Design, synthesis, and discovery of novel trans-stilbene analogues as potent and selective human cytochrome P450 1B1 inhibitors

J Med Chem. 2002 Jan 3;45(1):160-4. doi: 10.1021/jm010298j.

Abstract

A series of trans-stilbene derivatives containing a 3,5-dimethoxyphenyl moiety were prepared through a new efficient solution phase synthetic pathway, and their inhibitory activities were evaluated on human cytochrome P450s (CYP) 1A1, 1A2, and 1B1 to find a potent and selective CYP1B1 inhibitor. We found that a substituent at the 2-position of the stilbene skeleton plays a very important role in discriminating between CYP1As and CYP1B1. Among the compounds tested, the most selective and potent CYP1B1 inhibitor was 2,3',4,5'-tetramethoxystilbene. Compound 7j, 2-[2-(3,5-dimethoxy-phenyl)vinyl]thiophene, showed greater inhibitory activities but had a lower selectivity toward all of the CYP1s tested.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aryl Hydrocarbon Hydroxylases*
  • Bacteria / drug effects
  • Bacteria / enzymology
  • Cytochrome P-450 CYP1B1
  • Cytochrome P-450 Enzyme Inhibitors*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Membranes
  • Regression Analysis
  • Stilbenes / chemical synthesis*
  • Stilbenes / chemistry
  • Stilbenes / pharmacology
  • Structure-Activity Relationship

Substances

  • 1-(2,4-dimethoxyphenyl)-2-(3,5-dimethoxyphenyl)ethene
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Stilbenes
  • Aryl Hydrocarbon Hydroxylases
  • CYP1B1 protein, human
  • Cytochrome P-450 CYP1B1