title: Optimizing the control of apoptosis by amide/triazole isosteric substitution in a constrained peptoid.
abstract: 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.
authors.affiliation: Department of Chemical and Biomolecular Nanotechnology, Institute of Advanced Chemistry of Catalonia, IQAC-CSIC, E-08034 Barcelona, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Corredor
authors.forename: Jordi
authors.initials: J
authors.lastname: Bujons
authors.forename: Mar
authors.initials: M
authors.lastname: Orzáez
authors.forename: Mónica
authors.initials: M
authors.lastname: Sancho
authors.forename: Enrique
authors.initials: E
authors.lastname: Pérez-Payá
authors.forename: Ignacio
authors.initials: I
authors.lastname: Alfonso
authors.forename: Angel
authors.initials: A
authors.lastname: Messeguer
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D003500:Cyclization; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D034444:Peptoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000577:Amides; D034444:Peptoids; D014230:Triazoles