Alcohol dehydrogenases as tools for the preparation of enantiopure metabolites of drugs with methyl alkyl ketone moiety

Abstract

Three dehydrogenases - (R)-alcohol dehydrogenase from L. kefir, (SJ-aromatic alcohol dehydrogenase from T. sp. and (SJ-alcohol dehydrogenase from T. brockii - were tested for the preparation of enantiopure hydroxyl metabolites of pentoxifylline (PTX), propentofylline (PPT) and denbufylline (DBF). These metabolites have an important pharmacological significance. The experimental conditions were optimized for biocatalytic reactions. LKADH produced the chiral secondary alcohols: (R)-OHPTX, (R)-OHPPT and (R)-OHDBF, in an anti-Prelog's rule configuration. In contrast, TBADH and SAADH also generated chiral secondary alcohols, but according to Prelog's rule, giving (S)-OHPTX, (S)-OHPPT and (S)-OHDBF respectively. All the ADHs tested were characterized by a high enantioselectivity (ees of 99-100%), but the yield of bioconversion was only satisfactory for the reactions performed using LKADH, being in the 96-98% range for PPT and PTX respectively.