The Huisgen 1,3-dipolar cycloaddition reaction of organic azides and alkynes has gained considerable attention in recent years due to the introduction in 2001 of Cu(1) catalysis by Tornoe and Meldal, leading to a major improvement in both rate and regioselectivity of the reaction, as realized independently by the Meldal and the Sharpless laboratories. The great success of the Cu(1) catalyzed reaction is rooted in the fact that it is a virtually quantitative, very robust, insensitive, general, and orthogonal ligation reaction, suitable for even biomolecular ligation and in vivo tagging or as a polymerization reaction for synthesis of long linear polymers. The triazole formed is essentially chemically inert to reactive conditions, e.g. oxidation, reduction, and hydrolysis, and has an intermediate polarity with a dipolar moment of ∼5 D. The basis for the unique properties and rate enhancement for triazole formation under Cu(1) catalysis should be found in the high ∆G of the reaction in combination with the low character of polarity of the dipole of the noncatalyzed thermal reaction, which leads to a considerable activation barrier. In order to understand the reaction in detail, it therefore seems important to spend a moment to consider the structural and mechanistic aspects of the catalysis. The reaction is quite insensitive to reaction conditions as long as Cu(1) is present and may be performed in an aqueous or organic environment both in solution and on solid support.

Cu-catalyzed azide-alkyne cycloaddition.

Since the discovery of CuI-catalysed click chemistry, the field of peptidomimetics has expanded to include 1,4-connected 1,2,3-triazoles as useful peptide bond isosteres. Here, we report the synthesis of triazole-containing analogues of the naturally occurring tyrosinase inhibitor cyclo-[Pro-Val-Pro-Tyr] and show that the analogues retain enzyme inhibitory activity, demonstrating the effectiveness of a 1,4-connected 1,2,3-triazole as a trans peptide bond isostere.

/pdf/1-2-3-triazoles-as-peptide-bond-isosteres-synthesis-and-3qykfq0euj.pdf

1,2,3-Triazoles as peptide bond isosteres: synthesis and biological evaluation of cyclotetrapeptide mimics

Click chemistry is an efficient and chemoselective synthetic method for coupling molecular fragments under mild reaction conditions. Since the advent in 2001 of methods to improve stereochemical conservation, the click chemistry approach has been broadly used to construct diverse chemotypes in both chemical and biological fields. In this review, we discuss the application of click chemistry 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.

https://www.mdpi.com/1420-3049/18/8/9797/pdf

Click Chemistry in Peptide-Based Drug Design

Metal-free triazole turns: 1,5-Disubstituted peptidyl triazoles are obtained regioselectively from the 1,3-dipolar cycloaddition of peptidyl phosphoranes and azides. Peptide turns are thus formed that contain a conformationally locked cis peptide bond. Being regioselective and free of heavy metals, this reaction may find broad application in chemical biology and medicinal chemistry.

Metal-free, regioselective triazole ligations that deliver locked cis peptide mimetics.

A practical and efficient synthesis of spirobarbiturates of type III is reported when NH acidity of the imide function of the hydrophilic linker element allowed the introduction of different substituents. Structural characterization, which was based on both X-ray crystallography and spectroscopic investigations, indicated type II β-turn formation. Introduction of the molecular scaffold into solid phase peptide synthesis gave rise to spirocyclic neuropeptide analogs.

Proline Derived Spirobarbiturates as Highly Effective β-Turn Mimetics Incorporating Polar and Functionalizable Constraint Elements

Triazolopeptides : chirospecific synthesis and cis/trans prolyl ratios of structural isomers

Novel triazolopeptides: chirospecific synthesis and conformational studies of proline derived analogs

As cis / trans prolyl isomerization plays a crucial role in various biological processes, peptide mimics capable of modifying the cis / trans Xaa-Pro ratio are of particular interest. A practical approach toward proline derived triazolopeptides employing [3+2] azide–alkyne cycloadditions as the key reaction step and the analysis of their cis / trans prolyl ratios are reported. Structural investigations indicated the adjustability of both the cis-percentage and the conformational stability toward intramolecular H-bonding effects.

Triazolopeptides: Chirospecific Synthesis and cis/trans Prolyl Ratios of Structural Isomers.

Novel Triazolopeptides: Chirospecific Synthesis and Conformational Studies of Proline Derived Analogues.

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Triazolopeptides : chirospecific synthesis and cis/trans prolyl ratios of structural isomers

Novel triazolopeptides: chirospecific synthesis and conformational studies of proline derived analogs

Triazolopeptides: Chirospecific Synthesis and cis/trans Prolyl Ratios of Structural Isomers.

Novel Triazolopeptides: Chirospecific Synthesis and Conformational Studies of Proline Derived Analogues.