Potent inhibitors of the human UDP-glucuronosyltransferase 2B7 derived from the sesquiterpenoid alcohol longifolol

Ingo Bichlmaier, Mika Kurkela, Tanmaya Joshi, Antti Siiskonen, Tobias Rueffer, Heinrich Lang, Moshe Finel, Jari Yli-Kauhaluoma

Research output: Contribution to journalArticleScientificpeer-review

6 Citations (Scopus)

Abstract

The tricyclic sesquiterpenol (+)-longifolol served as a lead structure for the design of inhibitors of the human UDP-glucuronosyl-tronsferose (UGT) 2B7. Twenty-four homochiral and epimeric longifolol derivatives were synthesized and screened for their ability to inhibit the enzyme. The absolute configuration at the stereogenic center C1' was determined by X-ray crystallography and 2D NMR spectroscopy (gHSQC, gNOESY). The phenyl-substituted secondary alcohol 16b (beta-phenyllongifolol) displayed the highest affinity toward UGT2B7, and its inhibitory dissociation constant was 0.91 nm. The mode of inhibition was rapidly reversible and competitive. The inhibitor was not glucuronidated by UGT2B7 or other hepatic UGTs, presumably as a result of the high steric demand exerted by the phenyl group. Inhibition assays employing 14 other UGT isoforms suggested that inhibitor 76 b was highly selective for UGT2B7.

Original languageEnglish
Pages (from-to)881-889
Number of pages9
JournalCHEMMEDCHEM
Volume2
Issue number6
DOIs
Publication statusPublished - Jun 2007
Externally publishedYes
Publication typeA1 Journal article-refereed

Keywords

  • ENZYMATIC TRANSITION-STATES
  • DERIVATIVES
  • URIDINE
  • GLUCURONIDATION
  • ENANTIOMERS
  • ANALOGS
  • PROBE
  • ACID
  • 2B17

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