Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 24, Issue 15, Pages 3361-3365Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2014.05.095
Keywords
Azapeptides; Peptide mimic; Beta-turn; Caspase-9 activator; Apoptosis; Anti-cancer drug
Categories
Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC)
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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. (C) 2014 Elsevier Ltd. All rights reserved.
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