Isoform-selective inhibition of the human UDP-glucuronosyltransferase 2B7 by isolongifolol derivatives

J Med Chem. 2007 May 31;50(11):2655-64. doi: 10.1021/jm061204e. Epub 2007 May 3.

Abstract

A set of 48 derivatives of the tricyclic sesquiterpenol alcohol isolongifolol was synthesized. The set comprised homochiral and diastereomeric alcohols, amines, chlorohydrins, as well as carboxylic acids, phosphonic acids, and their corresponding esters. The absolute configuration of the epimeric compounds was assigned by 2D NMR experiments [gradient heteronuclear single quantum correlation (gHSQC) and gradient nuclear Overhauser enhancement spectroscopy (gNOESY)] in agreement with crystallographic data. The tricyclic derivatives were assessed as inhibitors of the human UDP-glucuronosyltransferase (UGT) 2B7. The phenyl-substituted secondary alcohol 26b was the best inhibitor in this series and its competitive inhibition constant was 18 nM. Compound 26b was not glucuronidated by UGT2B7 and other hepatic UGT enzymes, presumably due to the high steric hindrance exerted by its bulky phenyl substituent. Its inhibitory activity toward 14 other UGT isoforms of subfamily 1A and 2B was determined, and the data indicated that the tricyclic secondary alcohol 26b was highly selective for UGT2B7 (true selectivity >1000).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Glucuronosyltransferase / antagonists & inhibitors*
  • Glucuronosyltransferase / chemistry*
  • Humans
  • Isoenzymes / chemical synthesis*
  • Isoenzymes / chemistry
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Sesquiterpenes / chemical synthesis*
  • Sesquiterpenes / chemistry
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Isoenzymes
  • Sesquiterpenes
  • isolongifolol
  • UGT2B7 protein, human
  • Glucuronosyltransferase