Design and synthesis of novel azapeptide activators of apoptosis mediated by caspase-9 in cancer cells

作者：Bourguet Carine B; Boulay Pierre Luc; Claing Audrey; Lubell William D^*

来源：Bioorganic & Medicinal Chemistry Letters, 2014, 24(15): 3361-3365.

DOI：10.1016/j.bmcl.2014.05.095

• Azapeptides
• Peptide mimic
• Beta-turn
• Caspase-9 activator
• Apoptosis
• Anti-cancer drug

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.

• 出版日期2014-8-1