Electronic effects of para-substitution on acetophenones in the reaction of rat liver 3α-hydroxysteroid dehydrogenase Original Research Article

Stereoselective reductive metabolism of various p-substituted acetophenone derivatives was studied using isolated rat liver 3α-hydroxysteroid dehydrogenase (3α-HSD). Kinetic experiments were performed and analyzed by measuring the products by HPLC using a chiral column. The results demonstrated that the presence of an electron-withdrawing substituent on the benzene ring plays an important role in determining the reduction rate in the syntheses of various (S)-alcohols from their corresponding carbonyl compounds. A plot of log {(Vmax/Km)X/(Vmax/Km)H} versus the substituent parameter (π, σpara, Es) shows an increasing rate mainly for electron-withdrawing substituents, with a correlation coefficient (r2) of 0.97 which was obtained for triplicate data that were significant at the p < 0.0001 level. With this in mind, new drugs can be designed that exploit this reduction pathway by introducing an electron-withdrawing group adjacent to the reduction site when a reduction reaction is desired, or by adding an electron-donating group when minimization of the reduction pathway is desired.