Optimizing the control of apoptosis by amide/triazole isosteric substitution in a constrained peptoid

Apoptosis is a biological process relevant to several human diseases that is strongly regulated through protein–protein complex formation. We have previously reported a peptidomimetic compound as potent apoptotic modulator. Structural studies of this compound showed the presence of cis/trans isomers of the exocyclic tertiary amide bond in slow exchange. This information encouraged us to perform an isosteric replacement of the amide bond by a 1,2,3-triazole moiety, where different substitution patterns would mimic different amide rotamers. The syntheses of these restricted analogs have been carried out using the Ugi multicomponent reaction followed by an intramolecular cyclization. Unexpectedly, for one of the proposed structures, a novel β -lactam compound was formed. All compounds showed to efficiently inhibit apoptosis, in vitro and in cellular extracts, with slight differences for the corresponding regioisomers. We propose the binding to Apaf-1 as the inhibition mechanism.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Identification of novel apoptosis inhibitors. ► Identification of a new compound with an unexpected β-lactam structure. ► Use of click Chemistry and Ugi multicomponent reaction for the synthesis of novel heterocyclic derivatives.