Electronic effects of para-substitution on acetophenones in the reaction of rat liver 3alpha-hydroxysteroid dehydrogenase.
Stereoselective reductive metabolism of various p-substituted acetophenone derivatives was studied using isolated rat liver 3alpha-hydroxysteroid dehydrogenase (3alpha-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 {(V(max)/K(m))X/(V(max)/K(m))H} versus the substituent parameter (pi, sigma(para), Es) shows an increasing rate mainly for electron-withdrawing substituents, with a correlation coefficient (r(2)) 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.
Uwai
Koji
K
Department of Pharmaceutics, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Sendai 981-8558, Japan. uwai@tohoku-pharm.ac.jp
Konno
Noboru
N
Yasuta
Yuka
Y
Takeshita
Mitsuhiro
M
D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific) / Q000378:metabolism*; D000098:Acetophenones / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D004583:Electrons; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D010084:Oxidation-Reduction; D051381:Rats
D000098:Acetophenones; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C038699:acetophenone