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

Bioorg Med Chem Lett. 2017 Jun 1;27(11):2336-2344. doi: 10.1016/j.bmcl.2017.04.032. Epub 2017 Apr 13.

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.

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

MeSH terms

  • Apoptosis Regulatory Proteins
  • Azabicyclo Compounds / chemistry*
  • Azabicyclo Compounds / pharmacology*
  • Cell Line, Tumor
  • Chelating Agents / chemistry
  • Chelating Agents / pharmacology*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mitochondrial Proteins / metabolism*
  • Molecular Mimicry*
  • Zinc / chemistry*

Substances

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