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Efficient Synthesis of Conformationally Restricted Apoptosis Inhibitors Bearing a Triazole Moiety
Author(s) -
Corredor Miriam,
Garrido Maria,
Bujons Jordi,
Orzáez Mar,
PérezPayá Enrique,
Alfonso Ignacio,
Messeguer Angel
Publication year - 2015
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201502380
Subject(s) - moiety , conformational isomerism , chemistry , peptidomimetic , stereochemistry , intramolecular force , amide , ring (chemistry) , triazole , adduct , peptide bond , combinatorial chemistry , enzyme , molecule , biochemistry , peptide , organic chemistry
Abstract Apoptosis is a biological process relevant to different human diseases that is regulated through protein–protein interactions and complex formation. Peptidomimetic compounds based on linear peptoids and cyclic analogues with different ring sizes have been previously reported as potent apoptotic inhibitors. Among them, the presence of cis / trans conformers of an exocyclic tertiary amide bond in slow exchange has been characterized. This information encouraged us to perform an isosteric replacement of the amide bond by a 1,2,3‐triazole moiety, in which different substitution patterns would mimic different amide rotamers. The syntheses of these restricted analogues have been carried out through an Ugi multicomponent reaction followed by an intramolecular cyclization. The unexpected formation of a β‐lactam scaffold prompted us to study the course of the intramolecular cyclization of the Ugi adducts. In order to modulate this cyclization, a small library of compounds bearing both heterocyclic scaffolds has been synthesized and their activities as apoptosis inhibitors have been evaluated.