Stereochemical Sensitivity of the Human UDP-glucuronosyltransferases 2B7 and 2B17

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.

Stereoselective Glucuronidation of 5-(4′-Hydroxyphenyl)-5-phenylhydantoin by Human UDP-Glucuronosyltransferase (UGT) 1A1, UGT1A9, and UGT2B15: Effects of UGT-UGT Interactions

“…It has been demonstrated that some UGT enzymes stereoselectively catalyze glucuronidation (Court et al, 2002;Tougou et al, 2004;Bichlmaier et al, 2006;Sten et al, 2006). In the present study, we characterized different human UGT enzymes for glucuronide formation using racemic 4Ј-HPPH.…”

The regioselective glucuronidation of morphine by dimerized human UGT2B7, 1A1, 1A9 and their allelic variants

“…UGT subtypes including UGT1A9, UGT1A10, UGT2B7, UGT2B15, and UGT2B17 can stereo-selectively catalyze the glucuronidation of substrates and affect their metabolites` pharmacological effects [26,[29][30][31][32][33] . However, there was no report on whether morphine antinociception can be enhanced via the selective alteration of its metabolite ratios by UGT2B7 allelic variants or dimerized with other UGTs.…”

Silylative Kinetic Resolution of Racemic 1-Indanol Derivatives Catalyzed by Chiral Guanidine

“…1 H NMR (CDCl 3 ) δ: 7.43−7.39 (m, 1H), 7.30−7.21 (m, 3H), 5.22 (t, J = 6.0 Hz, 1H), 3.05 (ddd, J = 16.0, 8.5, 5.0 Hz, 1H), 2.81 (dt, J = 16.0, 7.5 Hz, 1H), 2.52−2.42 (m, 1H), 2.19 (br s, 1H), 1.99−1.88 (m, 1H). (R)-4-Methyl-2,3-dihydro-1H-inden-1-ol ((R)-8a) 26 (Scheme 2, 97% ee). [α] D 24 = −11.4 (c 1.46, CHCl 3 ); lit.…”

“…[α] D 24 = −11.4 (c 1.46, CHCl 3 ); lit. 26 [α] D 23 = −36.3 (c 1.5, CHCl 3 ), 99% ee for R. HPLC (CHIRALPAK OD-3, i-PrOH/ hexane = 1/30, flow rate = 0.65 mL/min): t R = 23.9 min (1.7%), t R = 30.0 min (98.3%). 1 H NMR (CDCl 3 ) δ: 7.26 (d, J = 7.0 Hz, 1H), 7.18 (dt, J = 7.5, 7.0 Hz, 1H), 7.10 (d, J = 7.0 Hz, 1H), 5.24 (dd, J = 6.0, 5.5 Hz, 1H), 2.98 (ddd, J = 16.0, 8.5, 5.0 Hz, 1H), 2.73 (ddd, J = 16.0, 8.0, 7.0 Hz, 1H), 2.54−2.44 (m, 1H), 2.29 (s, 3H), 2.07 (br s, 1H), 1.99−1.90 (m, 1H).…”

“…(R)-6-Methyl-2,3-dihydro-1H-inden-1-ol ((R)-8e) 26 (Scheme 2, 99% ee). [α] D 22 = −48.0 (c 1.00, CHCl 3 ); lit.…”