4-Connected azabicyclo[5.3.0]decane Smac mimetics-Zn2+ chelators as dual action antitumoral agents

Leonardo Manzoni, Alessandro Samela, Stefano Barbini, Silvia Cairati, Marta Penconi, Daniela Arosio, Daniele Lecis, Pierfausto Seneci

Research output: Contribution to journalArticlepeer-review

Abstract

Putative dual action compounds (DACs 3a–d) based on azabicyclo[5.3.0]decane (ABD) Smac mimetic scaffolds linked to Zn2+-chelating 2,2′-dipicolylamine (DPA) through their 4 position are reported and characterized. Their synthesis, their target affinity (cIAP1 BIR3, Zn2+) in cell-free assays, their pro-apoptotic effects, and their cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. A limited influence of Zn2+ chelation on in vitro activity of DPA-substituted DACs 3a–d was sometimes perceivable, but did not lead to strong cellular synergistic effects. In particular, the linker connecting DPA with the ABD scaffold seems to influence cellular Zn2+-chelation, with longer lipophilic linkers/DAC 3c being the optimal choice.

Original languageEnglish
Pages (from-to)2336-2344
Number of pages9
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number11
DOIs
Publication statusPublished - Jan 1 2017

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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