Hyperconjugation with lone pair of morpholine nitrogen stabilizes transition state for phenyl hydroxylation in CYP3A4 metabolism of (S)-N-[1-(3-morpholin-4-yl phenyl) ethyl]-3-phenylacrylamide

Shaikh AR; Broclawik E; Ismael M; Tsuboi H; Koyama M; Kubo M; Del Carpio CA; Miyamoto A

Chemical Physics Letters, Vol.419, No.4-6, 523-527, 2006

DOI10.1016/j.cplett.2005.12.015 Export Citation

Hyperconjugation with lone pair of morpholine nitrogen stabilizes transition state for phenyl hydroxylation in CYP3A4 metabolism of (S)-N-[1-(3-morpholin-4-yl phenyl) ethyl]-3-phenylacrylamide

Shaikh AR, Broclawik E, Ismael M, Tsuboi H, Koyama M, Kubo M, Del Carpio CA, Miyamoto A

Using quantum chemical modelling we describe a novel effect in the mechanism of CYP3A4 metabolism for the arene substrate with o-substituent yielding a lone pair donation to conjugate pi system; this will compensate for the loss of aromaticity on formation of the tetrahedral complex and lower the rate-determining energy barrier. (c) 2005 Elsevier B.V. All rights reserved.