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

TY - JOUR

T1 - Use of P450 Enzymes for Late-Stage Functionalization in Drug Discovery

AU - Poon, Vincent

AU - Bailey, Christopher

AU - Carvalho, Sandra

AU - Patterson, Stephen

AU - Fyfe, James W. B.

AU - Semenova, Olga

AU - Wrigley, Stephen K.

AU - Hopkins, Emily

AU - Manohar, Ravi

AU - Drake, Christopher

AU - Kokubun, Tetsuo

AU - Boyle, John

AU - Kvaerno, Lisbet

AU - Lees, Kristin

AU - Hoffmann, Karl F.

AU - Forde-Thomas, Josephine

AU - Wyllie, Susan

AU - Steele, Jonathan

AU - Gilbert, Ian H.

AU - Tarver, Gary J.

N1 - Publisher Copyright: © 2025 The Authors. Published by American Chemical Society

PY - 2025/10/23

Y1 - 2025/10/23

N2 - 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.

AB - 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.

KW - Neglected Diseases

KW - Biotransformation

KW - Drug discovery

KW - Cytochrome P450s

KW - Late-stage functionalisation

UR - https://www.scopus.com/pages/publications/105019556289

U2 - 10.1021/acs.jmedchem.5c01467

DO - 10.1021/acs.jmedchem.5c01467

M3 - Article

C2 - 41076635

SN - 0022-2623

VL - 68

SP - 21479

EP - 21488

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 20

ER -