Premium
Chiral inversion of RS‐8359: A selective and reversible MAO‐A inhibitor via oxido‐reduction of keto‐alcohol
Author(s) -
Itoh Kunio,
Hoshino Kouichi,
Endo Asuka,
Asakawa Tasuku,
Yamakami Kazumi,
Noji Chisa,
Kosaka Toshiyuki,
Tanaka Yorihisa
Publication year - 2006
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.20309
Subject(s) - chemistry , enantiomer , cofactor , alcohol dehydrogenase , stereochemistry , enzyme , alcohol , nad+ kinase , biochemistry
Abstract RS‐8359, (±)‐4‐(4‐cyanoanilino)‐5,6‐dihydro‐7‐hydroxy‐7 H ‐cyclopenta[ d ]‐pyrimidine is a selective and reversible MAO‐A inhibitor. The ( S )‐enantiomer of RS‐8359 has been demonstrated to be inverted to the ( R )‐enantiomer after oral administration to rats. In the current study, we investigated the chiral inversion mechanism and the properties of involved enzymes using rat liver subcellular fractions. The 7‐hydroxy function of RS‐8359 was oxidized at least by the two different enzymes. The cytosolic enzyme oxidized enantiospecifically the ( S )‐enantiomer with NADP as a cofactor. On the other hand, the microsomal enzyme catalyzed more preferentially the oxidation of the ( S )‐enantiomer than the ( R )‐enantiomer with NAD as a cofactor. With to product enantioselectivity of reduction of the 7‐keto derivative, it was found that only the alcohol bearing ( R )‐configuration was formed by the cytosolic enzyme with NADPH and the microsomal enzyme with NADH at almost equal rate. The reduction rate was much larger than the oxidation rate of 7‐hydroxy group. The results suggest that the chiral inversion might occur via an enantioselectivity of consecutive two opposing reactions, oxidation and reduction of keto‐alcohol group. In this case, the direction of chiral inversion from the ( S )‐enantiomer to the ( R )‐enantiomer is governed by the enantiospecific reduction of intermediate 7‐keto group to the alcohol with ( R )‐configuration. The enzyme responsible for the enantiospecific reduction of the 7‐keto group was purified from rat liver cytosolic fractions and identified as 3α‐hydroxysteroid dehydrogenase (3α‐HSD) via database search of peptide mass data obtained by nano‐LC/MS/MS. Chirality, 2006. © 2006 Wiley‐Liss, Inc.