title: Potent inhibitors of the human UDP-glucuronosyltransferase 2B7 derived from the sesquiterpenoid alcohol longifolol.
abstract: The tricyclic sesquiterpenol (+)-longifolol served as a lead structure for the design of inhibitors of the human UDP-glucuronosyltransferase (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 16 b (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 16 b was highly selective for UGT2B7.
authors.affiliation: Division of Pharmaceutical Chemistry, University of Helsinki, P.O. Box 56, 00014 Helsinki, Finland.
authors.forename: Ingo
authors.initials: I
authors.lastname: Bichlmaier
authors.forename: Mika
authors.initials: M
authors.lastname: Kurkela
authors.forename: Tanmaya
authors.initials: T
authors.lastname: Joshi
authors.forename: Antti
authors.initials: A
authors.lastname: Siiskonen
authors.forename: Tobias
authors.initials: T
authors.lastname: Rüffer
authors.forename: Heinrich
authors.initials: H
authors.lastname: Lang
authors.forename: Moshe
authors.initials: M
authors.lastname: Finel
authors.forename: Jari
authors.initials: J
authors.lastname: Yli-Kauhaluoma
mesh_terms: D000438:Alcohols / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D021281:Quantitative Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000438:Alcohols; D004791:Enzyme Inhibitors; D013729:Terpenes; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase