Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors

Bioorg Med Chem Lett. 2014 Apr 1;24(7):1820-4. doi: 10.1016/j.bmcl.2014.02.016. Epub 2014 Feb 24.

Abstract

The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the core tricycle involved two key steps: Rh-catalyzed hydrogenation of an unsaturated bicyclic ring system and a Ru-catalyzed ring closing alkene metathesis reaction. The final Smac mimetics bind to cIAP1 and XIAP BIR3 domains and elicit the desired phenotype in cellular proliferation assays. Dimeric IAP inhibitors were found to possess nanomolar potency in a cellular proliferation assay and favourable in vitro drug-like properties.

Keywords: Inhibitors of Apoptosis Proteins; Ring-closing metathesis; Smac; Structure-based drug design; XIAP; cIAP.

MeSH terms

  • Cell Line
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Heterocyclic Compounds, 3-Ring / chemical synthesis
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Humans
  • Inhibitor of Apoptosis Proteins / chemical synthesis
  • Inhibitor of Apoptosis Proteins / chemistry
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Heterocyclic Compounds, 3-Ring
  • Inhibitor of Apoptosis Proteins