Molecular design of cholesterols as inhibitors of DNA polymerase alpha

J Med Chem. 2004 Sep 23;47(20):4971-4. doi: 10.1021/jm030553v.

Abstract

The triterpenoid structure is a promising motif for the molecular design of DNA polymerase inhibitors.(1) In this study, 2-(cholesteryloxy)acetic acid (3), 2-(cholestanyl)acetic acid (7), and 2-(stigmasteryl)acetic acid (11) were found to selectively affect only DNA polymerase alpha (pol.alpha). The presence of a carboxyl group at position 28 appears to be essential for the inhibition of the pol.alpha activity. With pol.alpha, these compounds acted by competing with the template-primer DNA and noncompetitively with the substrate.

MeSH terms

  • Binding Sites
  • Cholesterol / analogs & derivatives
  • Cholesterol / chemistry*
  • Cholesterol / pharmacology*
  • DNA / metabolism
  • DNA Polymerase I / antagonists & inhibitors*
  • DNA Polymerase I / metabolism
  • Drug Design
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Inhibitory Concentration 50
  • Kinetics
  • Structure-Activity Relationship
  • Topoisomerase Inhibitors

Substances

  • Enzyme Inhibitors
  • Topoisomerase Inhibitors
  • DNA
  • Cholesterol
  • DNA Polymerase I