelial cells. The adhesion is based on the recognition and high avidity binding between the high-mannose glycans of the uroplakin and the FimH, a mannose-specific lectin located at the tip of type 1 fimbriae. We found that synthetic multiantennary mannopyranosides glycodendrons, harboring triazole functionality at the anomeric position, were potent hemagglutination inhibitors of guinea pig erythrocytes and E. coli. A mannosylated dendrimer exposing up to sixteen sugar residues showed an HAI titer of 1 μM and was thus 500-fold more potent than the corresponding monovalent Me α-D-mannopyranoside. The synthesis of the glycodendrons involved highly efficient solid-phase synthesis of branched L-lysine scaffolds, diazo transfer reaction on the terminal amine residues, and 1,3-dipolar copper-catalyzed azide-alkyne cycloaddn. using propargyl α-D-mannopyranoside.
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  57. 57.
    Patra, M.; Metzler-Nolte, N. Azidomethyl-Ruthenocene: Facile Synthesis of a Useful Metallocene Derivative and Its Application in the “Click” Labelling of Biomolecules Chem. Commun. (Cambridge, U. K.) 2011, 47, 11444– 11446 DOI: 10.1039/c1cc14537a
    [Crossref], [PubMed], [CAS]
    57.
    Azidomethyl-ruthenocene: facile synthesis of a useful metallocene derivative and its application in the click' labeling of biomolecules
    Patra, Malay; Metzler-Nolte, Nils
    Chemical Communications (Cambridge, United Kingdom) (2011), 47 (41), 11444-11446CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    A convenient synthesis of azidomethyl-ruthenocene and its use in the covalent labeling of amino acids, peptides and a peptide nucleic acid (PNA) monomer deriv. by Cu(I) catalyzed azide-alkyne coupling (Cu-AAC, "click chem.") are described.
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  58. 58.
    Ditmangklo, B.; Boonlua, C.; Suparpprom, C.; Vilaivan, T. Reductive Alkylation and Sequential Reductive Alkylation-Click Chemistry for On-Solid-Support Modification of Pyrrolidinyl Peptide Nucleic Acid Bioconjugate Chem. 2013, 24, 614– 625 DOI: 10.1021/bc3005914
    [ACS Full Text ACS Full Text], [CAS]
    58.
    Reductive Alkylation and Sequential Reductive Alkylation-Click Chemistry for On-Solid-Support Modification of Pyrrolidinyl Peptide Nucleic Acid
    Ditmangklo, Boonsong; Boonlua, Chalothorn; Suparpprom, Chaturong; Vilaivan, Tirayut
    Bioconjugate Chemistry (2013), 24 (4), 614-625CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    A methodol. for the site-specific attachment of fluorophores to the backbone of pyrrolidinyl peptide nucleic acids (PNAs) with an α/β-backbone derived from d-prolyl-(1S,2S)-2-aminocyclopentanecarboxylic acid (acpcPNA) has been developed. The strategy involves a postsynthetic reductive alkylation of the aldehyde-contg. labels onto the acpcPNA that was previously modified with (3R,4S)-3-aminopyrrolidine-4-carboxylic acid on the solid support. The reductive alkylation reaction is remarkably efficient and compatible with a range of reactive functional groups including Fmoc-protected amino, azide, and alkynes. This allows further attachment of readily accessible carboxyl-, alkyne-, or azide-contg. labels via amide bond formation or Cu-catalyzed azide-alkyne cycloaddn. (CuAAC, also known as click chem.). The label attached in this way does not neg. affect the affinity and specificity of the pairing of the acpcPNA to its DNA target. Applications of this methodol. in creating self-reporting pyrene- and thiazole orange-labeled acpcPNA probes that can yield a change in fluorescence in response to the presence of the correct DNA target have also been explored. A strong fluorescence enhancement was obsd. with thiazole orange-labeled acpcPNA in the presence of DNA. The specificity could be further improved by enzymic digestion with S1 nuclease, providing a 9- to 60-fold fluorescence enhancement with fully complementary DNA and a less than 3.5-fold enhancement with mismatched DNA targets.
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  59. 59.
    Wilson, H.; Byrne, S.; Bampos, N.; Mullen, K. M. Click” Functionalised Polymer Resins: A New Approach to the Synthesis of Surface Attached Bipyridinium and Naphthalene Diimide [2]rotaxanes Org. Biomol. Chem. 2013, 11, 2105– 2115 DOI: 10.1039/c3ob27273g
    [Crossref], [PubMed], [CAS]
    59.
    'Click' functionalised polymer resins: a new approach to the synthesis of surface attached bipyridinium and naphthalene diimide [2]rotaxanes
    Wilson, Hannah; Byrne, Sean; Bampos, Nick; Mullen, Kathleen M.
    Organic & Biomolecular Chemistry (2013), 11 (13), 2105-2115CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    Herein we describe the design and synthesis of a series of solid-tethered [2]rotaxanes utilizing crown ether-naphthalene diimide or crown ether-bipyridinium host guest interactions. TentaGel polystyrene resins were initially modified in a two-stage procedure to azide functionalized beads before the target supramol. architectures were attached using a copper catalyzed "click" procedure. The final assembly was examd. using IR spectroscopy and gel-phase 1H High Resoln. Magic Angle Spinning (HR MAS) NMR spectroscopy. The HR MAS technique enabled a direct comparison between the solid-tethered architectures and the synthesis and characterization of analogous soln.-based [2]rotaxanes to be made.
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  60. 60.
    Angelo, N. G.; Arora, P. S. Solution- and Solid-Phase Synthesis of Triazole Oligomers That Display Protein-like Functionality J. Org. Chem. 2007, 72, 7963– 7967 DOI: 10.1021/jo701292h
    [ACS Full Text ACS Full Text], [CAS]
    60.
    Solution- and solid-phase synthesis of triazole oligomers that display protein-like functionality
    Angelo, Nicholas G.; Arora, Paramjit S.
    Journal of Organic Chemistry (2007), 72 (21), 7963-7967CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    We recently developed a new class of oligomers that contain α-amino acid residues linked by 1,2,3-triazole groups (Angelo, N. G. at al., 2005). Synthesis of these oligomers involves an iterative sequence consisting of diazotransfer and Huisgen 1,3-dipolar cycloaddn. steps. In this contribution, we describe an efficient one-pot, two-step sequence for the prepn. of triazoles from the corresponding amino acid-derived amines and alkynes in soln. The one-pot sequence affords the desired products in significantly higher yields than our original method. We also outline a highly effective protocol for the synthesis of these triazole-based biomimetic oligomers on the solid phase. We find that amino acid derivs. and iterative formation of triazole rings require nontraditional reaction conditions for high yields.
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  61. 61.
    Cohrt, A. E.; Jensen, J. F.; Nielsen, T. E. Traceless Azido Linker for the Solid-Phase Synthesis of NH-1,2,3-Triazoles via Cu-Catalyzed Azide-Alkyne Cycloaddition Reactions Org. Lett. 2010, 12, 5414– 5417 DOI: 10.1021/ol102209p
    [ACS Full Text ACS Full Text], [CAS]
    61.
    Traceless azido linker for the solid-phase synthesis of NH-1,2,3-triazoles via Cu-catalyzed azide-alkyne cycloaddition reactions
    Cohrt, A. Emil; Jensen, Jakob F.; Nielsen, Thomas E.
    Organic Letters (2010), 12 (23), 5414-5417CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    A broadly useful acid-labile traceless azido linker for the solid-phase synthesis of NH-1,2,3-triazoles is presented. A variety of alkynes were efficiently immobilized on a range of polymeric supports by Cu(I)-mediated azide-alkyne cycloaddns. Supported triazoles showed excellent compatibility with subsequent peptide chem. Release of pure material (typically >95%) from the solid support was readily achieved by treatment with aq. TFA.
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  62. 62.
    Roice, M.; Johannsen, I.; Meldal, M. High Capacity Poly(ethylene Glycol) Based Amino Polymers for Peptide and Organic Synthesis QSAR Comb. Sci. 2004, 23, 662– 673 DOI: 10.1002/qsar.200420021
    [Crossref], [CAS]
    62.
    High capacity poly(ethylene glycol) based amino polymers for peptide and organic synthesis
    Roice, Michael; Johannsen, Ib; Meldal, Morten
    QSAR & Combinatorial Science (2004), 23 (8), 662-673CODEN: QCSSAU; ISSN:1611-020X. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A beaded, chem. stable, high capacity amino resin for solid-phase peptide synthesis under polar and non-polar conditions is described. By exhaustive redn. of amide carbonyl groups in crosslinked poly(ethylene glycol)-poly(acrylamide) copolymer (PEGA) a significant increase in functional amino groups is obtained. Furthermore, a resin contg. 90% PEG which is free of amide carbonyl groups is produced. The polymer was characterized by IR spectroscopy and the macroscopic properties of the beads were analyzed by microscopy. Excellent swelling properties in various solvents ranging from water to DCM were demonstrated. The chem. stability of the polymer in various reagents and solvents was investigated and changes in resin properties monitored by IR spectroscopy. The mech. stability of the resin was analyzed by measurement of compressive strain. The unique three dimensional structure of the swelled polyethylene glycol network facilitates fast and unhindered diffusion of reagents, and the support is excellent for synthesis of peptides or peptide mimetics, which can be produced in high yield/reaction vol. The efficacy of the new resin in solid-phase synthesis was demonstrated by synthesizing an α-MSH peptide fragment. A cyclic peptide mimetic was also synthesized on the new resin by the CuI-catalyzed intramol. cycloaddn. of alkyne and azide to form a triazole acting as a disulfide mimetic entity in very high yields and purity.
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  63. 63.
    Fürniss, D.; Mack, T.; Hahn, F.; Vollrath, S. B. L.; Koroniak, K.; Schepers, U.; Bräse, S. Peptoids and Polyamines Going Sweet: Modular Synthesis of Glycosylated Peptoids and Polyamines Using Click Chemistry Beilstein J. Org. Chem. 2013, 9, 56– 63 DOI: 10.3762/bjoc.9.7
    [Crossref], [PubMed], [CAS]
    63.
    Peptoids and polyamines going sweet: modular synthesis of glycosylated peptoids and polyamines using click chemistry
    Fuerniss, Daniel; Mack, Timo; Hahn, Frank; Vollrath, Sidonie B. L.; Koroniak, Katarzyna; Schepers, Ute; Brase, Stefan
    Beilstein Journal of Organic Chemistry (2013), 9 (), 56-63, No. 7CODEN: BJOCBH; ISSN:1860-5397. (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)
    Sugar moieties are present in a wide range of bioactive mols. Thus, having versatile and fast methods for the decoration of biomimetic mols. with sugars is of fundamental importance. The glycosylation of peptoids and polyamines as examples of such biomimetic mols. is reported here. The method uses Cu-catalyzed azide alkyne cycloaddn. to promote the reaction of azidosugars with either polyamines or peptoids. In addn., functionalized nucleic acids were attached to polyamines via the same route. Based on a modular solid-phase synthesis of peralkynylated peptoids with up to six alkyne groups, the latter were modified with azidosugar building blocks by using copper-catalyzed azide alkyne cycloaddns. In addn., the up-scaling of some particular azide-modified sugars is described.
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  64. 64.
    Chouikhi, D.; Barluenga, S.; Winssinger, N. Clickable Peptide Nucleic Acids (cPNA) with Tunable Affinity Chem. Commun. (Cambridge, U. K.) 2010, 46, 5476– 5478 DOI: 10.1039/c0cc01081b
    [Crossref], [PubMed], [CAS]
    64.
    Clickable peptide nucleic acids (cPNA) with tunable affinity
    Chouikhi, Dalila; Barluenga, Sofia; Winssinger, Nicolas
    Chemical Communications (Cambridge, United Kingdom) (2010), 46 (30), 5476-5478CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Peptide nucleic acids (PNAs) are functional analogs of natural oligonucleotides. Herein, the authors report the synthesis of PNAs bearing a triazole in lieu of the amide bond assembled using a "click" cycloaddn., their hybridization properties as well as the DNA-templated coupling of the azide and alkyne PNA fragments.
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  65. 65.
    Qin, S.-Y.; Xu, X.-D.; Chen, C.-S.; Chen, J.-X.; Li, Z.-Y.; Zhuo, R.-X.; Zhang, X.-Z. Supramolecular Architectures Self-Assembled from Asymmetrical Hetero Cyclopeptides Macromol. Rapid Commun. 2011, 32, 758– 764 DOI: 10.1002/marc.201100052
    [Crossref], [PubMed], [CAS]
    65.
    Supramolecular Architectures Self-assembled from Asymmetrical Hetero Cyclopeptides
    Qin, Si-Yong; Xu, Xiao-Ding; Chen, Chang-Sheng; Chen, Jing-Xiao; Li, Ze-Yong; Zhuo, Ren-Xi; Zhang, Xian-Zheng
    Macromolecular Rapid Communications (2011), 32 (9-10), 758-764CODEN: MRCOE3; ISSN:1022-1336. (Wiley-VCH Verlag GmbH & Co. KGaA)
    In this study, two asym., triazole-contg. cyclic peptides (CP1 and CP2) were designed and synthesized. The self-assembly behaviors of CP1 and CP2 at varying pHs were investigated in terms of transmission electron microscopy (TEM), CD, and Fourier transform IR (FT-IR) spectroscopy. It was found that the self-assembly of CP1 resulted in the formation of nanofibers with α-helix conformation, while CP2 self-assembled into well-ordered nanorods with anti-parallel β-sheet conformation. The strategy demonstrated here presents great potential for prepn. of well-defined nanostructures via rationally designing the mol. structures of cyclic peptides.
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  66. 66.
    Vollrath, S. B. L.; Fürniss, D.; Schepers, U.; Bräse, S. Amphiphilic Peptoid Transporters-Synthesis and Evaluation Org. Biomol. Chem. 2013, 11, 8197– 8201 DOI: 10.1039/c3ob41139g
    [Crossref], [PubMed], [CAS]
    66.
    Amphiphilic peptoid transporters - synthesis and evaluation
    Vollrath, Sidonie B. L.; Fuerniss, Daniel; Schepers, Ute; Braese, Stefan
    Organic & Biomolecular Chemistry (2013), 11 (47), 8197-8201CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    Cell-penetrating peptoids are an important class of peptidomimetics, which can replace highly biodegradable cell penetrating peptides for enhanced drug delivery. Typically, they contain pos. charged amino side chains which are synthesized via their protected analogs. To avoid the use of amine protecting groups a Click-chem. based modular synthesis of novel hydrophilic as well as amphiphilic cell penetrating peptoids was developed to generate novel structures for drug delivery in cells.
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  67. 67.
    Iwata, T.; Tanaka, K.; Tahara, T.; Nozaki, S.; Onoe, H.; Watanabe, Y.; Fukase, K. A Conformationally Fixed Analog of the Peptide Mimic Grb2-SH2 Domain: Synthesis and Evaluation against the A431 Cancer Cell Mol. BioSyst. 2013, 9, 1019– 1025 DOI: 10.1039/c3mb25462c
    [Crossref], [PubMed], [CAS]
    67.
    A conformationally fixed analog of the peptide mimic Grb2-SH2 domain: synthesis and evaluation against the A431 cancer cell
    Iwata, Takayuki; Tanaka, Katsunori; Tahara, Tsuyoshi; Nozaki, Satoshi; Onoe, Hirotaka; Watanabe, Yasuyoshi; Fukase, Koichi
    Molecular BioSystems (2013), 9 (5), 1019-1025CODEN: MBOIBW; ISSN:1742-2051. (Royal Society of Chemistry)
    A small peptide mimic of the Grb2-SH2 domain, which was previously prepd. through the template-assisted click approach and exhibited selective A431 tumor growth inhibition both in vitro and in vivo, was further elaborated on to enhance the interaction with target phosphorylated proteins. A conformationally fixed analog was efficiently synthesized by solid-supported ring-closing metathesis and Cu(I)/His-mediated self-activating Huisgen [3+2] cycloaddn. as the key steps, and exhibited a 10-fold enhanced affinity to a phosphorylated peptide, a truncated peptide analog of the Grb2-SH2-interacting phosphoproteins. A stronger interaction with the target phosphorylated proteins gave this cyclic analog cytotoxic activity in A431 cells.
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  68. 68.
    Jezowska, M.; Romanowska, J.; Bestas, B.; Tedebark, U.; Honcharenko, M. Synthesis of Biotin Linkers with the Activated Triple Bond Donor [p-(N-Propynoylamino)toluic Acid] (PATA) for Efficient Biotinylation of Peptides and Oligonucleotides Molecules 2012, 17, 14174– 14185 DOI: 10.3390/molecules171214174
    [Crossref], [PubMed], [CAS]
    68.
    Synthesis of biotin linkers with the activated triple bond donor [p-(N-propynoylamino)toluic acid] (PATA) for efficient biotinylation of peptides and oligonucleotides
    Jezowska, Martina; Romanowska, Joanna; Bestas, Burcu; Tedebark, Ulf; Honcharenko, Malgorzata
    Molecules (2012), 17 (), 14174-14185CODEN: MOLEFW; ISSN:1420-3049. (MDPI AG)
    Biotin is an important mol. for modern biol. studies including, e.g., cellular transport. Its exclusive affinity to fluorescent streptavidin/avidin proteins allows ready and specific detection. As a consequence methods for the attachment of biotin to various biol. targets are of high importance, esp. when they are very selective and can also proceed in water. One useful method is Huisgen dipolar [3+2]-cycloaddn., commonly referred to as click chem. As the authors have reported recently, the activated triple bond donor p-(N-propynoylamino)toluic acid (PATA) gives excellent results when used for conjugations at submicromolar concns. Thus, the authors thus designed and investigated two biotin linkers, with different lengths equipped with this activated triple bond donor and the synthesis of the target compds. was achieve by biotinylation of oligonucleotide precursors and a c-myc peptide, both in soln. and on solid support with excellent yields of conversion. The title compds. thus obtained included a biotin linker (I) which was capable of undergoing a click reaction with a suitable azide peptide, such as N-[2-[2-(2-azidoethoxy)ethoxy]acetyl]glycyl-L-alanyl-L-alanyl-L-lysyl-L-arginyl-L-valyl-L-lysyl-L-leucyl-L-aspartic acid (com. available solid-phase reactant).
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  69. 69.
    Cornier, P. G.; Boggián, D. B.; Mata, E. G.; Delpiccolo, C. M. L. Solid-Phase Based Synthesis of Biologically Promising Triazolyl Aminoacyl (peptidyl) Penicillins Tetrahedron Lett. 2012, 53, 632– 636 DOI: 10.1016/j.tetlet.2011.11.113
    [Crossref], [CAS]
    69.
    Solid-phase based synthesis of biologically promising triazolyl aminoacyl (peptidyl) penicillins
    Cornier, Patricia G.; Boggian, Dora B.; Mata, Ernesto G.; Delpiccolo, Carina M. L.
    Tetrahedron Letters (2012), 53 (6), 632-636CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    An efficient and versatile methodol. for the prepn. of valuable triazolyl aminoacyl (peptidyl) penicillins is described. Solid-phase Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddn. was used as the key step showing general applicability and excellent regioselectivity either with CuI or [Cu(CH3CN)4]PF6 as Cu(I) source.
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  70. 70.
    Zhang, L.; Zhang, L.; Luo, T.; Zhou, J.; Sun, L.; Xu, Y. Synthesis and Evaluation of a Dipeptide-Drug Conjugate Library as Substrates for PEPT1 ACS Comb. Sci. 2012, 14, 108– 114 DOI: 10.1021/co200141b
    [ACS Full Text ACS Full Text], [CAS]
    70.
    Synthesis and Evaluation of a Dipeptide-Drug Conjugate Library As Substrates for PEPT1
    Zhang, Lihui; Zhang, Li; Luo, Tian; Zhou, Jie; Sun, Lingyi; Xu, Yuhong
    ACS Combinatorial Science (2012), 14 (2), 108-114CODEN: ACSCCC; ISSN:2156-8944. (American Chemical Society)
    The oligopeptide transporter PEPT1 is considered as a valuable target for prodrug design, but its 3D structure and substrate specificity of PEPT1 are not fully understood. In this study, we designed a focused dipeptide conjugated azidothymidine (AZT) library and described a convenient and efficient solid phase synthesis scheme based on click chem. Over 60 candidate structures contg. various dipeptide sequences were obtained with high purity, and screened in a PEPT1 overexpressing cell model for their abilities to compete with the known ligand cephalexin. Some of the compds. selected to have medium or high affinity were tested for their in vivo transport in a single-pass intestinal perfusion expt. Results showed that the designed library contained some new structure features that have high affinities toward PEPT1 and could be further explored for their application in prodrug design and development.
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  71. 71.
    Eppel, S.; Portnoy, M. One-Pot Esterification-Click (CuAAC) and Esterification–acetylene Coupling (Glaser/Eglinton) for Functionalization of Wang Polystyrene Resin Tetrahedron Lett. 2013, 54, 5056– 5060 DOI: 10.1016/j.tetlet.2013.07.034
    [Crossref], [CAS]
    71.
    One-pot esterification-click (CuAAC) and esterification-acetylene coupling (Glaser/Eglinton) for functionalization of Wang polystyrene resin
    Eppel, Sagi; Portnoy, Moshe
    Tetrahedron Letters (2013), 54 (37), 5056-5060CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    We report three new sets of one-pot reactions for functionalization of Wang polystyrene resin and its derivs. We first show that it is possible to combine esterification and CuAAC (Copper-Catalyzed Alkyne-Azide Cycloaddn.) in a one-pot reaction with a very high yield. We also demonstrate for the first time that it is possible to combine esterification with either Glaser or Eglinton acetylene-couplings in a one-pot reaction. Finally, we show that the esterification, CuAAC, and Glaser-coupling reactions are all compatible with each other, and it is possible to run in parallel esterification/CuAAC and esterification/Glaser coupling in a single vessel. All reactions are performed at room temp. while the only sepn. method required is filtering and washing the resin.
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  72. 72.
    Trinh, T. T.; Oswald, L.; Chan-Seng, D.; Lutz, J.-F. Synthesis of Molecularly Encoded Oligomers Using a Chemoselective “AB + CD” Iterative Approach Macromol. Rapid Commun. 2014, 35, 141– 145 DOI: 10.1002/marc.201300774
    [Crossref], [PubMed], [CAS]
    72.
    Synthesis of Molecularly Encoded Oligomers Using a Chemoselective "AB + CD" Iterative Approach
    Trinh, Thanh Tam; Oswald, Laurence; Chan-Seng, Delphine; Lutz, Jean-Francois
    Macromolecular Rapid Communications (2014), 35 (2), 141-145CODEN: MRCOE3; ISSN:1022-1336. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A library of eight sequence-defined model oligomers, whose sequence is based on a (0,1) binary code, is prepd. through chemoselective repeating cycles of amidification and copper-assisted alkyne-azide cycloaddn. reactions from a non-modified Wang resin. This library is constructed from two AB (A = acid, B = alkyne) building blocks, i.e., 4-pentynoic acid and 2-methyl-4-pentynoic acid acting, resp., as non-coding (0) and coding (1) monomer, and 1-amino-11-azido-3,6,9-trioxaundecane as complementary CD (C = amine, D = azide) spacer building block. In particular, encoded triads are synthesized by consecutive covalent attachment of five building blocks (i.e., three coding/non-coding monomers and two spacers). In this communication, optimal protocols for the synthesis of the targeted oligomers are reported along with their full characterization by 1H NMR, MALDI-TOF mass spectrometry, and size-exclusion chromatog. It is found that all possible encoded triads (i.e., eight possibilities) could be synthesized using this approach. Indeed, monodisperse sequence-defined oligomers are prepd. and characterized in all cases.
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  73. 73.
    Punna, S.; Kuzelka, J.; Wang, Q.; Finn, M. G. Head-to-Tail Peptide Cyclodimerization by Copper-Catalyzed Azide-Alkyne Cycloaddition Angew. Chem., Int. Ed. 2005, 44, 2215– 2220 DOI: 10.1002/anie.200461656
    [Crossref], [PubMed], [CAS]
    73.
    Head-to-tail peptide cyclodimerization by copper-catalyzed azide-alkyne cycloaddition
    Punna, Sreenivas; Kuzelka, Jane; Wang, Qian; Finn, M. G.
    Angewandte Chemie, International Edition (2005), 44 (15), 2215-2220CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Oligopeptide cyclodimerization occurs selectively when precursors contg. azide and alkyne groups are exposed to copper(I) ions on polystyrene supports. Thus, resin-bound 11- and 19-mer Arg-Gly-Asp (RGD) peptides contg. L-propargylglycine as second residue and 5-azidopentanoyl-capped lysine N-terminus were treated with CuI for 16 h to effect cyclodimerization via formation of two triazole rings.
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  74. 74.
    Serim, S.; Mayer, S. V.; Verhelst, S. H. L. Tuning Activity-Based Probe Selectivity for Serine Proteases by on-Resin “Click” Construction of Peptide Diphenyl Phosphonates Org. Biomol. Chem. 2013, 11, 5714– 5721 DOI: 10.1039/c3ob40907d
    [Crossref], [PubMed], [CAS]
    74.
    Tuning activity-based probe selectivity for serine proteases by on-resin click' construction of peptide diphenyl phosphonates
    Serim, Sevnur; Mayer, Susanne V.; Verhelst, Steven H. L.
    Organic & Biomolecular Chemistry (2013), 11 (34), 5714-5721CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    Activity-based probes (ABPs) are powerful tools for functional proteomics studies. Their selectivity can be influenced by modification of a recognition element that interacts with pockets near the active site. For serine proteases there are a limited no. of simple and efficient synthetic procedures for the development of selective probes. Here we describe a new synthetic route combining solid and soln. phase chemistries to generate a small library of di-Ph phosphonate probes. Building blocks carrying a P1 recognition element and an electrophilic phosphonate warhead were prepd. in soln. and clicked' on-resin onto a tripeptide. We show the ability to modulate the activity and selectivity of di-Ph phosphonate ABPs and demonstrate activity-dependent labeling of endogenous proteases within a tissue proteome. The herein described synthetic approach therefore serves as a valuable method for rapid diversification of serine protease ABPs.
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  75. 75.
    Erdmann, R. S.; Wennemers, H. Functionalizable Collagen Model Peptides J. Am. Chem. Soc. 2010, 132, 13957– 13959 DOI: 10.1021/ja103392t
    [ACS Full Text ACS Full Text], [CAS]
    75.
    Functionalizable Collagen Model Peptides
    Erdmann, Roman S.; Wennemers, Helma
    Journal of the American Chemical Society (2010), 132 (40), 13957-13959CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    The functionalizability and conformational properties of azidoproline (Azp)-contg. collagen model peptides (CMPs) were studied. The results show that (4R)Azp has a similar stabilizing effect on the collagen triple helix as (4R)hydroxyproline and that functionalized CMPs are readily accessible by "click" chem. The resulting triazole-functionalized CMPs form stable triple helixes, demonstrating that sterically demanding moieties in three symmetry-related positions in all strands are tolerated. The straightforward synthesis and facile functionalizability of the Azp-contg. CMPs are intriguing for the development of functional collagen-based materials.
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  76. 76.
    Erdmann, R. S.; Wennemers, H. Conformational Stability of Triazolyl Functionalized Collagen Triple Helices Bioorg. Med. Chem. 2013, 21, 3565– 3568 DOI: 10.1016/j.bmc.2013.02.046
    [Crossref], [PubMed], [CAS]
    76.
    Conformational stability of triazolyl functionalized collagen triple helices
    Erdmann, Roman S.; Wennemers, Helma
    Bioorganic & Medicinal Chemistry (2013), 21 (12), 3565-3568CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    Functionalized collagen is attractive for the development of synthetic biomaterials. Herein we present the functionalization of azidoproline contg. collagen model peptides with various alkynes using Click chem. The influence on the stability of the collagen triple helix of the stereochem. of the introduced triazolyl prolines (4R or 4S), the position of their incorporation (Xaa or Yaa) and the substituents attached to them are shown. The results provide a useful guide for the optimal functionalization of collagen using Click chem.
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  77. 77.
    Neupane, L. N.; Kim, J. M.; Lohani, C. R.; Lee, K.-H. Selective and Sensitive Ratiometric Detection of Hg2+ in 100% Aqueous Solution with Triazole-Based Dansyl Probe J. Mater. Chem. 2012, 22, 4003– 4008 DOI: 10.1039/c2jm15664d
    [Crossref], [CAS]
    77.
    Selective and sensitive ratiometric detection of Hg2+ in 100% aqueous solution with triazole-based dansyl probe
    Neupane, Lok Nath; Kim, Joung Min; Lohani, Chuda Raj; Lee, Keun-Hyeung
    Journal of Materials Chemistry (2012), 22 (9), 4003-4008CODEN: JMACEP; ISSN:0959-9428. (Royal Society of Chemistry)
    An amino acid-based fluorescent sensor (I) bearing a triazole group was synthesized by solid phase synthesis using click chem. I showed highly sensitive ratiometric response to Hg2+ in 100% aq. soln. The dissocn. const. for Hg2+ in aq. soln. was calcd. to be 672 nM. I exhibited selective response to Hg2+ among 13 tested metal ions and the sensitive detection of Hg2+ by I was not interfered by other heavy metal ions, Group I and II metal ions. 1H NMR anal. revealed that two sulfonamide and triazole groups of I played a crit. role in the interactions with Hg2+. I penetrated live cells and detected intracellular Hg2+. I allowed selective and sensitive ratiometric detection of Hg2+ in live cells as well as in 100% aq. soln.
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  78. 78.
    Metaferia, B. B.; Rittler, M.; Gheeya, J. S.; Lee, A.; Hempel, H.; Plaza, A.; Stetler-Stevenson, W. G.; Bewley, C. a; Khan, J. Synthesis of Novel Cyclic NGR/RGD Peptide Analogs via on Resin Click Chemistry Bioorg. Med. Chem. Lett. 2010, 20, 7337– 7340 DOI: 10.1016/j.bmcl.2010.10.064
    [Crossref], [PubMed], [CAS]
    78.
    Synthesis of novel cyclic NGR/RGD peptide analogs via on resin click chemistry
    Metaferia, Belhu B.; Rittler, Matthew; Gheeya, Jinesh S.; Lee, Albert; Hempel, Heidi; Plaza, Alberto; Stetler-Stevenson, William G.; Bewley, Carole A.; Khan, Javed
    Bioorganic & Medicinal Chemistry Letters (2010), 20 (24), 7337-7340CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    Targeted drug deliveries as well as high resoln. imaging of cancerous tissues and organs via specific cancer cell markers have become important in chemotherapeutic interventions of cancer treatment. Short peptides such as RGD and NGR are showing promising results for targeted drug delivery and in vivo imaging. The authors have applied Huisgen's 1,3-dipolar cycloaddn. on resin to synthesize new cyclic RGD and NGR peptide analogs. Preliminary binding assays of these new analogs by fluorescence polarization indicates specific binding to purified CD13 (aminopeptidase N) and cell lysates from MCF-7 and SKOV-3 cancer cell lines.
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  79. 79.
    Valverde, I. E.; Bauman, A.; Kluba, C. A.; Vomstein, S.; Walter, M. A.; Mindt, T. L. 1,2,3-Triazoles as Amide Bond Mimics: Triazole Scan Yields Protease-Resistant Peptidomimetics for Tumor Targeting Angew. Chem., Int. Ed. 2013, 52, 8957– 8960 DOI: 10.1002/anie.201303108
    [Crossref], [PubMed], [CAS]
    79.
    1,2,3-Triazoles as Amide Bond Mimics: Triazole Scan Yields Protease-Resistant Peptidomimetics for Tumor Targeting
    Valverde, Ibai E.; Bauman, Andreas; Kluba, Christiane A.; Vomstein, Sandra; Walter, Martin A.; Mindt, Thomas L.
    Angewandte Chemie, International Edition (2013), 52 (34), 8957-8960CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The authors report a "triazole-based scan" of a bombesin peptide fragment, [Nle14]-BBN(7-14), for identifying novel peptidomimetics with improved properties. Using click chem.-based synthetic strategy, a triazole replacement for the peptide bond was incorporated into the above bombesin peptide fragment, and this led to the synthesis of a series of peptide-based radiotracers with retained nanomolar receptor affinity and an up-to-five fold improved serum stability. In vivo evaluation of a backbone-modified peptide analogs demonstrated the enhanced stability of the vector and its improved tumor-targeting capability. The authors expect that this new methodol. for the stabilization of peptides will find broader application in the field of tumor targeting with small peptides for drug delivery, imaging and peptide receptor radiotherapy.
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  80. 80.
    Saludes, J. P.; Morton, L. A.; Ghosh, N.; Beninson, L. A.; Chapman, E. R.; Fleshner, M.; Yin, H. Detection of Highly Curved Membrane Surfaces Using a Cyclic Peptide Derived from Synaptotagmin-I ACS Chem. Biol. 2012, 7, 1629– 1635 DOI: 10.1021/cb3002705
    [ACS Full Text ACS Full Text], [CAS]
    80.
    Detection of Highly Curved Membrane Surfaces Using a Cyclic Peptide Derived from Synaptotagmin-I
    Saludes, Jonel P.; Morton, Leslie A.; Ghosh, Nilanjan; Beninson, Lida A.; Chapman, Edwin R.; Fleshner, Monika; Yin, Hang
    ACS Chemical Biology (2012), 7 (10), 1629-1635CODEN: ACBCCT; ISSN:1554-8929. (American Chemical Society)
    The generation of highly curved membranes is essential to cell growth, division, and movement. Recent research in the field is focused to answer questions related to the consequences of changes in the topol. of the membrane once it is created, broadly termed as membrane curvature sensing. Most probes that were used to study curvature sensing are intact membrane active proteins such as DP1/Yop1p, ArfGAP1, BAR domains, and Synaptotagmin-I (Syt1). Taking a cue from nature, the authors created the cyclic peptide C2BL3C based on the membrane penetration C2B loop 3 of Syt1 via "Click" chem. Using a combination of spectroscopic techniques, the authors studied the peptide-lipid interactions of this peptide with synthetic phospholipid vesicles and exosomes from rat blood plasma. The macrocycle peptide probe was selective for lipid vesicles with highly curved surfaces (d < 100 nm). These results suggested that C2BL3C functions as a selective detector of highly curved phospholipid bilayers.
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  81. 81.
    Jagasia, R.; Holub, J. M.; Bollinger, M.; Kirshenbaum, K.; Finn, M. G. Peptide Cyclization and Cyclodimerization by Cu(I)-Mediated Azide-Alkyne Cycloaddition J. Org. Chem. 2009, 74, 2964– 2974 DOI: 10.1021/jo802097m
    [ACS Full Text ACS Full Text], [CAS]
    81.
    Peptide Cyclization and Cyclodimerization by CuI-Mediated Azide-Alkyne Cycloaddition
    Jagasia, Reshma; Holub, Justin M.; Bollinger, Markus; Kirshenbaum, Kent; Finn, M. G.
    Journal of Organic Chemistry (2009), 74 (8), 2964-2974CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Head-to-tail cyclodimerization of resin-bound oligopeptides bearing azide and alkyne groups occurs readily by 1,3-dipolar cycloaddn. upon treatment with CuI. The process was found to be independent of peptide sequence, sensitive to the proximity of the alkyne to the resin, sensitive to solvent compn., facile for α- and β-peptides but not for γ-peptides, and inhibited by the inclusion of tertiary amide linkages. Peptides shorter than hexamers were predominantly converted to cyclic monomers. Oligoglycine and oligo(β-alanine) chains underwent oligomerization by 1,3-dipolar cycloaddn. in the absence of a copper catalyst. These results suggest that cyclodimerization depends on the ability of the azido-alkyne peptide to form in-frame hydrogen bonds between chains in order to place the reacting groups in close proximity and lower the entropic penalty for dimerization. The properties of the resin and solvent are crucial, giving rise to a productive balance between swelling and interstrand hydrogen bonding. These findings allow for the design of optimal substrates for triazole-forming ring closure and for the course of the reaction to be controlled by the choice of conditions.
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  82. 82.
    Jølck, R. I.; Berg, R. H.; Andresen, T. L. Solid-Phase Synthesis of PEGylated Lipopeptides Using Click Chemistry Bioconjugate Chem. 2010, 21, 807– 810 DOI: 10.1021/bc100002a
    [ACS Full Text ACS Full Text], [CAS]
    82.
    Solid-phase synthesis of PEGylated lipopeptides using click chemistry
    Jolck Rasmus I; Berg Rolf H; Andresen Thomas L
    Bioconjugate chemistry (2010), 21 (5), 807-10 ISSN:.
    A versatile methodology for efficient synthesis of PEGylated lipopeptides via CuAAC "Click" conjugation between alkyne-bearing solid-supported lipopeptides and azido-functionalized PEGs is described. This new and very robust method offers a unique platform for synthesizing PEGylated lipopeptides with a high level of complexity. These molecules, obtained in a single purification step, are ideally suited for functionalization of solid-supported lipid bilayers and liposomal drug delivery systems and are particularly valuable in enzyme activation strategies.
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  83. 83.
    Güell, I.; Vilà, S.; Micaló, L.; Badosa, E.; Montesinos, E.; Planas, M.; Feliu, L. Synthesis of Cyclic Peptidotriazoles with Activity Against Phytopathogenic Bacteria Eur. J. Org. Chem. 2013, 2013, 4933– 4943 DOI: 10.1002/ejoc.201300215
    [Crossref], [CAS]
    83.
    Synthesis of Cyclic Peptidotriazoles with Activity Against Phytopathogenic Bacteria
    Gueell, Imma; Vila, Silvia; Micalo, Lluis; Badosa, Esther; Montesinos, Emilio; Planas, Marta; Feliu, Lidia
    European Journal of Organic Chemistry (2013), 2013 (22), 4933-4943CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Cyclic peptidotriazoles derived from the antimicrobial cyclic peptide c(Lys-Lys-Leu-Lys-Lys-Phe-Lys-Lys-Leu-Gln) (BPC194) were prepd. by incorporating a triazolyl amino acid at the 3-position. The synthesis was accomplished on solid-phase and involved as the key step a copper-catalyzed cycloaddn. reaction between a resin-bound alkyne or a resin-bound azide and a range of azides or alkynes in soln., resp. This methodol. was also applied to the synthesis of a conjugated peptide contg. a cyclic and a linear peptidyl sequence linked through a triazolyl ring. Cyclic peptidotriazoles were obtained in excellent purity starting either from an alkynyl or an azido peptidyl resin. These compds. were screened in vitro for their growth inhibition of bacterial phyto-pathogens and for their cytotoxic effects on eukaryotic cells. Peptide sequences with high antibacterial activity and low hemolysis were identified, constituting good candidates for the design of new antimicrobial agents.
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  84. 84.
    Vilà, S.; Camó, C.; Figueras, E.; Badosa, E.; Montesinos, E.; Planas, M.; Feliu, L. Solid-Phase Synthesis of Cyclic Lipopeptidotriazoles Eur. J. Org. Chem. 2014, 2014, 4785– 4794 DOI: 10.1002/ejoc.201402111
    [Crossref], [CAS]
    84.
    Solid-phase synthesis of cyclic lipopeptidotriazoles
    Vila, Silvia; Camo, Cristina; Figueras, Eduard; Badosa, Esther; Montesinos, Emilio; Planas, Marta; Feliu, Lidia
    European Journal of Organic Chemistry (2014), 2014 (22), 4785-4794CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The solid-phase synthesis of cyclic lipopeptidotriazoles derived from the cyclic decapeptide c(Lys-Lys2-Leu-Lys-Lys5-Phe-Lys-Lys-Leu-Gln) (BPC194), incorporating a triazolyl ring at Lys2 and a hexanoyl group at Lys5, was studied. Four different strategies that required the use of five orthogonal protecting groups (Fmoc, tBu, All, pNZ, ivDde) were explored. The influence of the side-chain protection of Lys2 and Lys5 with the ivDde and pNZ groups was evaluated by incorporating Lys2(ivDde)/Lys5(pNZ) or Lys2(pNZ)/Lys5(ivDde). The order of removal of these protecting groups and of the introduction of the hexanoyl and triazolyl moieties was also studied. The best strategy included: (i) synthesis of a cyclic peptidyl resin bearing Lys2(ivDde) and Lys5(pNZ); (ii) pNZ group removal; (iii) acylation with hexanoic acid; (iv) ivDde group removal; and (v) acylation with propiolic acid followed by an azide-alkyne 1,3-dipolar cycloaddn. By using this protocol, a set of cyclic lipopeptidotriazoles was prepd. in high purities.
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  85. 85.
    Pretze, M.; Mosch, B.; Bergmann, R.; Steinbach, J.; Pietzsch, J.; Mamat, C. Radiofluorination and First Radiopharmacological Characterization of a SWLAY Peptide-Based Ligand Targeting EphA2 J. Labelled Compd. Radiopharm. 2014, 57, 660– 665 DOI: 10.1002/jlcr.3237
    [Crossref], [PubMed], [CAS]
    85.
    Radiofluorination and first radiopharmacological characterization of a SWLAY peptide-based ligand targeting EphA2
    Pretze, Marc; Mosch, Birgit; Bergmann, Ralf; Steinbach, Joerg; Pietzsch, Jens; Mamat, Constantin
    Journal of Labelled Compounds and Radiopharmaceuticals (2014), 57 (11), 660-665CODEN: JLCRD4; ISSN:0362-4803. (John Wiley & Sons Ltd.)
    Peptides labeled with short-lived positron emitters are of considerable interest as probes for mol. imaging by positron emission tomog. Herein, the regioselective and convenient radiofluorination of a biol. relevant alkyne-modified SWLAY peptide bound on solid support with the radiolabeling building block 1-(3-azidopropyl)-4-(3-fluoropropyl)piperazine ([18F]AFP) is described. Peptides including this amino acid sequence are promising candidates for imaging of the erythropoietin-producing hepatoma cell line-A2 receptor (Eph), which is an interesting target for tumor imaging due to its overexpression in various tumor entities. The desired 18F-peptide could be prepd. in a total synthesis time of 140 min including the removal of the catalytic copper species and was obtained with a radiochem. yield of 11 ± 2% (n = 5) and a radiochem. purity >98%. The method's feasibility for a robust and bioorthogonal radiolabeling via the 1,3-dipolar Huisgen cycloaddn. was demonstrated. Preliminary radiopharmacol. studies regarding the metabolic stability of the peptides in cell culture supernatants and rat plasma were accomplished as well as the cellular assocn. of the 18F-peptide in erythropoietin-producing hepatoma cell line-A2-overexpressing human melanoma cells in vitro. Furthermore, an initial in vivo positron emission tomog. expt. was performed, which showed a fast metab. of the novel 18F-peptide.
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  86. 86.
    Sirion, U.; Lee, J.-H.; Bae, Y.-J.; Kim, H.-J.; Lee, B.-S.; Chi, D.-Y. Azide/Alkyne Resins for Quick Preparation of 1,4-Disubstituted 1,2,3-Triazoles Bull. Korean Chem. Soc. 2010, 31, 1843– 1847 DOI: 10.5012/bkcs.2010.31.7.1843
    [Crossref], [CAS]
    86.
    Azide/alkyne resins for quick preparation of 1,4-disubstituted 1,2,3-triazoles
    Sirion, Uthaiwan; Lee, Jae Hak; Bae, Yu Jin; Kim, Hee Jun; Lee, Byoung Se; Chi, Dae Yoon
    Bulletin of the Korean Chemical Society (2010), 31 (7), 1843-1847CODEN: BKCSDE; ISSN:0253-2964. (Korean Chemical Society)
    An efficient method for the prepn. of 1,4-disubstituted 1,2,3-triazole compds. is described using polymeric quaternary ammonium salts having azide or alkyne functionality to remove unreacted excess starting mols. (azide/alkyne). Cu metal could easily be removed by simple filtration with a short Na2SO4/SiO2 cartridge, affording highly regioselective products in high yield and excellent purity without the need for work-up, extn. and chromatog. purifn.
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  87. 87.
    Löber, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Click Linker: Efficient and High-Yielding Synthesis of a New Family of SPOS Resins by 1,3-Dipolar Cycloaddition Org. Lett. 2003, 5, 1753– 1755 DOI: 10.1021/ol034520l
    [ACS Full Text ACS Full Text], [CAS]
    87.
    Click linker: efficient and high-yielding synthesis of a new family of SPOS resins by 1,3-dipolar cycloaddition
    Lober Stefan; Rodriguez-Loaiza Pilar; Gmeiner Peter
    Organic letters (2003), 5 (10), 1753-5 ISSN:1523-7060.
    [reaction: see text] Highly efficient methodology for the construction of functionalized resins was presented involving 1,3-dipolar cycloaddition as the key reaction step. On the basis of this concept, the first series of click backbone amide linkers were synthesized and the application of the FIMT resin 3f to the parallel synthesis of putative dopaminergic agents was demonstrated leading to the selective receptor ligands 10i and 10s revealing high affinity to the D4 subtype.
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  88. 88.
    Löber, S.; Gmeiner, P. Click Chemistry on Solid Support: Synthesis of a New REM Resin and Application for the Preparation of Tertiary Amines Tetrahedron 2004, 60, 8699– 8702 DOI: 10.1016/j.tet.2004.05.099
    [Crossref], [CAS]
    88.
    Click chemistry on solid support: synthesis of a new REM resin and application for the preparation of tertiary amines
    Lober, Stefan; Gmeiner, Peter
    Tetrahedron (2004), 60 (39), 8699-8702CODEN: TETRAB; ISSN:0040-4020. (Elsevier B.V.)
    1,3-Dipolar cycloaddn. was employed for the synthesis of a highly practical regenerative Michael acceptor (REM) resin. Exploiting this concept, the resulting triazolylmethyl acrylate resin was used for an efficient parallel synthesis of tertiary amines by Michael addn., subsequent quaternization and cleavage by means of β-elimination.
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  89. 89.
    Bettinetti, L.; Löber, S.; Hübner, H.; Gmeiner, P. Parallel Synthesis and Biological Screening of Dopamine Receptor Ligands Taking Advantage of a Click Chemistry Based BAL Linker J. Comb. Chem. 2005, 7, 309– 316 DOI: 10.1021/cc049860s
    [ACS Full Text ACS Full Text], [CAS]
    89.
    Parallel synthesis and biological screening of dopamine receptor ligands taking advantage of a click chemistry based BAL linker
    Bettinetti, Laura; Loeber, Stefan; Huebner, Harald; Gmeiner, Peter
    Journal of Combinatorial Chemistry (2005), 7 (2), 309-316CODEN: JCCHFF; ISSN:1520-4766. (American Chemical Society)
    The click-chem.-derived formylindolyl(methyl)triazole (FIMT) resin was evaluated for the parallel solid-phase synthesis of a series of BP-897-type arylcarboxamides. By application of a five-step sequence (including loading by reductive amination, subsequent amide coupling, deprotection, palladium-catalyzed N-arylation, and acidic cleavage), a focused library of putative dopamine D3 receptor ligands was constructed. The final products revealed good to excellent purity and were screened for binding at monoaminergic G-protein-coupled receptors when selected library members proved to show excellent binding affinity, esp. toward the dopamine D3 receptor subtype.
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  90. 90.
    Loaiza, P. R.; Löber, S.; Hübner, H.; Gmeiner, P. Click Chemistry on Solid Phase: Parallel Synthesis of N-Benzyltriazole Carboxamides as Super-Potent G-Protein Coupled Receptor Ligands J. Comb. Chem. 2006, 8, 252– 261 DOI: 10.1021/cc050127q
    [ACS Full Text ACS Full Text], [CAS]
    90.
    Click chemistry on solid phase: parallel synthesis of N-benzyltriazole carboxamides as super-potent G-protein coupled receptor ligands
    Loaiza Pilar Rodriguez; Lober Stefan; Hubner Harald; Gmeiner Peter
    Journal of combinatorial chemistry (2006), 8 (2), 252-61 ISSN:1520-4766.
    The click chemistry-based backbone amide linker 1 was employed for an efficient and practical parallel synthesis of 1,2,3-triazole carboxamides when 1,3-dipolar cycloaddition was exploited for both the construction of a compound library and the functionalization of the resin. A three-step solid-phase-supported sequence included reductive amination by N-phenylpiperazinyl-substituted alkylamines, N-acylation by alkynoic acids, and azide-alkyne [3 + 2] cycloaddition. In most cases, cleavage under acidic conditions yielded the final products in excellent purities. A focused library of 60 target compounds was screened for G-protein coupled receptor binding employing eight biogenic amine receptors. Radioligand displacement experiments indicated a number of hit compounds revealing excellent receptor recognition when the methyl-substituted N-benzyltriazoles 29, 40, and 42 exhibited superior affinities for the alpha1 subtype (K(i) = 0.056-0.058 nM).
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  91. 91.
    Rodriguez Loaiza, P.; Löber, S.; Hübner, H.; Gmeiner, P. Click Chemistry Based Solid Phase Supported Synthesis of Dopaminergic Phenylacetylenes Bioorg. Med. Chem. 2007, 15, 7248– 7257 DOI: 10.1016/j.bmc.2007.08.038
    [Crossref], [PubMed], [CAS]
    91.
    Click chemistry based solid phase supported synthesis of dopaminergic phenylacetylenes
    Rodriguez Loaiza, Pilar; Loeber, Stefan; Huebner, Harald; Gmeiner, Peter
    Bioorganic & Medicinal Chemistry (2007), 15 (23), 7248-7257CODEN: BMECEP; ISSN:0968-0896. (Elsevier Ltd.)
    'Click resins' enable solid phase supported reactions to work under nearly perfect conditions fulfilling the requirements of click chem. Utilizing the formylpyrrolylmethyltriazole (FPMT) linker, which is readily available via copper(I)-catalyzed azide-alkyne cycloaddn., a backbone amide linker (BAL) strategy was successfully applied for a parallel synthesis of dopaminergic phenylacetylenes I [X = CH2, (CH2)3, (CH2)4; R1 = 3-HC≡C, 4-HC≡C, 3-PhC≡C, 4-PhC≡C; R2 = MeO, R3 = H; R2 = R3 = Cl]. A focused library of 20 test compds. revealing three points of diversity was generated by a four-step SPOS approach including microwave-assisted Sonogashira coupling. GPCR-ligand binding assays indicated excellent dopamine D3 and D4 receptor binding affinities which were identified to cause a partial agonist activity for the most potent test compds.
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  92. 92.
    Tietze, R.; Löber, S.; Hübner, H.; Gmeiner, P.; Kuwert, T.; Prante, O. Discovery of a Dopamine D4 Selective PET Ligand Candidate Taking Advantage of a Click Chemistry Based REM Linker Bioorg. Med. Chem. Lett. 2008, 18, 983– 988 DOI: 10.1016/j.bmcl.2007.12.026
    [Crossref], [PubMed], [CAS]
    92.
    Discovery of a dopamine D4 selective PET ligand candidate taking advantage of a click chemistry based REM linker
    Tietze, Rainer; Loeber, Stefan; Huebner, Harald; Gmeiner, Peter; Kuwert, Torsten; Prante, Olaf
    Bioorganic & Medicinal Chemistry Letters (2008), 18 (3), 983-988CODEN: BMCLE8; ISSN:0960-894X. (Elsevier Ltd.)
    Employing D4 selective azaindoles as lead compds., a focused library of the carbocyclic arene bioisosteres was synthesized using the click chem. derived triazolylmethyl acrylate resin. Ligand binding assays on monoaminergic GPCRs led to SARs that indicated further lead structure optimizations when the attachment of alkoxy substituents provided both an improvement of the biol. properties and the opportunity to introduce 18F as a radioisotope. Finally, radiosynthesis resulted in formation of the radioligand I that showed optimal log D7.4 of 2.8 and was detd. to be highly stable in human serum. Thus, compd. I represents a promising dopamine D4 selective radioligand for positron emission tomog. (PET).
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  93. 93.
    Sharma, P.; Moses, J. E. Ethynyldiisopropylsilyl: A New Alkynylsilane Protecting Group and “Click” Linker Org. Lett. 2010, 12, 2860– 2863 DOI: 10.1021/ol100968t
    [ACS Full Text ACS Full Text], [CAS]
    93.
    Ethynyldiisopropylsilyl: a new alkynylsilane protecting group and "Click" linker
    Sharma, Pallavi; Moses, John E.
    Organic Letters (2010), 12 (12), 2860-2863CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    A new silyl-based reagent has been developed for "catch and release" immobilization, combining click chem. with silyl protection. The traditional "all carbon" attachment to solid supports in a silyl type linker was substituted with a stable triazole, easily assembled using the CuAAC reaction. The methodol. introduces a novel ethynyldiiospropylchlorosilane reagent (EDIPS-Cl) as a functionalized protecting group linker.
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  94. 94.
    Riente, P.; Yadav, J.; Pericàs, M. A Click Strategy for the Immobilization of MacMillan Organocatalysts onto Polymers and Magnetic Nanoparticles Org. Lett. 2012, 14, 3668– 3671 DOI: 10.1021/ol301515d
    [ACS Full Text ACS Full Text], [CAS]
    94.
    A click strategy for the immobilization of MacMillan organocatalysts onto polymers and magnetic nanoparticles
    Riente, Paola; Yadav, Jagjit; Pericas, Miquel A.
    Organic Letters (2012), 14 (14), 3668-3671CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A chem. modified, first generation MacMillan imidazolidin-4-one has been anchored onto 1% DVB Merrifield resin and Fe3O4 (5.3 ± 1.4 nm) magnetic nanoparticles through copper-catalyzed alkyne azide cycloaddn. (CuAAC) reactions. The resulting immobilized catalysts have been successfully used in the asym. Friedel-Crafts alkylation of N-substituted pyrroles with α,β-unsatd. aldehydes. The PS-supported catalyst (B) showed higher catalytic activity and enantioselectivity, while the MNP-supported one (A) showed higher recyclability and could be used in a sequential process with intermediate magnetic decantation.
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  95. 95.
    Wang, Q.-Y.; Sheng, W.-S.; Sheng, S.-R.; Li, Y.; Cai, M.-Z. Click Chemistry on Polymer Support: Synthesis of 1-Vinyl- and 1-Allyl-1,2,3-Triazoles via Selenium Linker Synth. Commun. 2014, 44, 59– 67 DOI: 10.1080/00397911.2013.789112
    [Crossref], [CAS]
    95.
    Click Chemistry on Polymer Support: Synthesis of 1-Vinyl- and 1-Allyl-1,2,3-triazoles via Selenium Linker
    Wang, Qiu-Ying; Sheng, Wu-Sheng; Sheng, Shou-Ri; Li, Yan; Cai, Ming-Zhong
    Synthetic Communications (2014), 44 (1), 59-67CODEN: SYNCAV; ISSN:0039-7911. (Taylor & Francis, Inc.)
    Polystyrene-supported 2-azidoethyl Ph selenide and 3-azidopropyl Ph selenide reagents have been developed and applied to the traceless solid-phase org. synthesis of 1-vinyl- and 1-allyl-1,2,3-triazoles by CuI-mediated azide-alkyne cycloaddns. and subsequent cleavage from the polymer support through oxidn.-elimination reaction with 30% hydrogen peroxide. The advantages of this method include straightforward operation, good yield and purity of the products, and good stability and lack of odor for the reagents.
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  96. 96.
    Yadav, S. K.; Mahapatra, S. S.; Cho, J. W.; Lee, J. Y. Functionalization of Multiwalled Carbon Nanotubes with Poly (styrene-B-(ethylene-Co-Butylene)-B-Styrene) by Click Coupling J. Phys. Chem. C 2010, 114, 11395– 11400 DOI: 10.1021/jp1028382
    [ACS Full Text ACS Full Text], [CAS]
    96.
    Functionalization of Multiwalled Carbon Nanotubes with Poly(styrene-b-(ethylene-co-butylene)-b-styrene) by Click Coupling
    Yadav, Santosh Kumar; Mahapatra, Sibdas Singha; Cho, Jae Whan; Lee, Jae Yeol
    Journal of Physical Chemistry C (2010), 114 (26), 11395-11400CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    Multiwalled carbon nanotubes (MWCNTs) were functionalized with poly(styrene-b-(ethylene-co-butylene)-b-styrene) triblock copolymer (SEBS) using click chem. Different compns. of SEBS-functionalized MWCNTs were obtained from reaction of azide moiety-contg. SEBS on styrene units with alkyne-decorated MWCNTs. The SEBS-functionalized MWCNTs were characterized by FT-IR, Raman, XPS, SEM, and TEM measurements. The functionalized MWCNTs showed excellent dispersion in the SEBS matrix, and as a result, remarkably increased mech. properties and high dielec. consts. as well as enhanced thermal stability were obtained. The click coupled bonding of MWCNT with SEBS was very effective for controlling the material properties and achieving high performance materials.
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  97. 97.
    Ouerghui, A.; Elamari, H.; Ghammouri, S.; Slimi, R.; Meganem, F.; Girard, C. Polystyrene-Supported Triazoles for Metal Ions Extraction: Synthesis and Evaluation React. Funct. Polym. 2014, 74, 37– 45 DOI: 10.1016/j.reactfunctpolym.2013.10.007
    [Crossref], [CAS]
    97.
    Polystyrene-supported triazoles for metal ions extraction: Synthesis and evaluation
    Ouerghui, Abid; Elamari, Hichem; Ghammouri, Saadia; Slimi, Riadh; Meganem, Faouzi; Girard, Christian
    Reactive & Functional Polymers (2014), 74 (), 37-45CODEN: RFPOF6; ISSN:1381-5148. (Elsevier Ltd.)
    In order to prep. substituted polymers bearing functional groups to chelate metals for their application in extn. and/or depollution applications, Merrifield polymer was transformed into the known azidomethyl polystyrene. Click-chem. based on copper (I)-catalyzed Huisgen's reaction was then used to form polymer-grafted 1,4-triazoles using a variety of synthesized substituted alkynes. These polymer-supported triazoles were then used to ext. metals (Cd, Fe, Mg, Ni and Co) from aq. solns. A comparative study of metal extns. by these supported triazoles was made between the starting azidomethyl polystyrene and two natural clays taken from the Gafsa area (South-West Tunisia). Raw and purified clays from two Gafsa sites were found to ext. metals quite well with almost no selectivity, except for lower fixations of cadmium and magnesium. The synthesized polymers were found to ext. all metals with lower efficiencies than the clays. However, one of the polymer-supported triazole was found to ext. selectively cadmium with a high efficiency, reaching the levels of the natural clays.
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  98. 98.
    Zhu, M.; Lim, B. J.; Koh, M.; Park, S. B. Construction of Polyheterocyclic Benzopyran Library with Diverse Core Skeletons through Diversity-Oriented Synthesis Pathway ACS Comb. Sci. 2012, 14, 124– 134 DOI: 10.1021/co2001907
    [ACS Full Text ACS Full Text], [CAS]
    98.
    Construction of Polyheterocyclic Benzopyran Library with Diverse Core Skeletons through Diversity-Oriented Synthesis Pathway: Part II
    Zhu, Mingyan; Lim, Byung Jun; Koh, Minseob; Park, Seung Bum
    ACS Combinatorial Science (2012), 14 (2), 124-134CODEN: ACSCCC; ISSN:2156-8944. (American Chemical Society)
    As a continuation of our previous report, we accomplished the diversity-oriented synthesis of polyheterocyclic small-mol. library with privileged benzopyran substructure. To ensure the synthetic efficiency, we utilized the solid-phase parallel platform and the fluorous-tag-based soln.-phase parallel platform to construct a 284-member polyheterocyclic library with six distinct core skeletons with an av. purity of 87% on a scale of 5-10 mg. This library was designed to maximize the skeletal diversity with discrete core skeletons in three-dimensional space and the combinatorial diversity with four different benzopyranyl starting materials and various building blocks. Together with our reported benzopyranyl library, we completed the construction of polyheterocyclic benzopyran library with 11 unique scaffolds and their mol. diversity was visualized in chem. space using principal component anal. (PCA).
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  99. 99.
    Chen, G.; Tao, L.; Mantovani, G.; Ladmiral, V.; Burt, D. P.; Macpherson, J. V.; Haddleton, D. M. Synthesis of Azide/alkyne-Terminal Polymers and Application for Surface Functionalisation through a [2 + 3] Huisgen Cycloaddition Process, “Click Chemistry. Soft Matter 2007, 3, 732– 739 DOI: 10.1039/b618325e
    [Crossref], [CAS]
    99.
    Synthesis of azide/alkyne-terminal polymers and application for surface functionalization through a [2 + 3] Huisgen cycloaddition process, "click chemistry"
    Chen, Gaojian; Tao, Lei; Mantovani, Giuseppe; Ladmiral, Vincent; Burt, David P.; Macpherson, Julie V.; Haddleton, David M.
    Soft Matter (2007), 3 (6), 732-739CODEN: SMOABF; ISSN:1744-683X. (Royal Society of Chemistry)
    Living radical polymn. of Me methacrylate (MMA) and a fluorescent comonomer with 2-bromo-2-methylpropionic acid 3-azidopropyl ester and 2-bromo-2-methylhept-6-yn-3-one as initiators has been successfully employed for the synthesis of fluorescently tagged azide and alkyne terminated PMMA with Mn close to that predicted, PDI < 1.20, and good first order kinetics as expected for a living polymn. Cotton and org. resin surfaces have been functionalized with alkyne groups using a condensation with 4-chlorocarbonylbutyric acid prop-2-ynyl ester. The surfaces have been further modified using a Huisgen [2 + 3] cycloaddn. ("click") reaction of polymeric and small mol. azides. Different functional azides, mono azido-PEG and a new fluorescent hostasol deriv. have been prepd. and tested as model substrates for cotton surface modification. FTIR, tensiometry, FE-SEM and confocal spectroscopy have been used to characterize the modified surfaces. Tensiometry shows an increase in the hydrophobicity of the surface; verified by FE-SEM which shows a change in surface morphol. The use of the fluorescence label allows fluorescent and confocal microscopy to demonstrate the surface reactions. This approach is shown to be very general allowing soft and hard surfaces with different geometries to be modified. In particular it is an excellent method to alter the nature of org. resins allowing the incorporation of many different functionalities.
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  100. 100.
    Isobe, H.; Fujino, T.; Yamazaki, N.; Guillot-Nieckowski, M.; Nakamura, E. Triazole-Linked Analogue of Deoxyribonucleic Acid ((TL)DNA): Design, Synthesis, and Double-Strand Formation with Natural DNA Org. Lett. 2008, 10, 3729– 3732 DOI: 10.1021/ol801230k
    [ACS Full Text ACS Full Text], [CAS]
    100.
    Triazole-Linked Analogue of Deoxyribonucleic Acid (TLDNA): Design, Synthesis, and Double-Strand Formation with Natural DNA
    Isobe, Hiroyuki; Fujino, Tomoko; Yamazaki, Naomi; Guillot-Nieckowski, Marine; Nakamura, Eiichi
    Organic Letters (2008), 10 (17), 3729-3732CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    A new triazole-linked analog of DNA (TLDNA) has been designed and synthesized using click chem. The chain elongation reaction using copper-catalyzed Huisgen cycloaddn. was successful and gave the artificial oligonucleotide that formed a stable double strand with the complementary strand of natural DNA.
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  101. 101.
    Pourceau, G.; Meyer, A.; Vasseur, J.-J.; Morvan, F. Azide Solid Support for 3′-Conjugation of Oligonucleotides and Their Circularization by Click Chemistry J. Org. Chem. 2009, 74, 6837– 6842 DOI: 10.1021/jo9014563
    [ACS Full Text ACS Full Text], [CAS]
    101.
    Azide Solid Support for 3'-Conjugation of Oligonucleotides and Their Cyclization by Click Chemistry
    Pourceau, Gwladys; Meyer, Albert; Vasseur, Jean-Jacques; Morvan, Francois
    Journal of Organic Chemistry (2009), 74 (17), 6837-6842CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    A solid support bearing an azido linker was used to synthesize a 3'-azido-alkyl-oligonucleotide by phosphoramidite chem. The resulting oligonucleotide was either conjugated by 1,3-dipolar cycloaddn. on solid support or in soln. with mannose-propargyl deriv. and in soln. with dansyl propargyl. Besides, after introduction of an alkyne function at the 5'-end, the resulting oligonucleotide bearing both 3'-azide and 5'-alkyne functions was cyclized.
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  102. 102.
    Bouillon, C.; Meyer, A.; Vidal, S.; Jochum, A.; Chevolot, Y.; Cloarec, J.; Praly, J.; Vasseur, J.; Morvan, F. Microwave Assisted “ Click ” Chemistry for the Synthesis of Multiple Labeled-Carbohydrate Oligonucleotides on Solid Support J. Org. Chem. 2006, 71, 4700– 4702 DOI: 10.1021/jo060572n
    [ACS Full Text ACS Full Text], [CAS]
    102.
    Microwave Assisted "Click" Chemistry for the Synthesis of Multiple Labeled-Carbohydrate Oligonucleotides on Solid Support
    Bouillon, Camille; Meyer, Albert; Vidal, Sebastien; Jochum, Anne; Chevolot, Yann; Cloarec, Jean-Pierre; Praly, Jean-Pierre; Vasseur, Jean-Jacques; Morvan, Francois
    Journal of Organic Chemistry (2006), 71 (12), 4700-4702CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    A versatile approach has been developed for the multiple labeling of oligonucleotides. First, three linkers as a H-phosphonate monoester deriv. were condensed on a solid-supported T12 to introduce H-phosphonate diester linkages which were oxidized in the presence of propargylamine. Second, three galactosyl azide derivs. were conjugated to the solid-supported three-alkyne-modified T12 by a 1,3-cycloaddn. so-called "click chem." in the presence of Cu(I) assisted by microwaves.
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  103. 103.
    Pourceau, G.; Meyer, A.; Vasseur, J.-J.; Morvan, F. Synthesis of Mannose and Galactose Oligonucleotide Conjugates by Bi-Click Chemistry J. Org. Chem. 2009, 74, 1218– 1222 DOI: 10.1021/jo802536q
    [ACS Full Text ACS Full Text], [CAS]
    103.
    Synthesis of Mannose and Galactose Oligonucleotide Conjugates by Bi-click chemistry
    Pourceau, Gwladys; Meyer, Albert; Vasseur, Jean-Jacques; Morvan, Francois
    Journal of Organic Chemistry (2009), 74 (3), 1218-1222CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Glyco oligonucleotide conjugates, each exhibiting two mannose and two galactose residues, were efficiently synthesized by two successive 1,3-dipolar cycloaddn. (click chem.). Two phosphoramidite derivs. were used: one bearing a bromo-alkyl group as a precursor to azide functionalization and another bearing a propargyl group. After a first cycloaddn. with a mannosyl-azide deriv., the bromine atoms were substituted with NaN3 and a second click reaction was performed with a 1'-O-propargyl galactose, affording the hetero-glyco oligonucleotide conjugate.
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    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1MXktVOhug%253D%253D&md5=080573b704dd9d181b8ddcd0c623ae4a
  104. 104.
    Morvan, F.; Meyer, A.; Jochum, A.; Sabin, C.; Chevolot, Y.; Imberty, A.; Praly, J.-P.; Vasseur, J.-J.; Souteyrand, E.; Vidal, S. Fucosylated Pentaerythrityl Phosphodiester Oligomers (PePOs): Automated Synthesis of DNA-Based Glycoclusters and Binding to Pseudomonas Aeruginosa Lectin (PA-IIL) Bioconjugate Chem. 2007, 18, 1637– 1643 DOI: 10.1021/bc070129z
    [ACS Full Text ACS Full Text], [CAS]
    104.
    Fucosylated Penta-erythrityl Phosphodiester Oligomers (PePOs): Automated Synthesis of DNA-Based Glycoclusters and Binding to Pseudomonas aeruginosa Lectin (PA-IIL)
    Morvan, Francois; Meyer, Albert; Jochum, Anne; Sabin, Charles; Chevolot, Yann; Imberty, Anne; Praly, Jean-Pierre; Vasseur, Jean-Jacques; Souteyrand, Eliane; Vidal, Sebastien
    Bioconjugate Chemistry (2007), 18 (5), 1637-1643CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    The synthesis of propargylated pentaerythrityl phosphodiester oligomers (PePOs) was achieved using a DNA synthesizer with a bis-propargylated pentaerythritol-based phosphoramidite. An azido fucose deriv. was reacted under "click" chem. conditions activated by microwaves to construct a series of glycosylated PePOs bearing 4, 6, 8, and 10 L-fucose residues. Binding to the fucose-specific bacterial lectin (PA-IIL) was detd. for the fucosylated PePOs through an enzyme-linked lectin amplification competition assay. The IC50 values measured are 10-20 times better than for monovalent L-fucose and denotate for a "macromol." effect rather than a "cluster" effect.
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  105. 105.
    Pourceau, G.; Meyer, A.; Vasseur, J.-J.; Morvan, F. Combinatorial and Automated Synthesis of Phosphodiester Galactosyl Cluster on Solid Support by Click Chemistry Assisted by Microwaves J. Org. Chem. 2008, 73, 6014– 6017 DOI: 10.1021/jo8009837
    [ACS Full Text ACS Full Text], [CAS]
    105.
    Combinatorial and Automated Synthesis of Phosphodiester Galactosyl Cluster on Solid Support by Click Chemistry Assisted by Microwaves
    Pourceau, Gwladys; Meyer, Albert; Vasseur, Jean-Jacques; Morvan, Francois
    Journal of Organic Chemistry (2008), 73 (15), 6014-6017CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Small libraries of di-, tri-, and tetra-galactosyl clusters were efficiently synthesized using combinatorial methodol., on solid support, by click chem. assisted by microwaves, starting from different poly alkyne DNA-based scaffolds and two galactosyl azide derivs. The scaffold was synthesized by std. DNA solid-supported phosphoramidite chem. using a novel alkyne phosphoramidite and an alkyne solid support. The proportion of each glycocluster in a library was modulated using different molar ratios of both galactose azides.
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  106. 106.
    Pourceau, G.; Meyer, A.; Chevolot, Y.; Souteyrand, E.; Vasseur, J.-J.; Morvan, F. Oligonucleotide Carbohydrate-Centered Galactosyl Cluster Conjugates Synthesized by Click and Phosphoramidite Chemistries Bioconjugate Chem. 2010, 21, 1520– 1529 DOI: 10.1021/bc1001888
    [ACS Full Text ACS Full Text], [CAS]
    106.
    Oligonucleotide Carbohydrate-Centered Galactosyl Cluster Conjugates Synthesized by Click and Phosphoramidite Chemistries
    Pourceau, Gwladys; Meyer, Albert; Chevolot, Yann; Souteyrand, Eliane; Vasseur, Jean-Jacques; Morvan, Francois
    Bioconjugate Chemistry (2010), 21 (8), 1520-1529CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    Oligonucleotide glycoconjugates with a mannose or galactose core bearing four galactose residues introduced by phosphoramidite chem. and copper catalyzed azide alkyne 1,3-dipolar cycloaddn. (click chem.) have been synthesized. A first click reaction allowed the introduction on a solid support of a mannose core on which four pentynyl linkers were introduced using a phosphoramidite deriv. After the elongation of the oligonucleotide, a second click reaction performed either on solid support or in soln. allowed the introduction of four galactose azide derivs. Repeating the phosphoramidite and click chemistries afforded an oligonucleotide glycoconjugate dendrimer bearing 16 galactose units on its periphery.
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  107. 107.
    Meyer, A.; Noël, M.; Vasseur, J.-J.; Morvan, F. Hetero-Click Conjugation of Oligonucleotides with Glycosides Using Bifunctional Phosphoramidites Eur. J. Org. Chem. 2015, 2015, 2921– 2927 DOI: 10.1002/ejoc.201500165
    [Crossref], [CAS]
    107.
    Hetero-Click Conjugation of Oligonucleotides with Glycosides Using Bifunctional Phosphoramidites
    Meyer, Albert; Noel, Mathieu; Vasseur, Jean-Jacques; Morvan, Francois
    European Journal of Organic Chemistry (2015), 2015 (13), 2921-2927CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Two phosphoramidite derivs., each bearing two orthogonal functions: alkyne/thioacetyl or alkyne/tosyl,resp., were synthesized and used to generate hetero-glyco 5'-oligonucleotide conjugates. After coupling, the first conjugation was performed using CuAAC on solid support with an azide-bearing carbohydrate. For alkyne/thioacetyl phosphoramidite, the second conjugation was performed in soln. by a thiol "click" reaction using a bromoacetamide galactoside, whereas for alkyne/tosyl phosphoramidite, the tosyl group was converted into an azide and a second CuAAC was applied on solid support. Accordingly, a deoxycholic-centered hetero-glycocluster exhibiting two D-galactose and two L-fucose motifs, conjugated to an oligonucleotide, was successfully synthesized.
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  108. 108.
    Tähtinen, V.; Granqvist, L.; Virta, P. Synthesis of C-5, C-2′ and C-4′-Neomycin-Conjugated Triplex Forming Oligonucleotides and Their Affinity to DNA-Duplexes Bioorg. Med. Chem. 2015, 23, 4472– 4480 DOI: 10.1016/j.bmc.2015.06.013
    [Crossref], [PubMed], [CAS]
    108.
    Synthesis of C-5, C-2' and C-4'-neomycin-conjugated triplex forming oligonucleotides and their affinity to DNA-duplexes
    Tahtinen, Ville; Granqvist, Lotta; Virta, Pasi
    Bioorganic & Medicinal Chemistry (2015), 23 (15), 4472-4480CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    Neomycin-conjugated homopyrimidine oligo 2'-deoxyribonucleotides have been synthesized on a solid phase and their potential as triplex forming oligonucleotides (TFOs) with DNA-duplexes has been studied. For the synthesis of the conjugates, C-5, C-2' and C-4'-tethered alkyne-modified nucleoside derivs. were used as an integral part of the std. automated oligonucleotide chain elongation. An azide-derived neomycin was then conjugated to the incorporated terminal alkynes by Cu(I)-catalyzed 1,3-dipolar cycloaddn. (the click chem.). Concd. ammonia released the desired conjugates in acceptable purity and yields. The site of conjugation was expectedly important for the Hoogsteen-face recognition: C-5-conjugation showed a notable pos. effect, whereas the influence of the C-2' and C-4'-modification remained marginal. In addn. to conventional characterization methods (UV- and CD-spectroscopy), 19F NMR spectroscopy was applied for the monitoring of triplex/duplex/single strand-conversions.
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  109. 109.
    Kiviniemi, A.; Virta, P.; Lonnberg, H. Solid-Supported Synthesis and Click Conjugation of 4 ′- C-Alkyne Functionalized Oligodeoxyribonucleotides Bioconjugate Chem. 2010, 21, 1890– 1901 DOI: 10.1021/bc100268w
    [ACS Full Text ACS Full Text], [CAS]
    109.
    Solid-Supported Synthesis and Click Conjugation of 4'-C-Alkyne Functionalized Oligodeoxyribonucleotides
    Kiviniemi, Anu; Virta, Pasi; Lonnberg, Harri
    Bioconjugate Chemistry (2010), 21 (10), 1890-1901CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    4'-C-[N,N-Di(4-pentyn-1-yl)aminomethyl]thymidine and 4'-C-[N-methyl-N-(4-pentyn-1-yl)aminomethyl]thymidine 3'-(2-cyanoethyl-N,N-diisopropyl)phosphoramidites (1, 2) were synthesized, and one or two such monomers were incorporated into a 15-mer oligodeoxyribonucleotide. After chain assembly, azido-functionalized ligands, including appropriate derivs. of 1,4-phenylene-dimethane-amine, mannose, paromamine, and neomycin, were conjugated to the alkynyl groups by the click chem. on a solid support. The influence of the 4'-modifications on the melting temp. with DNA and 2'-O-Me RNA targets was studied. Oligonucleotides contg. one to four mannose ligands in the central part of the chain (up to two 4'-C-[N,N-di(4-pentyn-1-yl)aminomethyl]thymidine units) form equally stable duplexes with complementary 2'-OMe RNA as the corresponding unmodified DNA sequence. At high salt content, the mannose conjugation is even stabilizing. On using a DNA target, a modest destabilization occurs. All the amino group bearing conjugates stabilized the duplexes, the DNA·DNA duplexes more than the DNA·2'-O-Me RNA duplexes.
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  110. 110.
    Jayaprakash, K. N.; Peng, C. G.; Butler, D.; Varghese, J. P.; Maier, M. A.; Rajeev, K. G.; Manoharan, M. Non-Nucleoside Building Blocks for Copper-Assisted and Copper-Free Click Chemistry for the Efficient Synthesis of RNA Conjugates Org. Lett. 2010, 12, 5410– 5413 DOI: 10.1021/ol102205j
    [ACS Full Text ACS Full Text], [CAS]
    110.
    Non-Nucleoside Building Blocks for Copper-Assisted and Copper-Free Click Chemistry for the Efficient Synthesis of RNA Conjugates
    Jayaprakash, K. N.; Peng, Chang-Geng; Butler, David; Varghese, Jos P.; Maier, Martin A.; Rajeev, Kallanthottathil G.; Manoharan, Muthiah
    Organic Letters (2010), 12 (23), 5410-5413CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    Novel non-nucleoside alkyne monomers compatible with oligonucleotide synthesis were designed, synthesized, and efficiently incorporated into RNA and RNA analogs during solid-phase synthesis. These modifications allowed site-specific conjugation of ligands to the RNA oligonucleotides through copper-assisted (CuAAC) and copper-free strain-promoted azide-alkyne cycloaddn. (SPAAC) reactions. The SPAAC click reactions of cyclo-octyne-oligonucleotides with various classes of azido-functionalized ligands in soln. phase and on solid phase were efficient and quant. and occurred under mild reaction conditions. The SPAAC reaction provides a method for the synthesis of oligonucleotide-ligand conjugates uncontaminated with copper ions.
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  111. 111.
    Kiviniemi, A.; Virta, P.; Drenichev, M. S.; Mikhailov, S. N.; Lönnberg, H. Solid-Supported 2′-O-Glycoconjugation of Oligonucleotides by Azidation and Click Reactions Bioconjugate Chem. 2011, 22, 1249– 1255 DOI: 10.1021/bc200097g
    [ACS Full Text ACS Full Text], [CAS]
    111.
    Solid-Supported 2'-O-Glycoconjugation of Oligonucleotides by Azidation and Click Reactions
    Kiviniemi, Anu; Virta, Pasi; Drenichev, Mikhail S.; Mikhailov, Sergey N.; Lonnberg, Harri
    Bioconjugate Chemistry (2011), 22 (6), 1249-1255CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    2'-O-[(2-Bromoethoxy)methyl]cytidine and 2'-O-[(2-azidoethoxy)methyl]cytidine have been prepd. and introduced as appropriately protected 3'-phosphoramidite and 3'-(H-phosphonate) (2) building blocks, resp., into 2'-O-Me oligoribonucleotides. The support-bound oligonucleotides were subjected to two consecutive conjugations with alkynyl-functionalized monosaccharides. The first saccharide was introduced by a Cu(I) promoted click reaction with 2 and the second by azidation of the 2-bromoethoxy group followed by the click reaction. The influence of the 2'-glycoconjugations on hybridization with DNA and 2'-O-Me RNA targets was studied. Two saccharide units within a 15-mer oligonucleotide had a barely noticeable effect on the duplex stability, while introduction of a third one moderately decreased the melting temp.
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  112. 112.
    Thaner, R. V.; Eryazici, I.; Farha, O. K.; Mirkin, C. A.; Nguyen, S. T. Facile One-Step Solid-Phase Synthesis of Multitopic organic–DNA Hybrids via “Click” Chemistry Chem. Sci. 2014, 5, 1091– 1096 DOI: 10.1039/c3sc53206b
    [Crossref], [CAS]
    112.
    Facile one-step solid-phase synthesis of multi-topic organic-DNA hybrids via "click" chemistry
    Thaner, Ryan V.; Eryazici, Ibrahim; Farha, Omar K.; Mirkin, Chad A.; Nguyen, Son Binh T.
    Chemical Science (2014), 5 (3), 1091-1096CODEN: CSHCCN; ISSN:2041-6520. (Royal Society of Chemistry)
    A broad range of synthetically challenging-to-access small mol.-DNA hybrids can be readily synthesized in "one pot" and in high yields by coupling multi-azide cores to alkyne-modified DNAs on a solid support using click chem. The multi-functional products can be obtained in pure forms and on large scales (1 μmol) in a facile fashion. In addn., the distribution of the products can be controlled by changing the concn. of the azide core in soln. and the strand-loading d. on the solid-supports.
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  113. 113.
    Ligeour, C.; Meyer, A.; Vasseur, J.-J.; Morvan, F. Bis- and Tris-Alkyne Phosphoramidites for Multiple 5′-Labeling of Oligonucleotides by Click Chemistry Eur. J. Org. Chem. 2012, 2012, 1851– 1856 DOI: 10.1002/ejoc.201101763
    [Crossref], [CAS]
    113.
    Bis- and Tris-Alkyne Phosphoramidites for Multiple 5'-Labeling of Oligonucleotides by Click Chemistry
    Ligeour, Caroline; Meyer, Albert; Vasseur, Jean-Jacques; Morvan, Francois
    European Journal of Organic Chemistry (2012), 2012 (9), 1851-1856, S1851/1-S1851/9CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Three new phosphoramidites exhibiting two or three alkyne functions were prepd. and introduced at the 5'-end of oligonucleotides. The resulting bis- and tris-alkyne oligonucleotides were conjugated with acetylthiohexyl, ferrocene-carboamide hexyl, or carbohydrate-Pr azides by using click chem. (CuAAC) to afford poly-conjugated oligonucleotides. Conjugations were performed either in soln. or on solid support with high efficiency.
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  114. 114.
    Astakhova, I. K.; Wengel, J. Interfacing Click Chemistry with Automated Oligonucleotide Synthesis for the Preparation of Fluorescent DNA Probes Containing Internal Xanthene and Cyanine Dyes Chem. - Eur. J. 2013, 19, 1112– 1122 DOI: 10.1002/chem.201202621
    [Crossref], [PubMed], [CAS]
    114.
    Interfacing Click Chemistry with Automated Oligonucleotide Synthesis for the Preparation of Fluorescent DNA Probes Containing Internal Xanthene and Cyanine Dyes
    Astakhova, I. Kira; Wengel, Jesper
    Chemistry - A European Journal (2013), 19 (3), 1112-1122CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Double-labeled oligonucleotide probes contg. fluorophores interacting by energy-transfer mechanisms are essential for modern bioanal., mol. diagnostics, and in vivo imaging techniques. Although bright xanthene and cyanine dyes are gaining increased prominence within these fields, little attention has thus far been paid to probes contg. these dyes internally attached, a fact which is mainly due to the quite challenging synthesis of such oligonucleotide probes. Herein, by using 2'-O-propargyl uridine phosphoramidite and a series of xanthenes and cyanine azide derivs., the authors have for the first time performed solid-phase copper(I)-catalyzed azide-alkyne cycloaddn. (CuAAC) click labeling during the automated phosphoramidite oligonucleotide synthesis followed by postsynthetic click reactions in soln. The authors' novel strategy is rapid and efficient for the prepn. of novel oligonucleotide probes contg. internally positioned xanthene and cyanine dye pairs and thus represents a significant step forward for the prepn. of advanced fluorescent oligonucleotide probes. Furthermore, the novel xanthene and cyanine labeled probes display unusual and very promising photophys. properties resulting from energy-transfer interactions between the fluorophores controlled by nucleic acid assembly. Potential benefits of using these novel fluorescent probes within, for example, mol. diagnostics and fluorescence microscopy include: Considerable Stokes shifts (40-110 nm), quenched fluorescence of single-stranded probes accompanied by up to 7.7-fold light-up effect of emission upon target DNA/RNA binding, remarkable sensitivity to single-nucleotide mismatches, generally high fluorescence brightness values (FB up to 26), and hence low limit of target detection values (LOD down to <5 nM).
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  115. 115.
    Liu, Y.; Wang, X.-F.; Chen, Y.; Zhang, L.-H.; Yang, Z.-J. A Solid-Phase Method for peptide–siRNA Covalent Conjugates Based on Click Chemistry MedChemComm 2012, 3, 506– 511 DOI: 10.1039/c2md00198e
    [Crossref], [CAS]
    115.
    A solid-phase method for peptide-siRNA covalent conjugates based on click chemistry
    Liu, Yang; Wang, Xiao-Feng; Chen, Yue; Zhang, Li-He; Yang, Zhen-Jun
    MedChemComm (2012), 3 (4), 506-511CODEN: MCCEAY; ISSN:2040-2503. (Royal Society of Chemistry)
    In order to prep. a new delivery system by chem. modification, peptide-siRNA conjugates have been obtained by a solid-phase click chem. strategy, using an alkynyl nucleoside analog "clicked" onto a peptide-derivatized CPG (Controlled Pore Glass) followed by oligonucleotides synthesis. The 3'-sense strand conjugate maintained good gene silencing activity, while that of the 3'-antisense strand conjugate decreased somewhat.
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  116. 116.
    Wenska, M.; Alvira, M.; Steunenberg, P.; Stenberg, A.; Murtola, M.; Strömberg, R. An Activated Triple Bond Linker Enables “Click” Attachment of Peptides to Oligonucleotides on Solid Support Nucleic Acids Res. 2011, 39, 9047– 9059 DOI: 10.1093/nar/gkr603
    [Crossref], [PubMed], [CAS]
    116.
    An activated triple bond linker enables "click" attachment of peptides to oligonucleotides on solid support
    Wenska, Malgorzata; Alvira, Margarita; Steunenberg, Peter; Stenberg, Aasa; Murtola, Merita; Stroemberg, Roger
    Nucleic Acids Research (2011), 39 (20), 9047-9059CODEN: NARHAD; ISSN:0305-1048. (Oxford University Press)
    A general procedure, based on a new activated alkyne linker, for the prepn. of peptide-oligonucleotide conjugates (POCs) on solid support has been developed. With this linker, conjugation is effective at room temp. (RT) in millimolar concn. and submicromolar amts. This is made possible since the use of a readily attachable activated triple bond linker enhances the Cu(I) catalyzed 1,3-dipolar cycloaddn. (click reaction). The preferred scheme for conjugate prepn. involves sequential conjugation to oligonucleotides on solid support of (i) an H-phosphonate-based aminolinker; (ii) the triple bond donor p-(N-propynoylamino)toluic acid (PATA); and (iii) azido-functionalized peptides. The method gives conversion of oligonucleotide to the POC on solid support, and only involves a single purifn. step after complete assembly. The synthesis is flexible and can be carried out without the need for specific automated synthesizers since it has been designed to utilize com. available oligonucleotide and peptide derivs. on solid support or in soln. Methodol. for the ready conversion of peptides into "clickable" azidopeptides with the possibility of selecting either N-terminus or C-terminus connection also adds to the flexibility and usability of the method. Examples of synthesis of POCs include conjugates of oligonucleotides with peptides known to be membrane penetrating and nuclear localization signals.
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  117. 117.
    Schoffelen, S.; Meldal, M. Alkyne–Azide Reactions. In Modern Alkyne Chemsitry: Catalytic and Atom-Economic Transformations; Trost, B. M.; Li, C.-J., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA.: Weinheim, Germany, 2015; Vol. 1, pp 115– 142.
    There is no corresponding record for this reference.
  118. 118.
    Ötvös, S. B.; Georgiádes, Á.; Ádok-Sipiczki, M.; Mészáros, R.; Pálinkó, I.; Sipos, P.; Fülöp, F. A Layered Double Hydroxide, a Synthetically Useful Heterogeneous Catalyst for Azide–alkyne Cycloadditions in a Continuous-Flow Reactor Appl. Catal., A 2015, 501, 63– 73 DOI: 10.1016/j.apcata.2015.05.003
    [Crossref], [CAS]
    118.
    A layered double hydroxide, a synthetically useful heterogeneous catalyst for azide-alkyne cycloadditions in a continuous-flow reactor
    Otvos, Sandor B.; Georgiades, Adam; Adok-Sipiczki, Monika; Meszaros, Rebeka; Palinko, Istvan; Sipos, Pal; Fulop, Ferenc
    Applied Catalysis, A: General (2015), 501 (), 63-73CODEN: ACAGE4; ISSN:0926-860X. (Elsevier B.V.)
    A Cu(II)Fe(III)-layered double hydroxide is shown to efficiently catalyze 1,3-dipolar cycloaddns. of org. azides to alkynes leading to valuable 1,2,3-triazoles. The benefits of continuous processing were exploited for reaction optimization and synthesis, and the prodn. of triazoles was realized in an inherently safe and scalable manner. It was established that the catalytic activity of the as-prepd. material can be derived from in situ redn. of Cu(II), generating lattice defects contg. the catalytically active Cu(I) species. It was verified that oxidative homocoupling of the alkyne component was responsible for the conversion of Cu(II) to Cu(I), but a cooperation of certain structural items of the hydrotalcite-like material could also contribute to the outstanding catalytic efficiency. After a successful gram-scale triazole synthesis under high-pressure/high-temp. conditions, no destruction of the catalyst structure was found, suggesting that the layered double hydroxide acted as a highly robust catalytic system.
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  119. 119.
    Worrell, B. T.; Malik, J. A.; Fokin, V. V. Direct Evidence of a Dinuclear Copper Intermediate in Cu(I)-Catalyzed Azide-Alkyne Cycloadditions Science 2013, 340, 457– 460 DOI: 10.1126/science.1229506
    [Crossref], [PubMed], [CAS]
    119.
    Direct evidence of a dinuclear copper intermediate in Cu(I)-catalyzed azide-alkyne cycloadditions
    Worrell, B. T.; Malik, J. A.; Fokin, V. V.
    Science (Washington, DC, United States) (2013), 340 (6131), 457-460CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Copper(I)-catalyzed azide-alkyne cycloaddn. has become a commonly employed method for the synthesis of complex mol. architectures under challenging conditions. Despite the widespread use of copper-catalyzed cycloaddn. reactions, the mechanism of these processes has remained difficult to establish due to the involvement of multiple equil. between several reactive intermediates. Real-time monitoring of a representative cycloaddn. process via heat-flow reaction calorimetry revealed that monomeric copper acetylide complexes are not reactive toward org. azides unless an exogenous copper catalyst is added. Furthermore, crossover expts. with an isotopically enriched exogenous copper source illustrated the stepwise nature of the carbon-nitrogen bond-forming events and the equivalence of the two copper atoms within the cycloaddn. steps.
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  120. 120.
    Scriven, E. F.; Turnbull, K. Azides: Their Preparation and Synthetic Uses Chem. Rev. 1988, 88, 297– 368 DOI: 10.1021/cr00084a001
    [ACS Full Text ACS Full Text], [CAS]
    120.
    Azides: their preparation and synthetic uses
    Scriven, Eric F. V.; Turnbull, Kenneth
    Chemical Reviews (Washington, DC, United States) (1988), 88 (2), 297-368CODEN: CHREAY; ISSN:0009-2665.
    A review with 737 refs. A list of reviews that have appeared since 1970 on azides and related topics is included.
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  121. 121.
    Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Organic Azides: An Exploding Diversity of a Unique Class of Compounds Angew. Chem., Int. Ed. 2005, 44, 5188– 5240 DOI: 10.1002/anie.200400657
    [Crossref], [PubMed], [CAS]
    121.
    Organic azides. An exploding diversity of a unique class of compounds
    Brase, Stefan; Gil, Carmen; Knepper, Kerstin; Zimmermann, Viktor
    Angewandte Chemie, International Edition (2005), 44 (33), 5188-5240CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    A review. Since the discovery of org. azides by Peter Griess more than 140 years ago, numerous syntheses of these energy-rich mols. were developed. In more recent times in particular, completely new perspectives were developed for their use in peptide chem., combinatorial chem., and heterocyclic synthesis. Org. azides have assumed an important position at the interface between chem., biol., medicine, and materials science. In this Review, the fundamental characteristics of azide chem. and current developments are presented. The focus will be placed on cycloaddns. (Huisgen reaction), aza ylide chem., and the synthesis of heterocycles. Further reactions such as the aza-Wittig reaction, the Sundberg rearrangement, the Staudinger ligation, the Boyer and Boyer-Aube rearrangements, the Curtius rearrangement, the Schmidt rearrangement, and the Hemetsberger rearrangement bear witness to the versatility of modern azide chem.
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  122. 122.
    L'Abbé, G. Decomposition and Addition Reactions of Organic Azides Chem. Rev. 1969, 69, 345– 363 DOI: 10.1021/cr60259a004
    [ACS Full Text ACS Full Text], [CAS]
    122.
    Decomposition and addition reactions of organic azides
    L'abbe, G.
    Chemical Reviews (Washington, DC, United States) (1969), 69 (3), 345-63CODEN: CHREAY; ISSN:0009-2665.
    A review with 364 references. Decompn. reactions and addn. reactions are discussed. Subjects reviewed include nitrenes as intermediates, concerted mechanisms, acid catalysis, and 1,3-dipolar cycloaddns.
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  123. 123.
    Le Chevalier Isaad, A.; Barbetti, F.; Rovero, P.; D'Ursi, A. M.; Chelli, M.; Chorev, M.; Papini, A. M. N A -Fmoc-Protected Ω-Azido- and Ω-Alkynyl-L-Amino Acids as Building Blocks for the Synthesis of “Clickable” Peptides Eur. J. Org. Chem. 2008, 2008, 5308– 5314 DOI: 10.1002/ejoc.200800717
    [Crossref]
    There is no corresponding record for this reference.
  124. 124.
    Barral, K.; Moorhouse, A. D.; Moses, J. E. Efficient Conversion of Aromatic Amines into Azides: A One-Pot Synthesis of Triazole Linkages Org. Lett. 2007, 9, 1809– 1811 DOI: 10.1021/ol070527h
    [ACS Full Text ACS Full Text], [CAS]
    124.
    Efficient Conversion of Aromatic Amines into Azides: A One-Pot Synthesis of Triazole Linkages
    Barral, Karine; Moorhouse, Adam D.; Moses, John E.
    Organic Letters (2007), 9 (9), 1809-1811CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    An efficient and improved procedure for the prepn. of arom. azides and their application in the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddn. ("click reaction") is described. The synthesis of arom. azides from the corresponding amines is accomplished under mild conditions with tert-Bu nitrite and azidotrimethylsilane. 1,4-Disubstituted 1,2,3-triazoles, e.g., I, were obtained in excellent yields from a variety of arom. amines without the need for isolation of the azide intermediates.
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  125. 125.
    Alper, P. B.; Hung, S.-C.; Wong, C.-H. Metal Catalyzed Diazo Transfer for the Synthesis of Azides from Amines Tetrahedron Lett. 1996, 37, 6029– 6032 DOI: 10.1016/0040-4039(96)01307-X
    [Crossref], [CAS]
    125.
    Metal catalyzed diazo transfer for the synthesis of azides from amines
    Alper, Phil B.; Hung, Shang-Cheng; Wong, Chi-Huey
    Tetrahedron Letters (1996), 37 (34), 6029-6032CODEN: TELEAY; ISSN:0040-4039. (Elsevier)
    An improved method for the synthesis of azides is described. Diazo transfer from triflyl azide occurs effectively with Cu++, Ni++ or Zn++ as a catalyst. The process is amenable to scaleup, can be carried out using com. available reagents and does not require anhyd. conditions. When metals are scavenged from the reaction, the rate drops by many orders of magnitude.
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  126. 126.
    Yan, R.-B.; Yang, F.; Wu, Y.; Zhang, L.-H.; Ye, X.-S. An Efficient and Improved Procedure for Preparation of Triflyl Azide and Application in Catalytic Diazotransfer Reaction Tetrahedron Lett. 2005, 46, 8993– 8995 DOI: 10.1016/j.tetlet.2005.10.103
    [Crossref], [CAS]
    126.
    An efficient and improved procedure for preparation of triflyl azide and application in catalytic diazotransfer reaction
    Yan, Ri-Bai; Yang, Fan; Wu, Yanfen; Zhang, Li-He; Ye, Xin-Shan
    Tetrahedron Letters (2005), 46 (52), 8993-8995CODEN: TELEAY; ISSN:0040-4039. (Elsevier B.V.)
    An efficient and improved procedure for prepn. of triflyl azide and application in catalytic diazotransfer reaction are described. The amt. of highly toxic reagents NaN3 and Tf2O, is significantly reduced comparing with the previous protocol.
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  127. 127.
    Titz, A.; Radic, Z.; Schwardt, O.; Ernst, B. A Safe and Convenient Method for the Preparation of Triflyl Azide, and Its Use in Diazo Transfer Reactions to Primary Amines Tetrahedron Lett. 2006, 47, 2383– 2385 DOI: 10.1016/j.tetlet.2006.01.157
    [Crossref], [CAS]
    127.
    A safe and convenient method for the preparation of triflyl azide, and its use in diazo transfer reactions to primary amines
    Titz, Alexander; Radic, Zorana; Schwardt, Oliver; Ernst, Beat
    Tetrahedron Letters (2006), 47 (14), 2383-2385CODEN: TELEAY; ISSN:0040-4039. (Elsevier B.V.)
    A safe and convenient method for the copper(II)-catalyzed diazo transfer from triflyl azide to primary amines is reported. By replacing CH2Cl2 by toluene the formation of hazardous side products, for example, azido-chloromethane and diazidomethane can be avoided.
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  128. 128.
    Beckmann, H. S. G.; Wittmann, V. One-Pot Procedure for Diazo Transfer and Azide-Alkyne Cycloaddition: Triazole Linkages from Amines Org. Lett. 2007, 9, 1– 4 DOI: 10.1021/ol0621506
    [ACS Full Text ACS Full Text], [CAS]
    128.
    One-Pot Procedure for Diazo Transfer and Azide-Alkyne Cycloaddition: Triazole Linkages from Amines
    Beckmann, Henning S. G.; Wittmann, Valentin
    Organic Letters (2007), 9 (1), 1-4CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    A one-pot reaction for Cu(II)-catalyzed diazo transfer and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddn. (sometimes called click reaction) is reported. 1,4-Disubstituted 1,2,3-triazoles are obtained in excellent yields from a variety of readily available amines without the need for isolation of the azide intermediates. The reaction has a broad scope and is esp. practical for the synthesis of multivalent structures because compds. substituted with multiple azides are potentially unstable.
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  129. 129.
    Nyffeler, P. T.; Liang, C.-H.; Koeller, K. M.; Wong, C.-H. The Chemistry of Amine-Azide Interconversion: Catalytic Diazotransfer and Regioselective Azide Reduction J. Am. Chem. Soc. 2002, 124, 10773– 10778 DOI: 10.1021/ja0264605
    [ACS Full Text ACS Full Text], [CAS]
    129.
    The Chemistry of Amine-Azide Interconversion: Catalytic Diazo transfer and Regioselective Azide Reduction
    Nyffeler, Paul T.; Liang, Chang-Hsing; Koeller, Kathryn M.; Wong, Chi-Huey
    Journal of the American Chemical Society (2002), 124 (36), 10773-10778CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Azides have proven to be useful precursors to amines in org. syntheses. This report describes an improvement of the diazo transfer reaction and the first example of a regioselective azide redn. of compds. contg. multiple azides. The use of a specific ratio of solvents and zinc chloride as a catalyst resulted in a more efficient diazo transfer reaction capable of delivering >90% conversion per amine with shorter reaction times than those previously reported. Azides can be reduced with good regioselectivity in moderate yields by a modification of the Staudinger reaction using trimethylphosphine at low temps. Electronic factors det. the selectivity for azide redn., and the reaction is predictable by NMR anal. of the starting material. Several examples for the diazo transfer and regioselective azide redn. reactions are given, and a mechanistic hypothesis for both is proposed.
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  130. 130.
    Zaragoza, F.; Petersen, S. V. Solid-Phase Synthesis of Substituted 1,2,3-Triazoles Tetrahedron 1996, 52, 10823– 10826 DOI: 10.1016/0040-4020(96)00603-5
    [Crossref], [CAS]
    130.
    Solid-phase synthesis of substituted 1,2,3-triazoles
    Zaragoza, Florencio; Petersen, Susanne Vejle
    Tetrahedron (1996), 52 (32), 10823-10826CODEN: TETRAB; ISSN:0040-4020. (Elsevier)
    Diversely substituted 1,2,3-triazoles I (R = CH2CO2CH2Ph, 4-MeOC6H4CH2, CH2CH2C6H4NO2-4) have been synthesized on a solid support. A resin-bound 3-oxobutyramide could be effectively condensed with primary aliph. amines RNH2. The resulting 3-amino-2-butenoic acid amides were then cyclized by treatment with tosyl azide in the presence of a tertiary amine. Acidolytic cleavage from the support yielded the corresponding 1,2,3-triazoles in purities up to 82% (HPLC).
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  131. 131.
    Katritzky, A. R.; El Khatib, M.; Bol’shakov, O.; Khelashvili, L.; Steel, P. J. Benzotriazol-1-Yl-Sulfonyl Azide for Diazotransfer and Preparation of Azidoacylbenzotriazoles J. Org. Chem. 2010, 75, 6532– 6539 DOI: 10.1021/jo101296s
    [ACS Full Text ACS Full Text], [CAS]
    131.
    Benzotriazol-1-yl-sulfonyl Azide for Diazotransfer and Preparation of Azidoacylbenzotriazoles
    Katritzky, Alan R.; El Khatib, Mirna; Bol'shakov, Oleg; Khelashvili, Levan; Steel, Peter J.
    Journal of Organic Chemistry (2010), 75 (19), 6532-6539CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Benzotriazol-1-yl-sulfonyl azide BtSO2N3 (Bt = 1,2,3-benzotriazol-1-yl) was synthesized and found to be a new cryst., stable, and easily available diazo-transfer reagent for converting various primary amines R1NH2 (R1 = 4-MeOC6H4, 3-pyridyl, PhCH2CH2, etc.) and N-unsubstituted amino acids, e.g. L-H2NCHR2CO2H (R2 = Me, i-Pr, i-Bu, PhCH2), to the corresponding azides R1N3 and α-azido carboxylic acids, e.g. (S)-N3CHR2CO2H, resp. On treatment with SOCl2 and 1H-benzotriazole, the latter gave N-(α-azidoacyl)benzotriazoles, e.g. (S)-N3CHR2COBt, which readily underwent benzotriazole substitution reactions with various N-, O-, C- and S-nucleophiles to afford a wide variety of azido-substituted amides, peptides, esters, ketones, and thioesters.
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  132. 132.
    Laus, G.; Adamer, V.; Hummel, M.; Kahlenberg, V.; Wurst, K.; Nerdinger, S.; Schottenberger, H. Crystal Structure of 2-Ethylimidazole-1-Sulfonyl Azide: A New Azidation Reagent Crystals 2012, 2, 118– 126 DOI: 10.3390/cryst2010118
    [Crossref], [CAS]
    132.
    Crystal structure of 2-ethylimidazole-1-sulfonyl azide: a new azidation reagent
    Laus, Gerhard; Adamer, Verena; Hummel, Michael; Kahlenberg, Volker; Wurst, Klaus; Nerdinger, Sven; Schottenberger, Herwig
    Crystals (2012), 2 (), 118-126CODEN: CRYSBC; ISSN:2073-4352. (MDPI AG)
    Cryst. 2-ethylimidazole-1-sulfonyl azide was designed as a convenient reagent with improved thermal stability for electrophilic azidation of carbanions. The compd. crystd. in the monoclinic space group P21/c. Crystallog. data are given. The mols. are arranged into chains by short C-H···O contacts along a 2-fold screw axis. The quaternary 1-azidosulfonyl-2-methyl-3-ethylimidazolium tetrafluoroborate crystd. in Fdd2 with two independent ion pairs which engage in C-H···F interactions.
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  133. 133.
    Goddard-Borger, E. D.; Stick, R. V. An Efficient, Inexpensive, and Shelf-Stable Diazotransfer Reagent: Imidazole-1-Sulfonyl Azide Hydrochloride Org. Lett. 2007, 9, 3797– 3800 DOI: 10.1021/ol701581g
    [ACS Full Text ACS Full Text], [CAS]
    133.
    An Efficient, Inexpensive, and Shelf-Stable Diazotransfer Reagent: Imidazole-1-sulfonyl Azide Hydrochloride
    Goddard-Borger, Ethan D.; Stick, Robert V.
    Organic Letters (2007), 9 (19), 3797-3800CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    The design and synthesis of a new diazotransfer reagent, imidazole-1-sulfonyl azide hydrochloride, are reported. This reagent has proven to equal triflyl azide in its ability to act as a "diazo donor" in the conversion of both primary amines into azides and activated methylene substrates into diazo compds. Crucially, this reagent can be prepd. in a one-pot reaction on a large scale from inexpensive materials, is shelf-stable, and is conveniently cryst.
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  134. 134.
    Fischer, N.; Goddard-Borger, E. D.; Greiner, R.; Klapötke, T. M.; Skelton, B. W.; Stierstorfer, J. Sensitivities of Some Imidazole-1-Sulfonyl Azide Salts J. Org. Chem. 2012, 77, 1760– 1764 DOI: 10.1021/jo202264r
    [ACS Full Text ACS Full Text], [CAS]
    134.
    Sensitivities of Some Imidazole-1-sulfonyl Azide Salts
    Fischer, Niko; Goddard-Borger, Ethan D.; Greiner, Robert; Klapoetke, Thomas M.; Skelton, Brian W.; Stierstorfer, Joerg
    Journal of Organic Chemistry (2012), 77 (4), 1760-1764CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    Imidazole-1-sulfonyl azide hydrochloride, an inexpensive and effective diazo transfer reagent, was recently found to be impact sensitive. To identify safer-to-handle forms of this reagent, several different salts of imidazole-1-sulfonyl azide were prepd., and their sensitivity to heat, impact, friction, and electrostatic discharge was quant. detd. A no. of these salts exhibited improved properties and can be considered safer than the aforementioned hydrochloride. The solid-state structures of the chloride and less sensitive hydrogen sulfate were detd. by single-crystal x-ray diffraction in an effort to provide some insight into the different properties of the materials.
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  135. 135.
    Ye, H.; Liu, R.; Li, D.; Liu, Y.; Yuan, H.; Guo, W.; Zhou, L.; Cao, X.; Tian, H.; Shen, J.; Wang, P. G. A Safe and Facile Route to Imidazole-1-Sulfonyl Azide as a Diazotransfer Reagent Org. Lett. 2013, 15, 18– 21 DOI: 10.1021/ol3028708
    [ACS Full Text ACS Full Text], [CAS]
    135.
    A Safe and Facile Route to Imidazole-1-sulfonyl Azide as a Diazotransfer Reagent
    Ye, Hui; Liu, Ruihua; Li, Dongmei; Liu, Yonghui; Yuan, Haixin; Guo, Weikang; Zhou, Lifei; Cao, Xuefeng; Tian, Hongqi; Shen, Jie; Wang, Peng George
    Organic Letters (2013), 15 (1), 18-21CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A facile approach to the diazo-transfer reagent of imidazole-1-sulfonyl azide was reported. The procedure was well optimized to clarify potential explosion risks. A high prodn. yield as well as small batch variation was achieved even without careful pretreatment of reagents and solvents. HPLC and NMR methods to monitor the process were provided. These features made this protocol suitable for large scale prepn. in academia and industry as well.
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  136. 136.
    Van Dongen, S. F. M.; Teeuwen, R. L. M.; Nallani, M.; van Berkel, S. S.; Cornelissen, J. J. L. M.; Nolte, R. J. M.; van Hest, J. C. M. Single-Step Azide Introduction in Proteins via an Aqueous Diazo Transfer Bioconjugate Chem. 2009, 20, 20– 23 DOI: 10.1021/bc8004304
    [ACS Full Text ACS Full Text], [CAS]
    136.
    Single-Step Azide Introduction in Proteins via an Aqueous Diazo Transfer
    van Dongen, Stijn F. M.; Teeuwen, Rosalie L. M.; Nallani, Madhavan; van Berkel, Sander S.; Cornelissen, Jeroen J. L. M.; Nolte, Roeland J. M.; van Hest, Jan C. M.
    Bioconjugate Chemistry (2009), 20 (1), 20-23CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    The controlled introduction of azides in proteins provides targetable handles for selective protein manipulation. The authors present here an efficient diazo transfer protocol that can be applied in an aq. soln., leading to the facile introduction of azides in the side chains of lysine residues and at the N-terminus of enzymes, e.g. horseradish peroxidase (HRP) and the red fluorescent protein DsRed. The effective introduction of azides was verified by mass spectrometry, after which the azido-proteins were used in Cu(I)-catalyzed [3+2] cycloaddn. reactions. Azido-HRP retained its catalytic activity after conjugation of a small mol. This modified protein could also be successfully immobilized on the surface of an acetylene-covered polymersome. Azido-DsRed was coupled to an acetylene-bearing protein allowing it to act as a fluorescent label, demonstrating the wide applicability of the diazo transfer procedure.
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  137. 137.
    Lartia, R.; Murat, P.; Dumy, P.; Defrancq, E. Versatile Introduction of Azido Moiety into Oligonucleotides through Diazo Transfer Reaction Org. Lett. 2011, 13, 5672– 5675 DOI: 10.1021/ol202397e
    [ACS Full Text ACS Full Text], [CAS]
    137.
    Versatile Introduction of Azido Moiety into Oligonucleotides through Diazo Transfer Reaction
    Lartia, Remy; Murat, Pierre; Dumy, Pascal; Defrancq, Eric
    Organic Letters (2011), 13 (20), 5672-5675CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    The use of a diazo transfer (DZT) reagent enables clean and efficient conversion of amino oligodeoxyribonucleotides (ODNs) into their azido counterparts under mild conditions. ODNs bearing an amino tether at the 3', 5', or any internal position could be modified in this manner thus demonstrating the versatility of this reaction. Easy access to such azido-modified ODNs is of great interest for conjugation in particular through click' copper catalyzed 1,3-dipolar cycloaddn. (CuAAC reaction).
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  138. 138.
    Bastian, A. A.; Warszawik, E. M.; Panduru, P.; Arenz, C.; Herrmann, A. Regioselective Diazo-Transfer Reaction at the C3-Position of the 2-Desoxystreptamine Ring of Neamine Antibiotics Chem. - Eur. J. 2013, 19, 9151– 9154 DOI: 10.1002/chem.201300912
    [Crossref], [PubMed], [CAS]
    138.
    Regioselective Diazo-Transfer Reaction at the C3-Position of the 2-Desoxystreptamine Ring of Neamine Antibiotics
    Bastian, Andreas A.; Warszawik, Eliza M.; Panduru, Praveen; Arenz, Christoph; Herrmann, Andreas
    Chemistry - A European Journal (2013), 19 (28), 9151-9154CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Imidazole-1-sulfonyl azide 7 was successfully used as a diazo-transfer reagent for regioselective azide introduction in neamine antibiotics avoiding any protective group strategy. The authors demonstrated that the reactivity of the amino groups within this class of antibiotics can be controlled by pH and addn. of catalyst. Key to the single specific transformation of the amino group at the C-3 position of the 2-desoxystreptamine ring is its low pKa value. The resulting regioselectivity for six different neamine antibiotics reached up to 98%. In addn., regioselective azide introduction for neomycin B was done at gram scale.
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  139. 139.
    Johansson, H.; Pedersen, D. S. Azide- and Alkyne-Derivatised A-Amino Acids Eur. J. Org. Chem. 2012, 2012, 4267– 4281 DOI: 10.1002/ejoc.201200496
    [Crossref], [CAS]
    139.
    Azide- and Alkyne-Derivatised α-Amino Acids (Eur. J. Org. Chem. 23/2012)
    Johansson, Henrik; Pedersen, Daniel Sejer
    European Journal of Organic Chemistry (2012), 2012 (23), 4267-4281CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The cover picture shows a small selection of optically active azide- and alkyne-derivatised α-amino acids. Following the discovery of the copper-catalyzed azide alkyne cycloaddn. (CuAAC) reaction, azide- and alkyne-derivatised α-amino acids are finding an ever increasing no. of applications in all areas of chem. Herein, we describe currently available methods, shortcomings and future prospects for the synthesis of these useful amino acid derived building blocks that permits chemists to construct complex structures from simple beginnings; the sky is the limit. Details are presented in the Microreview by H. Johansson and D. Pedersen on p. 4267 ff. We are grateful to Pablo Bronstein (Bronstein.studio) for creating the cover picture.
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  140. 140.
    Bowen, J. L.; Kelly, M. A.; Gumbleton, M.; Davies, P. R.; Allender, C. J. A Simple Zero Length Surface-Modification Approach for Preparing Novel Bifunctional Supports for Co-Immobilisation Studies Tetrahedron Lett. 2012, 53, 3727– 3730 DOI: 10.1016/j.tetlet.2012.04.116
    [Crossref], [CAS]
    140.
    A simple zero length surface-modification approach for preparing novel bifunctional supports for co-immobilisation studies
    Bowen, Jenna L.; Kelly, Marc A.; Gumbleton, Mark; Davies, Philip R.; Allender, Chris J.
    Tetrahedron Letters (2012), 53 (29), 3727-3730CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    A straightforward method of creating a bifunctional support possessing pre-defined ratios of amine and chloromethyl groups based upon a controlled conversion of std. Merrifield resin is presented. It avoids the extensive optimization of reactant concns. and reaction conditions required by existing methods. Furthermore, it avoids increases in the spacer/linker length that lead to detrimental redns. in the rigidity of the grafted layer. The method will allow for efficient, predictable and reproducible co-immobilization of mol. species.
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  141. 141.
    Lundquist, J. T.; Pelletier, J. C. Improved Solid-Phase Peptide Synthesis Method Utilizing Alpha-Azide-Protected Amino Acids Org. Lett. 2001, 3, 781– 783 DOI: 10.1021/ol0155485
    [ACS Full Text ACS Full Text], [CAS]
    141.
    Improved solid-phase peptide synthesis method utilizing α-azide-protected amino acids
    Lundquist, Joseph T., IV; Pelletier, Jeffrey C.
    Organic Letters (2001), 3 (5), 781-783CODEN: ORLEF7; ISSN:1523-7060. (American Chemical Society)
    Pure α-azido acids were prepd. using an efficient diazo transfer method followed by buffered workup. These building blocks were used to prep. small peptides on Wang resin by two approaches. Peptides prone to diketopiperazine formation were prepd. in good yields by coupling acids to resin bound iminophosphoranes during Fmoc-Wang synthesis. The iminophosphoranes can also be hydrolyzed under neutral conditions to provide unprotected amines ready for further coupling.
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  142. 142.
    Rijkers, D. T. S.; van Vugt, H. H. R.; Jacobs, H. J. F.; Liskamp, R. M. J. A Convenient Synthesis of Azido Peptides by Post-Assembly Diazo Transfer on the Solid Phase Applicable to Large Peptides Tetrahedron Lett. 2002, 43, 3657– 3660 DOI: 10.1016/S0040-4039(02)00629-9
    [Crossref], [CAS]
    142.
    A convenient synthesis of azido peptides by post-assembly diazo transfer on the solid phase applicable to large peptides
    Rijkers, Dirk T. S.; van Vugt, H. H. Ricardo; Jacobs, Hans J. F.; Liskamp, Rob M. J.
    Tetrahedron Letters (2002), 43 (20), 3657-3660CODEN: TELEAY; ISSN:0040-4039. (Elsevier Science Ltd.)
    An efficient method for the conversion of solid phase bound peptide amines into azides by a diazo transfer using triflyl azide in the presence of divalent copper ions is described. α-Azido acids and azido peptides (up to 30 amino acids in length) are obtained in good yields and high purities after cleavage from the solid support.
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  143. 143.
    Hansen, M. B.; van Gurp, T. H. M.; van Hest, J. C. M.; Löwik, D. W. P. M. Simple and Efficient Solid-Phase Preparation of Azido-Peptides Org. Lett. 2012, 14, 2330– 2333 DOI: 10.1021/ol300740g
    [ACS Full Text ACS Full Text], [CAS]
    143.
    Simple and efficient solid-phase preparation of azido-peptides
    Hansen, Morten B.; van Gurp, Theodorus H. M.; van Hest, Jan C. M.; Loewik, Dennis W. P. M.
    Organic Letters (2012), 14 (9), 2330-2333CODEN: ORLEF7; ISSN:1523-7052. (American Chemical Society)
    A shelf-stable and easily prepd. diazotransfer reagent, imidazole-1-sulfonyl azide hydrochloride, was used to transform the N-terminus of a model peptide on solid phase into an azide moiety. It is demonstrated that this conversion was accomplished within 30 min with high efficiency under aq. conditions on a NovaPEG resin or in DMF on polystyrene beads.
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  144. 144.
    Vlieghe, P.; Lisowski, V.; Martinez, J.; Khrestchatisky, M. Synthetic Therapeutic Peptides: Science and Market Drug Discovery Today 2010, 15, 40– 56 DOI: 10.1016/j.drudis.2009.10.009
    [Crossref], [PubMed], [CAS]
    144.
    Synthetic therapeutic peptides: science and market
    Vlieghe, Patrick; Lisowski, Vincent; Martinez, Jean; Khrestchatisky, Michel
    Drug Discovery Today (2010), 15 (1/2), 40-56CODEN: DDTOFS; ISSN:1359-6446. (Elsevier B.V.)
    A review. The decreasing no. of approved drugs produced by the pharmaceutical industry, which has been accompanied by increasing expenses for R&D, demands alternative approaches to increase pharmaceutical R&D productivity. This situation has contributed to a revival of interest in peptides as potential drug candidates. New synthetic strategies for limiting metab. and alternative routes of administration have emerged in recent years and resulted in a large no. of peptide-based drugs that are now being marketed. This review reports on the unexpected and considerable no. of peptides that are currently available as drugs and the chem. strategies that were used to bring them into the market. As demonstrated here, peptide-based drug discovery could be a serious option for addressing new therapeutic challenges.
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  145. 145.
    Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Mechanism of the Ligand-Free CuI-Catalyzed Azide-Alkyne Cycloaddition Reaction Angew. Chem., Int. Ed. 2005, 44, 2210– 2215 DOI: 10.1002/anie.200461496
    [Crossref], [PubMed], [CAS]
    145.
    Mechanism of the ligand-free CuI-catalyzed azide-alkyne cycloaddition reaction
    Rodionov, Valentin O.; Fokin, Valery V.; Finn, M. G.
    Angewandte Chemie, International Edition (2005), 44 (15), 2210-2215CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The Cu-catalyzed azide-alkyne cycloaddn. depends on rapid formation of CuI-acetylide complexes from terminal alkynes and their ability to activate org. azides. A kinetics study uncovered a bimol. dependence on the metal and an unusually fast intramol. variant of the process.
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  146. 146.
    Proteau-Gagné, A.; Rochon, K.; Roy, M.; Albert, P.-J.; Guérin, B.; Gendron, L.; Dory, Y. L. Systematic Replacement of Amides by 1,4-disubstituted[1,2,3]triazoles in Leu-Enkephalin and the Impact on the Delta Opioid Receptor Activity Bioorg. Med. Chem. Lett. 2013, 23, 5267– 5269 DOI: 10.1016/j.bmcl.2013.08.020
    [Crossref], [PubMed], [CAS]
    146.
    Systematic replacement of amides by 1,4-disubstituted[1,2,3]triazoles in Leu-enkephalin and the impact on the delta opioid receptor activity
    Proteau-Gagne, Arnaud; Rochon, Kristina; Roy, Melissa; Albert, Pierre-Julien; Guerin, Brigitte; Gendron, Louis; Dory, Yves L.
    Bioorganic & Medicinal Chemistry Letters (2013), 23 (19), 5267-5269CODEN: BMCLE8; ISSN:0960-894X. (Elsevier B.V.)
    Using Cu(I)-catalyzed azide-alkyne cycloaddn. in a mixed classical org. phase and solid phase peptide synthesis approach, we synthesized four analogs of Leu-enkephalin to systematically replace amides by 1,4-disubstituted[1,2,3]triazoles. The peptidomimetics obtained were characterized by competitive binding, contractility assays and ERK1/2 phosphorylation. The present study reveals that the analog bearing a triazole between Phe and Leu retains some potency, more than all the others, suggesting that the hydrogen bond acceptor capacity of the last amide of Leu-enkephalin is essential for the biol. activity of the peptide.
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  147. 147.
    Hausner, S. H.; Marik, J.; Gagnon, M. K. J.; Sutcliffe, J. L. In Vivo Positron Emission Tomography (PET) Imaging with an Alpha v Beta 6 Specific Peptide Radiolabeled Using 18F-“Click” Chemistry: Evaluation and Comparison with the Corresponding 4-[18F]fluorobenzoyl- and 2-[18F]fluoropropionyl-Peptides J. Med. Chem. 2008, 51, 5901– 5904 DOI: 10.1021/jm800608s
    [ACS Full Text ACS Full Text], [CAS]
    147.
    In Vivo Positron Emission Tomography (PET) Imaging with an αvβ6 Specific Peptide Radiolabeled using 18F-"Click" Chemistry: Evaluation and Comparison with the Corresponding 4-[18F]Fluorobenzoyl- and 2-[18F]Fluoropropionyl-Peptides
    Hausner, Sven H.; Marik, Jan; Gagnon, M. Karen J.; Sutcliffe, Julie L.
    Journal of Medicinal Chemistry (2008), 51 (19), 5901-5904CODEN: JMCMAR; ISSN:0022-2623. (American Chemical Society)
    Numerous radiolabeled peptides have been utilized for in vivo imaging of a variety of cell surface receptors. For applications in PET using [18F]fluorine, peptides are radiolabeled via a prosthetic group approach. We previously developed soln.-phase 18F-"click" radiolabeling and solid-phase radiolabeling using 4-[18F]fluorobenzoic and 2-[18F]fluoropropionic acids. Here we compare the three different radiolabeling approaches and report the effects on PET imaging and pharmacokinetics. The prosthetic groups did have an effect; metabolites with significantly different polarities were obsd.
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  148. 148.
    Norgren, A.; Budke, C.; Majer, Z.; Heggemann, C.; Koop, T.; Sewald, N. On-Resin Click-Glycoconjugation of Peptoids Synthesis 2009, 3, 488– 494 DOI: 10.1055/s-0028-1083302
    [Crossref]
    There is no corresponding record for this reference.
  149. 149.
    Rechenmacher, F.; Neubauer, S.; Mas-Moruno, C.; Dorfner, P. M.; Polleux, J.; Guasch, J.; Conings, B.; Boyen, H.-G.; Bochen, A.; Sobahi, T. R.; Burgkart, R.; Spatz, J. P.; Fässler, R.; Kessler, H. A Molecular Toolkit for the Functionalization of Titanium-Based Biomaterials That Selectively Control Integrin-Mediated Cell Adhesion Chem. - Eur. J. 2013, 19, 9218– 9223 DOI: 10.1002/chem.201301478
    [Crossref], [PubMed], [CAS]
    149.
    A Molecular Toolkit for the Functionalization of Titanium-Based Biomaterials That Selectively Control Integrin-Mediated Cell Adhesion
    Rechenmacher, Florian; Neubauer, Stefanie; Mas-Moruno, Carlos; Dorfner, Petra M.; Polleux, Julien; Guasch, Judith; Conings, Bert; Boyen, Hans-Gerd; Bochen, Alexander; Sobahi, Tariq R.; Burgkart, Rainer; Spatz, Joachim P.; Faessler, Reinhard; Kessler, Horst
    Chemistry - A European Journal (2013), 19 (28), 9218-9223CODEN: CEUJED; ISSN:0947-6539. (Wiley-VCH Verlag GmbH & Co. KGaA)
    We present a click chem.-based mol. toolkit for the biofunctionalization of materials to selectively control integrin-mediated cell adhesion. To this end, α5β1-selective RGD peptidomimetics were covalently immobilized on Ti-based materials, and the capacity to promote the selective binding of α5β1 was evaluated using a solid-phase integrin binding assay. This functionalization strategy yielded surfaces with a nine-fold increased affinity for α5β1, in comparison to control samples, and total selectivity against the binding of the closely related integrin αvβ3. Moreover, our methodol. allowed the screening of several phosphonic acid contg. anchoring units to find the best spacer-anchor moiety required for establishing an efficient binding to titanium and to promote selective integrin binding. The integrin subtype specificity of these biofunctionalized surfaces was further examd. in vitro by inducing selective adhesion of genetically modified fibroblasts, which express exclusively the α5β1 integrin. The versatility of our mol. toolkit was proven by shifting the cellular specificity of the materials from α5β1- to αvβ3-expressing fibroblasts by using an αvβ3-selective peptidomimetic as coating mol. The results shown here represent the first functionalization of Ti-based materials with α5β1- or αvβ3-selective peptidomimetics that allow an unprecedented control to discriminate between α5β1- and αvβ3-mediated adhesions. The role of these two integrins in different biol. events is still a matter of debate and is frequently discussed in literature. Thus, such bioactive titanium surfaces will be of great relevance for the study of integrin-mediated cell adhesion and the development of new biomaterials targeting specific cell types.
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  150. 150.
    Liu, Y.; Zhang, L.; Wan, J.; Li, Y.; Xu, Y.; Pan, Y. Design and Synthesis of Cyclo[-Arg-Gly-Asp-Ψ(triazole)-Gly-Xaa-] Peptide Analogues by Click Chemistry Tetrahedron 2008, 64, 10728– 10734 DOI: 10.1016/j.tet.2008.08.090
    [Crossref], [CAS]
    150.
    Design and synthesis of cyclo[-Arg-Gly-Asp-ψ(triazole)-Gly-Xaa-] peptide analogues by click chemistry
    Liu, Yaqin; Zhang, Lihui; Wan, Jieping; Li, Yesen; Xu, Yuhong; Pan, Yuanjiang
    Tetrahedron (2008), 64 (47), 10728-10734CODEN: TETRAB; ISSN:0040-4020. (Elsevier Ltd.)
    A simple and mild synthesis of a new family of cyclopeptide analogs cyclo[-Arg-Gly-Asp-ψ(triazole)-Gly-Xaa-] (Xaa = Gly, Ala, Leu, Ile, Cys, Met, Asp, Asn, Glu, Lys, Arg, His, Phe, Trp, Pro, GlyGly, nonexistant) that is obtained by cyclization with click chem. was investigated. In addn., the method was also successfully expanded to the synthesis of their analogs of different ring sizes. The result supports the potential utility of click chem. in the prepn. of novel integrin domain-binding antagonists and other cyclopeptide analogs.
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  151. 151.
    Schweinsberg, C.; Maes, V.; Brans, L.; Blauenstein, P.; Tourwe, D. A.; Schubiger, P. A.; Schibli, R.; Garayoa, E. G. Novel Glycated [99mTc(CO)3]-Labeled Bombesin Analogues for Improved Targeting of Gastrin-Releasing Peptide Receptor-Positive Tumors Bioconjugate Chem. 2008, 19, 2432– 2439 DOI: 10.1021/bc800319g
    [ACS Full Text ACS Full Text], [CAS]
    151.
    Novel Glycated [99mTc(CO)3]-Labeled Bombesin Analogues for Improved Targeting of Gastrin-Releasing Peptide Receptor-Positive Tumors
    Schweinsberg, Christian; Maes, Veronique; Brans, Luc; Blauenstein, Peter; Tourwe, Dirk A.; Schubiger, P. August; Schibli, Roger; Garayoa, Elisa Garcia
    Bioconjugate Chemistry (2008), 19 (12), 2432-2439CODEN: BCCHES; ISSN:1043-1802. (American Chemical Society)
    Radiolabeled bombesin (BBS) analogs are promising pharmaceuticals for imaging of cancer cells expressing gastrin-releasing peptide receptors (GRPR). However, most of the radiolabeled BBS derivs. show a high accumulation of activity in the liver and a strong hepatobiliary excretion, both unfavorable for imaging and therapy of abdominal lesions. For this reason, we introduced hydrophilic carbohydrated linker moieties into our BBS analogs to reduce the abdominal accumulation and to improve the tumor-to-background ratios. A stabilized BBS(7-14) sequence bearing the (NαHis)Ac-chelator was modified with amino acid linkers contg. a lysine or propargylglycine residue. The .vepsiln.-amino group of a lysine was either coupled to shikimic acid or reacted with glucose to form the Amadori conjugate. Alternatively, a glucose was attached to the peptide via "click" chem. with the propargylglycine side chain. The peptides were synthesized on Rink amide resin using solid-phase peptide synthesis and labeled with 99mTc using the tricarbonyl technique. Binding and degrdn. were tested in vitro in GRPR-expressing PC-3 cells. Biodistribution and SPECT/CT imaging studies were performed in nude mice bearing PC-3 tumor xenografts. The new peptides showed a log D between -0.2 and -0.5 and kept the high affinity for GRPR with Kd values of <0.5 nM. In vitro, they were rapidly internalized into the tumor cells and showed an increased cellular retention and stability (t1/2 > 35 min). In vivo, all new compds. exhibited higher tumor-to-background ratios compared to the nonglycated ref. Thus, the best results were obtained with the triazole coupled glucose with a 4-fold increased uptake and retention in tumor tissue (3.6 and 2.5%ID/g at 1.5 h and 5 h p.i, resp.) and a significantly reduced accumulation in the liver (0.6 vs 2.4%ID/g, 1.5 h p.i., resp.). Apart from higher tumor-to-liver ratios (17-fold, 1.5 h p.i.), both tumor-to-kidney and tumor-to-blood ratios could be significantly improved by a factor of 1.5 and 2.7, resp. (1.5 h p.i., P < 0.05). The imaging studies proved the redn. of abdominal background, and tumor xenografts could clearly be visualized. In conclusion, the introduction of a carbohydrated linker substantially improved the biodistribution properties of BBS analogs labeled with the 99mTc-tricarbonyl core.
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  152. 152.
    Liu, T.; Qian, Z.; Xiao, Q.; Pei, D. High-Throughput Screening of One-Bead-One-Compound Libraries: Identification of Cyclic Peptidyl Inhibitors against calcineurin/NFAT Interaction ACS Comb. Sci. 2011, 13, 537– 546 DOI: 10.1021/co200101w
    [ACS Full Text ACS Full Text], [CAS]
    152.
    High-Throughput Screening of One-Bead-One-Compound Libraries: Identification of Cyclic Peptidyl Inhibitors against Calcineurin/NFAT Interaction
    Liu, Tao; Qian, Ziqing; Xiao, Qing; Pei, Dehua
    ACS Combinatorial Science (2011), 13 (5), 537-546CODEN: ACSCCC; ISSN:2156-8944. (American Chemical Society)
    One-bead-one-compd. (OBOC) libraries provide a powerful tool for drug discovery as well as biomedical research. However, screening a large no. of beads/compds. (>1 million) and rank ordering the initial hits (which are covalently attached to a solid support) according to their potencies still pose significant tech. challenges. In this work, we have integrated some of the latest tech. advances from our own as well as other labs. to develop a general methodol. for rapidly screening large OBOC libraries. The methodol. has been applied to synthesize and screen a cyclic peptide library that features: (1) spatially segregated beads contg. cyclic peptides on the surface layer and linear encoding peptides in their interior; (2) rapid on-bead screening of the library (>1 million) by a multistage procedure (magnetic bead sorting, enzyme-linked assay, and fluorescence based screening); (3) selective release of cyclic peptides from single pos. beads for soln.-phase detn. of their binding affinities; and (4) hit identification by partial Edman degrdn./mass spectrometry (PED/MS). Screening of the library against protein phosphatase calcineurin (Cn) identified a series of cyclic peptides that bind to the substrate-docking site for nuclear factor of activated T cells (NFAT) with KD values of ∼1 μM. Further improvement of the affinity and specificity of these compds. may lead to a new class of immunosuppressive agents that are more selective and therefore less toxic than cyclosporine A and FK506.
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  153. 153.
    Lee, S. S.; Lim, J.; Cha, J. Peptide Libraries for Screening and Other Applications. Patent WO 2012/026887, 2012.
    There is no corresponding record for this reference.
  154. 154.
    Aucagne, V.; Valverde, I. E.; Marceau, P.; Galibert, M.; Dendane, N.; Delmas, A. F. Towards the Simplification of Protein Synthesis: Iterative Solid-Supported Ligations with Concomitant Purifications Angew. Chem., Int. Ed. 2012, 51, 11320– 11324 DOI: 10.1002/anie.201206428
    [Crossref], [PubMed], [CAS]
    154.
    Towards the Simplification of Protein Synthesis: Iterative Solid-Supported Ligations with Concomitant Purifications
    Aucagne, Vincent; Valverde, Ibai E.; Marceau, Philippe; Galibert, Mathieu; Dendane, Nabil; Delmas, Agnes F.
    Angewandte Chemie, International Edition (2012), 51 (45), 11320-11324CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The authors introduced N3-Esoc-ONp 1 as a new reagent for the contemporary tagging of peptides at their N-terminus and demonstrated its potential in capture/release purifications. The authors extended this concept to a promising self-purifying N-to-C iterative triazole ligation strategy, exemplified by the synthesis of a polypeptide contg. 160 residues. Solid-phase coupling of four peptide segments led to high purity material without any chromatog. purifn. steps.
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  155. 155.
    Hüttl, C.; Hettrich, C.; Riedel, M.; Henklein, P.; Rawel, H.; Bier, F. F. Development of Peptidyl Lysine Dendrons: 1,3-Dipolar Cycloaddition for Peptide Coupling and Antibody Recognition Chem. Biol. Drug Des. 2015, 85, 565– 573 DOI: 10.1111/cbdd.12444
    [Crossref], [PubMed], [CAS]
    155.
    Development of Peptidyl Lysine Dendrons: 1,3-Dipolar Cycloaddition for Peptide Coupling and Antibody Recognition
    Huettl, Christine; Hettrich, Cornelia; Riedel, Melanie; Henklein, Petra; Rawel, Harshadrai; Bier, Frank F.
    Chemical Biology & Drug Design (2015), 85 (5), 565-573CODEN: CBDDAL; ISSN:1747-0277. (Wiley-Blackwell)
    A straightforward synthesis strategy to multimerize a peptide mimotopes for antibody B13-DE1 recognition is described based on lysine dendrons as multivalent scaffolds. Lysine dendrons that possess N-terminal alkyne residues at the periphery were quant. functionalized with azido peptides using click chem. The solid-phase peptide synthesis (SPPS) allows prepg. the peptide dendron in high purity and establishing the possibility of automation. The presented peptide dendron is a promising candidate as multivalent ligand and was used for antibody B13-DE1 recognition. The binding affinity increases with higher dendron generation without loss of specificity. The anal. of biospecific interaction between the synthesized peptide dendron and the antibody was done via surface plasmon resonance (SPR) technique. The presented results show a promising tool for investigations of antigen-antibody reactions.
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  156. 156.
    He, A.; Sheng, S.; Huang, Z.; Liu, L.; Cai, M. Solid-Phase Organic Synthesis of 1, 4- N -Vinyl- and 1, 4- N -Allyl-Triazoles with the Sulfonate Linker J. Heterocycl. Chem. 2014, 51, 1862– 1865 DOI: 10.1002/jhet.1857
    [Crossref], [CAS]
    156.
    Solid-Phase Organic Synthesis of 1,4-N-Vinyl- and 1,4-N-Allyl-Triazoles with the Sulfonate Linker
    He, Aiying; Sheng, Shouri; Huang, Zhenzhong; Liu, Li; Cai, Mingzhong
    Journal of Heterocyclic Chemistry (2014), 51 (6), 1862-1865CODEN: JHTCAD; ISSN:1943-5193. (Wiley-Blackwell)
    Polymer-supported 2-azidoethyl sulfonate and 3-azidopropyl sulfonate reagents have been developed and applied to the solid-phase org. synthesis of 1-vinyl- and 1-allyl-1,2,3-triazoles, resp., by CuI-mediated azide-alkyne cycloaddns. and subsequent cleavage from the polymer support through elimination reaction promoted by DBU. The advantages of this new synthetic method include simple operation and high yields of the products, as well as good stability of the reagents.
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  157. 157.
    Zabrodski, T.; Baskin, M.; Kaniraj, P.; Maayan, G. Click To Bind: Microwave-Assisted Solid-Phase Synthesis of Peptoids Incorporating Pyridine–Triazole Ligands and Their Copper(II) Complexes Synlett 2015, 26, 461– 466 DOI: 10.1055/s-0034-1378938
    [Crossref], [CAS]
    157.
    Click To Bind: Microwave-Assisted Solid-Phase Synthesis of Peptoids Incorporating Pyridine-Triazole Ligands and Their Copper(II) Complexes
    Zabrodski, Tamar; Baskin, Maria; Kaniraj, Prathap Jeya; Maayan, Galia
    Synlett (2015), 26 (4), 461-466CODEN: SYNLES; ISSN:0936-5214. (Georg Thieme Verlag)
    The authors describe a fast and efficient incorporation of the ligands 2-(1H-1,2,3-triazol-4-yl)pyridine and 2-(1H-1,2,3-triazol-1-ylmethyl)-pyridine into N-substituted glycine peptoid oligomers by the azide-alkyne cycloaddn. (click) reaction on a solid support under microwave irradn. Peptoids bearing these ligands formed stable complexes with copper(II).
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  158. 158.
    Holub, J. M.; Jang, H.; Kirshenbaum, K. Clickity-Click: Highly Functionalized Peptoid Oligomers Generated by Sequential Conjugation Reactions on Solid-Phase Support Org. Biomol. Chem. 2006, 4, 1497– 1502 DOI: 10.1039/b518247f
    [Crossref], [PubMed], [CAS]
    158.
    Clickity-click: highly functionalized peptoid oligomers generated by sequential conjugation reactions on solid-phase support
    Holub, Justin M.; Jang, Hangjun; Kirshenbaum, Kent
    Organic & Biomolecular Chemistry (2006), 4 (8), 1497-1502CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    N-Substituted glycine peptoid oligomers were used as substrates for azide-alkyne [3 + 2] cycloaddn. conjugation reactions and then elaborated through addnl. rounds of oligomerization and cycloaddn. This novel sequential conjugation technique allowed for the generation of complex peptidomimetic products in which multiple heterogeneous pendant groups were site-specifically positioned along the oligomer scaffold. Studies of a water-sol. estradiol-ferrocene peptoid conjugate demonstrated a potential application for the modular synthesis of biosensors.
    >> More from SciFinder ®
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  159. 159.
    Gasser, G.; Hüsken, N.; Köster, S. D.; Metzler-Nolte, N. Synthesis of Organometallic PNA Oligomers by Click Chemistry Chem. Commun. (Cambridge, U. K.) 2008, 3675– 3677 DOI: 10.1039/b805369c
    [Crossref], [PubMed], [CAS]
    159.
    Synthesis of organometallic PNA oligomers by click chemistry
    Gasser, Gilles; Huesken, Nina; Koester, S. David; Metzler-Nolte, Nils
    Chemical Communications (Cambridge, United Kingdom) (2008), (31), 3675-3677CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    The facile side-specific insertion, on the solid phase, of one or two ferrocene moieties into peptide nucleic acid (PNA) oligomers by click chem. is presented.
    >> More from SciFinder ®
    https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD1cXptVKmu7w%253D&md5=1ca0761c8df29f6610b978a6cb6b13e1
  160. 160.
    Qiu, J.; El-Sagheer, A. H.; Brown, T. Solid Phase Click Ligation for the Synthesis of Very Long Oligonucleotides Chem. Commun. (Cambridge, U. K.) 2013, 49, 6959– 6961 DOI: 10.1039/c3cc42451k
    [Crossref], [PubMed], [CAS]
    160.
    Solid phase click ligation for the synthesis of very long oligonucleotides
    Qiu, Jieqiong; El-Sagheer, Afaf H.; Brown, Tom
    Chemical Communications (Cambridge, United Kingdom) (2013), 49 (62), 6959-6961CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Oligonucleotides have been ligated efficiently on solid-phase using Cu-catalyzed [3+2] azide-alkyne cycloaddn. (CuAAC) and strain-promoted alkyne azide cycloaddn. (SPAAC) reaction to produce up to 186-mer triazole linked DNA products. Multiple sequential ligation reactions can be carried out by using a masked azide approach. This work suggests a novel modular approach to the synthesis of large complex oligonucleotide analogs.
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  161. 161.
    Paritala, H.; Suzuki, Y.; Carroll, K. S. Efficient Microwave-Assisted Solid Phase Coupling of Nucleosides, Small Library Generation and Mild Conditions for Release of Nucleoside Derivatives Tetrahedron Lett. 2013, 54, 1869– 1872 DOI: 10.1016/j.tetlet.2013.01.109
    [Crossref], [PubMed], [CAS]
    161.
    Efficient microwave-assisted solid phase coupling of nucleosides, small library generation, and mild conditions for release of nucleoside derivatives
    Paritala, Hanumantharao; Suzuki, Yuta; Carroll, Kate S.
    Tetrahedron Letters (2013), 54 (14), 1869-1872CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    Nucleosides are essential bio-mols. that participate in a wide array of biol. processes involved in maintaining physiol. homeostasis. Recent efforts geared toward the synthesis of nucleoside analogs and development of nucleoside combinatorial libraries using solid phase synthesis have contributed invaluable information toward drug design and development. These studies have provided information concerning the structural requirements of substrate binding pockets of enzymes and evaluation of enzyme kinetics. However, the synthesis of nucleosides and its corresponding analogs remains a challenging and time consuming process. Herein, we report an efficient, microwave assisted solid phase coupling of nucleosides, combinatorial chem. on the coupled nucleosides to generate small library, and mild cleavage conditions to release solid support gave nucleoside analogs, e.g. I. We anticipate these findings will accelerate the development of synthetic methods or combinatorial library design of nucleoside analogs in similar settings.
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  162. 162.
    Yamada, T.; Peng, C. G.; Matsuda, S.; Addepalli, H.; Jayaprakash, K. N.; Alam, M. R.; Mills, K.; Maier, M. A.; Charisse, K.; Sekine, M.; Manoharan, M.; Rajeev, K. G. Versatile Site-Specific Conjugation of Small Molecules to siRNA Using Click Chemistry J. Org. Chem. 2011, 76, 1198– 1211 DOI: 10.1021/jo101761g
    [ACS Full Text ACS Full Text], [CAS]
    162.
    Versatile Site-Specific Conjugation of Small Molecules to siRNA Using Click Chemistry
    Yamada, Takeshi; Peng, Chang Geng; Matsuda, Shigeo; Addepalli, Haripriya; Jayaprakash, K. Narayanannair; Alam, Md. Rowshon; Mills, Kathy; Maier, Martin A.; Charisse, Klaus; Sekine, Mitsuo; Manoharan, Muthiah; Rajeev, Kallanthottathil G.
    Journal of Organic Chemistry (2011), 76 (5), 1198-1211CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    We have previously demonstrated that conjugation of small mol. ligands to small interfering RNAs (siRNAs) and anti-microRNAs results in functional siRNAs and antagomirs in vivo. Here we report on the development of an efficient chem. strategy to make oligoribonucleotide-ligand conjugates using the copper-catalyzed azide-alkyne cycloaddn. (CuAAC) or click reaction. Three click reaction approaches were evaluated for their feasibility and suitability for high-throughput synthesis: the CuAAC reaction at the monomer level prior to oligonucleotide synthesis, the soln.-phase post-synthetic "click conjugation", and the "click conjugation" on an immobilized and completely protected alkyne-oligonucleotide scaffold. Nucleosides bearing 5'-alkyne moieties were used for conjugation to the 5'-end of the oligonucleotide. Previously described 2'- and 3'-O-propargylated nucleosides were prepd. to introduce the alkyne moiety to the 3' and 5' termini and to the internal positions of the scaffold. Azido-functionalized ligands bearing lipophilic long chain alkyl, cholesterol, oligo-amine, and carbohydrate were utilized to study the effect of physicochem. characteristics of the incoming azide on click conjugation to the alkyne-oligonucleotide scaffold in soln. and on immobilized solid support. We found that microwave-assisted click conjugation of azido-functionalized ligands to a fully protected solid-support bound alkyne-oligonucleotide prior to deprotection was the most efficient "click conjugation" strategy for site-specific, high-throughput oligonucleotide conjugate synthesis tested. The siRNA conjugates synthesized using this approach effectively silenced expression of a luciferase gene in a stably transformed HeLa cell line.
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  163. 163.
    Meyer, A.; Vasseur, J.-J.; Morvan, F. Synthesis of Monoconjugated and Multiply Conjugated Oligonucleotides by “Click Thiol” Thiol-Michael-Type Additions and by Combination with CuAAC “Click Huisgen. Eur. J. Org. Chem. 2013, 2013, 465– 473 DOI: 10.1002/ejoc.201201311
    [Crossref], [CAS]
    163.
    Synthesis of Monoconjugated and Multiply Conjugated Oligonucleotides by "Click Thiol" Thiol-Michael-Type Additions and by Combination with CuAAC "Click Huisgen"
    Meyer, Albert; Vasseur, Jean-Jacques; Morvan, Francois
    European Journal of Organic Chemistry (2013), 2013 (3), 465-473CODEN: EJOCFK; ISSN:1099-0690. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Monoconjugated and multiply conjugated oligonucleotides were efficiently synthesized by starting from mono-thiohexyl- or tetra-thiohexyl-oligonucleotides and treatment with acrylamide derivs. (carbohydrates, ferrocene, biotin, fluorescent dyes, deoxycholic acid). The thiol Michael-type addns. (TMTAs) occurred during the deprotection and release of the oligonucleotides from the solid support, so no addnl. time for conjugation was needed. Sequential combination either of copper-catalyzed azide-alkyne cycloaddn. (CuAAC) on solid support and then TMTA or of TMTA followed by CuAAC in soln. allowed the synthesis of several oligonucleotides decorated with two different biomols.
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  164. 164.
    Morvan, F.; Meyer, A.; Vasseur, J.-J.; Vidal, S.; Cloarec, J.; Chevolot, Y.; Souteyrand, E. Method for the Synthesis of Oligonucleotide Derivatives. Patent WO 2007/125429, 2007.
    There is no corresponding record for this reference.
  165. 165.
    Crumpton, J. B.; Santos, W. L. Site-Specific Incorporation of Diamondoids on DNA Using Click Chemistry Chem. Commun. (Cambridge, U. K.) 2012, 48, 2018– 2020 DOI: 10.1039/c2cc16860j
    [Crossref], [PubMed], [CAS]
    165.
    Site-specific incorporation of diamondoids on DNA using click chemistry
    Crumpton, Jason B.; Santos, Webster L.
    Chemical Communications (Cambridge, United Kingdom) (2012), 48 (14), 2018-2020CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    A simple and robust solid phase synthetic method for the ligation of diamondoids on the phosphate backbone of DNA with "click" chem. using [Cu(CH3CN)4]PF6 without a stabilizing ligand is reported. It was found that as the size of diamondoid increased, a corresponding increase in melting temp. was obsd.
    >> More from SciFinder ®
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  166. 166.
    Loaiza, P. R.; Löber, S.; Hübner, H.; Gmeiner, P. Parallel Synthesis of Potent Dopaminergic N-Phenyltriazole Carboxamides Applying a Novel Click Chemistry Based Phenol Linker Bioorg. Med. Chem. 2009, 17, 5482– 5487 DOI: 10.1016/j.bmc.2009.06.041
    [Crossref], [PubMed], [CAS]
    166.
    Parallel synthesis of potent dopaminergic N-phenyltriazole carboxamides applying a novel click chemistry based phenol linker
    Loaiza, Pilar Rodriguez; Loeber, Stefan; Huebner, Harald; Gmeiner, Peter
    Bioorganic & Medicinal Chemistry (2009), 17 (15), 5482-5487CODEN: BMECEP; ISSN:0968-0896. (Elsevier B.V.)
    Taking advantage of click chem. based methodol. to construct novel SPOS (solid phase org. synthesis) resins, the triazolylmethyl linked catechol was discovered, which is readily available via copper(I)-catalyzed azide-alkyne cycloaddn. (CuAAC) of azidomethyl substituted polystyrene with O-propargylcatechol and can be applied for the parallel synthesis of N-phenyltriazole carboxamides. As a proof-of-concept, a 'catch-and-release' strategy could be successfully applied for a parallel synthesis of dopaminergic phenyltriazoles. A focused model library of 20 test compds. revealing three points of diversity was generated by a three-step SPOS approach. Product purifn. was performed employing a solid-supported carboxylic acid anhydride as a scavenger. GPCR-ligand binding screening revealed dopamine D3 receptor ligands with Ki values in the single digit nanomolar range.
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  167. 167.
    Alexandra, L. F.; Vicent, L.; Celine, P.; Sami, B.; Kaynoush, N. Kit Useful for Detecting, Separating and/or Characterizating a Molecule of Interest. Patent WO 2010/029504, 2010.
    There is no corresponding record for this reference.
  168. 168.
    Funder, E. D.; Jensen, A. B.; Tørring, T.; Kodal, A. L. B.; Azcargorta, A. R.; Gothelf, K. V. Synthesis of Dopamine and Serotonin Derivatives for Immobilization on a Solid Support J. Org. Chem. 2012, 77, 3134– 3142 DOI: 10.1021/jo2025477
    [ACS Full Text ACS Full Text], [CAS]
    168.
    Synthesis of dopamine and serotonin derivatives for immobilization on a solid support
    Funder, Erik Daa; Jensen, Anne Bjoernskov; Toerring, Thomas; Kodal, Anne Louise Bank; Azcargorta, Ane Rebolledo; Gothelf, Kurt Vesterager
    Journal of Organic Chemistry (2012), 77 (7), 3134-3142CODEN: JOCEAH; ISSN:0022-3263. (American Chemical Society)
    The two important neurotransmitters dopamine and serotonin are synthesized with short PEG tethers and immobilized on a magnetic solid support. The tether is attached to the arom. moiety of the neurotransmitters to conserve their original functional groups. This approach causes minimal alteration of the original structure with the aim of optimizing the immobilized neurotransmitters for aptamer selection by SELEX. For the dopamine deriv., the tether is attached to the arom. core of a dopamine precursor by the Sonogashira reaction. For serotonin, a link to the indole core is introduced by a Claisen rearrangement from the allylated phenol moiety of serotonin. The tethers are azide-functionalized, which enables coupling to alkyne-modified magnetic beads. The coupling to the magnetic beads is quantified by UV spectroscopy using Fmoc-monitoring of the immobilized dopamine and serotonin derivs.
    >> More from SciFinder ®
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  169. 169.
    David, H.; Mantovani, G.; Ladmiral, V. Polymers. Patent WO 2007/104948, 2007.
    There is no corresponding record for this reference.
  170. 170.
    Ortega-Muñoz, M.; Lopez-Jaramillo, J.; Hernandez-Mateo, F.; Santoyo-Gonzalez, F. Synthesis of Glyco-Silicas by Cu(I)-Catalyzed “Click-Chemistry” and Their Applications in Affinity Chromatography Adv. Synth. Catal. 2006, 348, 2410– 2420 DOI: 10.1002/adsc.200600254
    [Crossref], [CAS]
    170.
    Synthesis of glyco-silica by Cu(I)-catalyzed "click-chemistry" and their applications in affinity chromatography
    Ortega-Munoz, Mariano; Lopez-Jaramillo, Javier; Hernandez-Mateo, Fernando; Santoyo-Gonzalez, Francisco
    Advanced Synthesis & Catalysis (2006), 348 (16 + 17), 2410-2420CODEN: ASCAF7; ISSN:1615-4150. (Wiley-VCH Verlag GmbH & Co. KGaA)
    The covalent immobilization of suitable alkyne/azide carbohydrate derivs. on complementarily functionalized azide/alkyne silica was performed by click ligation through the Cu(I)-catalyzed 1,3-dipolar cycloaddn. reaction of such compds. The new glyco-silica have shown to be efficient and valuable bio-selective affinity chromatog. supports for the purifn. of lectins as well as for the one-pot fluorescent labeling of those proteins. The synthetic methodol. is simple, high yielding and flexible, allowing the prepn. of tailored glyco-silica with potential future applications in the immobilization of other biomols.
    >> More from SciFinder ®
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  171. 171.
    Li, X.; Shen, G.; Zhang, F.; Yang, B.; Liang, X. Click Aspartic Acid as H ILIC SPE Material for Selective Enrichment of N-Linked Glycopeptides J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2013, 941, 45– 49 DOI: 10.1016/j.jchromb.2013.10.003
    [Crossref], [PubMed], [CAS]
    171.
    Click aspartic acid as H ILIC SPE material for selective enrichment of N-linked glycopeptides
    Li, Xiuling; Shen, Guobin; Zhang, FeiFang; Yang, Bingcheng; Liang, Xinmiao
    Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences (2013), 941 (), 45-49CODEN: JCBAAI; ISSN:1570-0232. (Elsevier B.V.)
    A novel hydrophilic interaction chromatog. (HILIC) material was developed via clicking aspartic acid onto silica gel (termed as Click AA). The material demonstrated highly hydrophilic property and was used as solid phase extn. sorbent for selective enrichment of glycopeptides. By optimization of extn. conditions, Click AA exhibited high selectivity to glycopeptides with various peptide length and different types of glycans, which was much superior to similar com. products. The application of Click AA to simulated proteomic samples further proved its specialty toward glycopeptides.
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  172. 172.
    Wang, Y.; Assaf, Z.; Liu, X.; Ziarelli, F.; Latifi, A.; Lamrabet, O.; Quéléver, G.; Qu, F.; Zhang, C.-C.; Peng, L. A “Click” Chemistry Constructed Affinity System for 2-Oxoglutaric Acid Receptors and Binding Proteins Org. Biomol. Chem. 2014, 12, 6470– 6475 DOI: 10.1039/C4OB01005A
    [Crossref], [PubMed], [CAS]
    172.
    A "click" chemistry constructed affinity system for 2-oxoglutaric acid receptors and binding proteins
    Wang, Yang; Assaf, Zeinab; Liu, Xinjun; Ziarelli, Fabio; Latifi, Amel; Lamrabet, Otmane; Quelever, Gilles; Qu, Fanqi; Zhang, Cheng-Cai; Peng, Ling
    Organic & Biomolecular Chemistry (2014), 12 (33), 6470-6475CODEN: OBCRAK; ISSN:1477-0520. (Royal Society of Chemistry)
    An ingenious and specific affinity resin designed to capture the 2-oxoglutaric acid (2-OG) binding proteins was constructed by appending a 2-OG tag to the solid resin via a Cu-catalyzed Huisgen "click" reaction. The so-obtained affinity resin was able to recognize, retain and sep. the established 2-OG binding protein NtcA in both the pure form and crude cellular ext., thus constituting a valuable means of searching for novel 2-OG receptors with a view to exploring the signaling pathways of 2-OG, a key Krebs cycle intermediate with unprecedented signalling functions.
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Received 29 May 2015
Published online 11 December 2015
Published in print 11 January 2016
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