Dual action Smac mimetics–zinc chelators as pro-apoptotic antitumoral agents

Leonardo Manzoni, Davide Gornati, Mattia Manzotti, Silvia Cairati, Alberto Bossi, Daniela Arosio, Daniele Lecis, Pierfausto Seneci

Research output: Contribution to journalArticle

Abstract

Dual action compounds (DACs) based on 4-substituted aza-bicyclo[5.3.0]decane Smac mimetic scaffolds (ABDs) linked to a Zn2+-chelating moiety (DPA, o-hydroxy, m-allyl, N-acyl (E)-phenylhydrazone) through their 10 position are reported and characterized. Their synthesis, their target affinity (XIAP BIR3, Zn2+) in cell-free assays, their pro-apoptotic effects and cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. The results are interpreted to evaluate the influence of Zn2+ chelators on cell-free potency and on cellular permeability of DACs, and to propose novel avenues towards more potent antitumoral DACs based on Smac mimetics and Zn2+ chelation.

Original languageEnglish
Pages (from-to)4613-4619
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number19
DOIs
Publication statusPublished - Oct 1 2016

Keywords

  • Apoptosis
  • Dual action compounds
  • Peptidomimetics
  • Smac mimetics
  • Zinc chelation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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  • Cite this

    Manzoni, L., Gornati, D., Manzotti, M., Cairati, S., Bossi, A., Arosio, D., Lecis, D., & Seneci, P. (2016). Dual action Smac mimetics–zinc chelators as pro-apoptotic antitumoral agents. Bioorganic and Medicinal Chemistry Letters, 26(19), 4613-4619. https://doi.org/10.1016/j.bmcl.2016.08.065