Discovery, characterization, and structure-activity relationships studies of proapoptotic polyphenols targeting B-cell lymphocyte/leukemia-2 proteins

J Med Chem. 2003 Sep 25;46(20):4259-64. doi: 10.1021/jm030190z.


Among the most promising chemopreventive agents, certain natural polyphenols have recently received a great deal of attention because of their demonstrated inhibitory activity against tumorigenesis. In view of their anticancer properties, these compounds also hold great promise as potential chemotherapeutic agents. However, to translate these chemopreventive agents into chemotherapeutic compounds, their exact mechanisms of action must be delineated. By using a multidisciplinary approach guided by modern nuclear magnetic resonance spectroscopy techniques, fluorescence polarization displacement assays, and cell-based assays, we have begun to unravel the mechanisms of actions of certain polyphenols such as Gossypol (a compound from cotton seed extracts) and Purpurogallin (a natural compound extracted from Quercus sp. nutgall) and their derivatives. Our findings suggest that these natural products bind and antagonize the antiapoptotic effects of B-cell lymphocyte/leukemia-2 (Bcl-2) family proteins such as Bcl-x(L). Our in vitro and in vivo data not only open a window of opportunities for the development of novel cancer treatments with these compounds but also provide structural information that can be used for the design and development of novel and more effective analogues.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • Benzocycloheptenes / chemistry
  • Benzocycloheptenes / pharmacology
  • Binding Sites
  • Cell Survival / drug effects
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Flavonoids*
  • Gossypol / pharmacology
  • HeLa Cells
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Nuclear Magnetic Resonance, Biomolecular
  • Phenols / chemistry*
  • Phenols / pharmacology*
  • Polymers / chemistry*
  • Polymers / pharmacology*
  • Polyphenols
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Structure-Activity Relationship
  • Tumor Cells, Cultured
  • bcl-X Protein


  • Antineoplastic Agents
  • BCL2L1 protein, human
  • Benzocycloheptenes
  • Flavonoids
  • Phenols
  • Polymers
  • Polyphenols
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein
  • Gossypol
  • purpurogallin