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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.
AuthorsCarine B Bourguet, Pierre-Luc Boulay, Audrey Claing, William D Lubell
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 24 Issue 15 Pg. 3361-5 (Aug 01 2014) ISSN: 1464-3405 [Electronic] England
PMID24986663 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Ltd. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Aza Compounds
  • Oligopeptides
  • Caspase 9
Topics
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Apoptosis (drug effects)
  • Aza Compounds (chemical synthesis, chemistry, pharmacology)
  • Breast Neoplasms (drug therapy, metabolism, pathology)
  • Caspase 9 (metabolism)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Oligopeptides (chemical synthesis, chemistry, pharmacology)
  • Structure-Activity Relationship

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