Stereochemical sensitivity of the human UDP-glucuronosyltransferases 2B7 and 2B17

Journal of Medicinal Chemistry
Ingo BichlmaierJari Yli-Kauhaluoma

Abstract

A set of 28 enantiomers comprising rigid and flexible secondary alcohols was synthesized by the asymmetric Corey-Bakshi-Shibata reduction. The enantiomerically pure alcohols were subjected to enzymatic glucuronidation assays employing the human UDP-glucuronosyltransferases (UGTs) 2B7 and 2B17. Both UGTs displayed high levels of stereoselectivity, favoring the conjugation of the (R)-enantiomers over their respective (S)-stereoisomers at eudismic ratios up to 256. The spatial arrangement of the hydroxy group determined the diastereoselectivity of the UGT2B17-catalyzed reaction in agreement with Pfeiffer's rule (eudismic activity quotient = 0.83 +/- 0.14). Inhibition studies revealed that the enantiomers had similar affinities toward the enzymes. The diastereoselectivity of the UGT-catalyzed conjugation stemmed, therefore, from the arrangement of the substrates in the catalytic site, rather than from distinct affinities toward the enzymes. Taken together, this study showed that metabolic enzymes that are generally conceived to be rather "flexible" in nature are capable of displaying high levels of chiral distinction.

References

Jan 1, 1984·European Journal of Clinical Pharmacology·E J Ariëns
Oct 15, 1983·Lancet·W H Inman, N S Rawson
Dec 24, 1997·Clinical and Experimental Pharmacology & Physiology·R Meech, P I Mackenzie
Jan 5, 2002·Drug Metabolism Reviews·M B FisherS A Wrighton
Oct 3, 2002·Nature Reviews. Drug Discovery·Israel AgranatJohn Caldwell
Oct 31, 2002·Human Psychopharmacology·Ian A Paul
Apr 16, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·David TurgeonAlain Bélanger
Feb 24, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Peter G WellsJoseph K Ritter
Apr 2, 2005·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Leena LuukkanenMoshe Finel
Jun 14, 2005·Medicinal Research Reviews·Gavin J Kilpatrick, Terry W Smith
Jul 26, 2005·Nature Reviews. Drug Discovery·Hans-Jürgen Federsel

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Citations

Aug 30, 2014·Chemical Communications : Chem Comm·Gheorghe-Doru RoibanManfred T Reetz
Mar 7, 2013·Drug Metabolism Reviews·Satya Prakash TripathiAbhay T Sangamwar
Jul 18, 2008·The Journal of Organic Chemistry·Mark A PenickGeorge R Negrete
Dec 13, 2017·The Journal of Organic Chemistry·Shuhei YoshimatsuKenya Nakata
May 4, 2007·Journal of Medicinal Chemistry·Ingo BichlmaierJari Yli-Kauhaluoma

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