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

Bioorg Med Chem Lett. 2016 Oct 1;26(19):4613-4619. doi: 10.1016/j.bmcl.2016.08.065. Epub 2016 Aug 22.


Dual action compounds (DACs) based on 4-substituted aza-bicyclo[5.3.0]decane Smac mimetic scaffolds (ABDs) linked to a Zn(2+)-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, Zn(2+)) 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 Zn(2+) 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 Zn(2+) chelation.

Keywords: Apoptosis; Dual action compounds; Peptidomimetics; Smac mimetics; Zinc chelation.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Cell Line, Tumor
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacology*
  • Chromatography, High Pressure Liquid
  • Drug Screening Assays, Antitumor
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Mitochondrial Proteins / chemistry*
  • Molecular Mimicry*
  • Spectrophotometry, Ultraviolet
  • Zinc / chemistry*


  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • Chelating Agents
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Zinc