Hydroxylation of diclofenac: an illustration of the complementary roles of biomimetic metalloporphyrin catalysts and yeasts expressing human cytochromes P450 in drug metabolism studies

Abstract Preparative hydroxylation of aromatic compounds such as drugs remain a difficult challenge. Here we show that the two main human metabolites of the anti-inflammatory drug diclofenac, 5-hydroxy- and 4′-hydroxy-diclofenac, can be prepared from diclofenac in high yields by using two complementary model systems for human cytochromes P450. The former, which results from hydroxylation of the most reactive aromatic position of diclofenac, was obtained by using H 2 O 2 or t -BuOOH in the presence of an iron porphyrin. The latter could only be prepared from bioconversion of diclofenac with a recombinant yeast expressing human cytochrome P450 2C9.