Synthesis and biological evaluation of Apogossypolone derivatives as pan-active inhibitors of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins

J Med Chem. 2010 Nov 25;53(22):8000-11. doi: 10.1021/jm100746q. Epub 2010 Oct 29.

Abstract

Overexpression of antiapoptotic Bcl-2 family proteins is commonly related with tumor maintenance, progression, and chemoresistance. Inhibition of these antiapoptotic proteins is an attractive approach for cancer therapy. Guided by nuclear magnetic resonance (NMR) binding assays, a series of 5,5' substituted compound 6a (Apogossypolone) derivatives was synthesized and identified pan-active antagonists of antiapoptotic Bcl-2 family proteins, with binding potency in the low micromolar to nanomolar range. Compound 6f inhibits the binding of BH3 peptides to Bcl-X(L), Bcl-2, and Mcl-1 with IC(50) values of 3.10, 3.12, and 2.05 μM, respectively. In a cellular assay, 6f potently inhibits cell growth in several human cancer cell lines in a dose-dependent manner. Compound 6f further displays in vivo efficacy in transgenic mice and demonstrated superior single-agent antitumor efficacy in a PPC-1 mouse xenograft model. Together with its negligible toxicity, compound 6f represents a promising drug lead for the development of novel apoptosis-based therapies for cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Drug Screening Assays, Antitumor
  • Drug Stability
  • Female
  • Gossypol / analogs & derivatives*
  • Gossypol / chemical synthesis
  • Gossypol / chemistry
  • Gossypol / pharmacology
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Microsomes / metabolism
  • Models, Molecular
  • Naphthoquinones / chemical synthesis*
  • Naphthoquinones / chemistry
  • Naphthoquinones / pharmacology
  • Neoplasm Transplantation
  • Peptide Fragments / metabolism
  • Protein Binding
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Rats
  • Structure-Activity Relationship
  • Transplantation, Heterologous

Substances

  • 6,6',7,7'-tetrahydroxy-3,3'-dimethyl-5,5'-bis(4-methylphenethyl)-2,2'-binaphthyl-1,1',4,4'-tetraone
  • Antineoplastic Agents
  • Bax protein (53-86)
  • Naphthoquinones
  • Peptide Fragments
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • apogossypolone
  • Gossypol