Use of P450 Enzymes for Late-Stage Functionalization in Drug Discovery

Herein, we demonstrate the use of a commercially available enzymatic kit to achieve late-stage hydroxylation of biologically relevant compounds by using the PolyCYPs screening kit. A selection of promising biotransformations were scaled up, products isolated, and structures elucidated. Isolated compounds were screened against a range of pathogens, namely, Schistosoma mansoni, Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei to obtain biological data. This approach has allowed data generation more efficiently than the chemical synthesis of the same molecules. Importantly, it has been demonstrated that production of hits of interest can also be scaled up to enable further study. We also demonstrate the biosynthetic synthesis of a lead compound in fewer steps than using standard synthetic chemistry, offering faster access to compounds for screening or further transformation. This approach has the potential to save time and resources in a drug discovery program, by reducing the necessity to synthesize late-stage intermediates and develop new chemistry.