title: Application of constrained aza-valine analogs for Smac mimicry.
abstract: Constrained azapeptides were designed based on the Ala-Val-Pro-Ile sequence from the second mitochondria-derived activator of caspases (Smac) protein and tested for ability to induce apoptosis in cancer cells. Diels-Alder cyclizations and Alder-ene reactions on azopeptides enabled construction of a set of constrained aza-valine dipeptide building blocks, that were introduced into mimics using effective coupling conditions to acylate bulky semicarbazide residues. Evaluation of azapeptides 7-11 in MCF-7 breast cancer cells indicated aza-cyclohexanylglycyine analog 11 induced cell death more efficiently than the parent tetrapeptide likely by a caspase-9 mediated apoptotic pathway. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 235-244, 2016.
authors.affiliation: Département De Chimie, Université De Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, Canada.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Chingle
authors.affiliation: Département De Pharmacologie, Université De Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Ratni
authors.affiliation: Département De Pharmacologie, Université De Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, 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, QC, H3C 3J7, Canada.
authors.forename: William D
authors.initials: WD
authors.lastname: Lubell
mesh_terms: D000215:Acylation; D020816:Amino Acid Motifs; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018716:Molecular Mimicry; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D012663:Semicarbazides / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001372:Aza Compounds; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D010455:Peptides; D012663:Semicarbazides; C506433:CASP9 protein, human; D053453:Caspase 9
keywords: apoptosis; aza-Diels Alder; aza-valine; azopeptide; semicarbazide