Rational design, synthesis and characterization of potent, drug-like monomeric Smac mimetics as pro-apoptotic anticancer agents

Bioorg Med Chem Lett. 2012 Mar 15;22(6):2204-8. doi: 10.1016/j.bmcl.2012.01.098. Epub 2012 Feb 2.

Abstract

A set of phenyl-substituted Smac mimetics/IAP inhibitor analogues of lead compound 2a was synthesized, aiming to retain its strong cell-free potency while increasing its bioavailability. Seventeen compounds 2b-r were prepared and characterized in vitro, using cell-free and cellular assays. Among them, the p-CF(3) substituted analogue 2m showed the best permeability through cell membranes, and was selected for further in vitro and in vivo studies due to its strong, sub-micromolar cellular potency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Binding Sites
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Humans
  • Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
  • Inhibitor of Apoptosis Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Mitochondrial Proteins / chemistry*
  • Models, Molecular
  • Molecular Structure
  • Peptidomimetics / chemical synthesis*
  • Peptidomimetics / pharmacology
  • Protein Binding
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • DIABLO protein, human
  • Inhibitor of Apoptosis Proteins
  • Intracellular Signaling Peptides and Proteins
  • Mitochondrial Proteins
  • Peptidomimetics