Eudismic analysis of tricyclic sesquiterpenoid alcohols: Lead structures for the design of potent inhibitors of the human UDP-glucuronosyltransferase 2B7

Ingo Bichlmaier, Mika Kurkela, Antti Siiskonen, Moshe Finel, Jari Yli-Kauhaluoma

Research output: Contribution to journalArticleScientificpeer-review

8 Citations (Scopus)

Abstract

The epimeric tricyclic sesquiterpenoid alcohols globulol, epiglobulol, cedrol, epicedrol, longifolol, and isolongifolol were investigated in their ability to inhibit the recombinant human UDP-glucuronosyltransferase (UGT) 2B7. The stereoisomers displayed rapidly reversible competitive inhibition, which was substrate-independent. Longifolol and its stereoisomer isolongifolol displayed the lowest competitive inhibition constants (K-ic) of 23 and 26 nM, respectively. The K-ic values of cedrol and its epimer epicedrol were 0.15 and 0.21 mu M, those of globulol and epiglobulol were 5.4 and 4.0 mu M, respectively. The diastereomeric alcohols exhibited nearly identical affinities toward UGT2B7 indicating that the spatial arrangement of the hydroxy group had no influence on the dissociation of the enzyme-terpenoid complex. The high affinities stemmed presumably from mere hydrophobic interactions between the hydrocarbon scaffold of the terpenoid alcohol and the binding site of the enzyme. Glucuronidation assays revealed that there were large differences in the rates at which the epimeric alcohols were conjugated. Therefore, the spatial arrangement of the hydroxy group controlled the rate of the UGT2B7-catalyzed reaction. The introduction of a methyl group into the side chain of isolongifolol and longifolol increased the steric hindrance. As a result, the rate of the UGT2B7-catalyzed reaction was decreased by more than 88%. The findings indicated that the rate of the UGT2B7-catalyzed glucuronidation is significantly controlled by stereochemical and steric factors. Considering the high inhibition levels exerted by the tricyclic sesquiterpenoid alcohols, these compounds might serve as valuable lead structures for the design of potent inhibitors for UGT2B7. (c) 2007 Elsevier Inc. All rights reserved.

Original languageEnglish
Pages (from-to)386-400
Number of pages15
JournalBIOORGANIC CHEMISTRY
Volume35
Issue number5
DOIs
Publication statusPublished - Oct 2007
Externally publishedYes
Publication typeA1 Journal article-refereed

Keywords

  • metabolism
  • enzyme
  • inhibition
  • stereochemistry
  • UGT
  • longifolene
  • HUMAN LIVER
  • GLUCURONIDATION
  • METABOLISM
  • SELECTIVITY
  • EXPRESSION
  • DISEASE
  • UGT1
  • 2B17

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