Selectivity of pyripyropene derivatives in inhibition toward acyl-CoA:cholesterol acyltransferase 2 isozyme

J Antibiot (Tokyo). 2008 Aug;61(8):503-8. doi: 10.1038/ja.2008.67.

Abstract

Selectivity of 96 semisynthetic derivatives prepared from fungal pyripyropene A, originally isolated as a potent inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), toward ACAT1 and ACAT2 isozymes was investigated in the cell-based assay using ACAT1- and ACAT2-expressing CHO cells. Eighteen derivatives including PR-71 (7-O-isocaproyl derivative) showed much more potent ACAT2 inhibition (IC50: 6.0 to 62 nM) than pyripyropene A (IC50: 70 nM). Among them, however, natural pyripyropene A showed the highest selectivity toward ACAT2 with a selectivity index (SI) of >1000, followed by PR-71 (SI, 667).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cholesterol Esters / metabolism
  • Cricetinae
  • Cricetulus
  • Enzyme Inhibitors / pharmacology*
  • Inhibitory Concentration 50
  • Isoenzymes
  • Oleic Acid / metabolism
  • Pyridines / pharmacology*
  • Rats
  • Sesquiterpenes / pharmacology*
  • Sterol O-Acyltransferase / antagonists & inhibitors*
  • Sterol O-Acyltransferase / metabolism
  • Sterol O-Acyltransferase 2
  • Substrate Specificity

Substances

  • Cholesterol Esters
  • Enzyme Inhibitors
  • Isoenzymes
  • Pyridines
  • Sesquiterpenes
  • pyripyropene A
  • Oleic Acid
  • Sterol O-Acyltransferase
  • sterol O-acyltransferase 1