title: Design and synthesis of novel azapeptide activators of apoptosis mediated by caspase-9 in cancer cells.
abstract: A set of azapeptides was designed based on the Ala-Val-Pro-Ile peptide (derived from Smac protein) to activate caspase-9 and induce apoptosis in breast cancer cells. The diversity-oriented synthesis of the aza-peptides 5-9 was accomplished by alkylation of the aza-residue of aza-Gly-Pro dipeptide 15 using potassium tert-butoxide and a range of different alkyl halides. The resulting protected aza-dipeptide building blocks were then introduced into mimics 5-9 using standard coupling conditions. Biological evaluation of 5-9 was performed in MDA-MB-231 breast cancer cells, and indicated that the aza-Gly and aza-Phe analogs 5 and 7 were most efficient in inducing cell death by a caspase-9 mediated apoptotic pathway. Revealing a relationship between azabicycloalkanone and aza peptide mimics, novel AVPI mimics were synthesized which exhibit utility for studying structure-activity relationships to develop leads for activating apoptosis in cancer cells.
authors.affiliation: Département de Chimie, Université de Montréal, C.P. 6128 Succursale Centre-Ville, Montréal H3C 3J7 QC, Canada.
authors.forename: Carine B
authors.initials: CB
authors.lastname: Bourguet
authors.affiliation: Département de Pharmacologie, Université de Montréal, C.P. 6128 Succursale Centre-Ville, Montréal H3C 3J7 QC, Canada.
authors.forename: Pierre-Luc
authors.initials: PL
authors.lastname: Boulay
authors.affiliation: Département de Pharmacologie, Université de Montréal, C.P. 6128 Succursale Centre-Ville, Montréal H3C 3J7 QC, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Claing
authors.affiliation: Département de Chimie, Université de Montréal, C.P. 6128 Succursale Centre-Ville, Montréal H3C 3J7 QC, Canada. Electronic address: Lubell@chimie.umontreal.ca.
authors.forename: William D
authors.initials: WD
authors.lastname: Lubell
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053453:Caspase 9 / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D009842:Oligopeptides; D053453:Caspase 9
keywords: Anti-cancer drug; Apoptosis; Azapeptides; Beta-turn; Caspase-9 activator; Peptide mimic