Eudismic analysis of tricyclic sesquiterpenoid alcohols: lead structures for the design of potent inhibitors of the human UDP-glucuronosyltransferase 2B7.
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 microM, those of globulol and epiglobulol were 5.4 and 4.0 microM, 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.
Bichlmaier
Ingo
I
Faculty of Pharmacy, Division of Pharmaceutical Chemistry, University of Helsinki, P.O. Box 56, FI-00014 Helsinki, Finland.
Kurkela
Mika
M
Siiskonen
Antti
A
Finel
Moshe
M
Yli-Kauhaluoma
Jari
J
D000438:Alcohols / Q000737:chemistry*; D002384:Catalysis; D002625:Chemistry, Organic / Q000379:methods; D015195:Drug Design; D014453:Glucuronosyltransferase / Q000737:chemistry*; D006801:Humans; D006838:Hydrocarbons / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D020033:Protein Isoforms; D013237:Stereoisomerism; D013379:Substrate Specificity; D013729:Terpenes / Q000737:chemistry*; D014530:Uridine Diphosphate / Q000737:chemistry*
D000438:Alcohols; D006838:Hydrocarbons; D020033:Protein Isoforms; D013729:Terpenes; D014530:Uridine Diphosphate; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase