Semisynthesis of an Analogue of Antitumor Bicyclic Hexapeptide RA-VII by Fixing the Ala-2/Tyr-3 Bond to Cis by Incorporating a Triazole cis-Amide Bond Surrogate

Abstract

We prepared an analogue of an antitumor bicyclic hexapeptide RA-VII whose amide configuration between residues 2 and 3 was fixed to cis by incorporating a triazole cis-amide bond surrogate. This analogue was shown, by NMR studies, to take almost the same conformation as that of the minor conformer of RA-VII. It showed no cytotoxic activity.

Synthetic Studies toward Aryl-(4-aryl-4H-[1,2,4]triazole-3-yl)-amine from 1,3-Diarylthiourea as Urea Mimetics

“…15 Replacement of the Ala-NMe-Tyr(OMe) amide bond in RA-VII, a plant-origin antitumor bicyclic hexapeptide, with [1,2,4]triazole yielded the pseudopeptide. 16 As anticipated, the pseudopeptide reproduced the conformation of the minor cis-peptide isomer but was devoid of cytotoxic activity. Interestingly, replacement of urea function in β 3 -adrenergic receptor agonists with triazole resulted in improved oral bioavailability accompanied by retention of potency, selectivity, and in vivo efficacy.…”

“…Another interesting application of triazole was to employ it as a cis -amide bond surrogate . Replacement of the Ala-NMe-Tyr(OMe) amide bond in RA-VII, a plant-origin antitumor bicyclic hexapeptide, with [1,2,4]triazole yielded the pseudopeptide . As anticipated, the pseudopeptide reproduced the conformation of the minor cis -peptide isomer but was devoid of cytotoxic activity.…”

New Family of Peptidomimetics Based on the Imidazole Motif

“…In particular, aza heterocycles such as tetrazoles, 1,2,4-triazole,s and more often 1,2,3-triazoles were synthesized. Early work in this area had focused on the use of 1,4-substituted triazoles, which were obtained by Cu I -mediated Huisgen reaction, but recent developments of this reaction allowed a reversed regioselectivity owing to the use of ruthenium catalysts .…”

Formation of a cyclic tetrapeptide mimic by thermal azide–alkyne 1,3-dipolar cycloaddition

“…1 Of the various possibilities for designing peptidomimetics, one has recently become particularly popular, namely the incorporation of triazole units. 2 Not only do triazole rings impart conformational rigidity, 3 but they also mimic the cis-4 or trans-conformations 5 of amide bonds, depending on whether they are 1,5-or 1,4disubstituted. Another reason for the increasing popularity of triazoles in the construction of peptidomimetics is their facile regioselective accessibility via copper(I) 6 or ruthenium(II) 7 catalysed azide-alkyne 1,3-dipolar cycloaddition.…”