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

Vincent Poon; Christopher Bailey; Sandra Carvalho; Stephen Patterson; James W. B. Fyfe; Olga Semenova; Stephen K. Wrigley; Emily Hopkins; Ravi Manohar; Christopher Drake; Tetsuo Kokubun; John Boyle; Lisbet Kvaerno; Kristin Lees; Karl F. Hoffmann; Josephine Forde-Thomas; Susan Wyllie; Jonathan Steele; Ian H. Gilbert; Gary J.  Tarver

doi:10.1021/acs.jmedchem.5c01467

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

Vincent Poon, Christopher Bailey, Sandra Carvalho, Stephen Patterson, James W. B. Fyfe, Olga Semenova, Stephen K. Wrigley, Emily Hopkins, Ravi Manohar, Christopher Drake, Tetsuo Kokubun, John Boyle, Lisbet Kvaerno, Kristin Lees, Karl F. Hoffmann, Josephine Forde-Thomas, Susan Wyllie, Jonathan Steele, Ian H. Gilbert (Lead / Corresponding author), Gary J. Tarver (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	21479-21488
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	68
Issue number	20
Early online date	12 Oct 2025
DOIs	https://doi.org/10.1021/acs.jmedchem.5c01467
Publication status	Published - 23 Oct 2025

Keywords

Neglected Diseases
Biotransformation
Drug discovery
Cytochrome P450s
Late-stage functionalisation

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.jmedchem.5c01467Licence: CC BY

Final published versionFinal published version, 3.27 MBLicence: CC BY

Cite this

Poon, V., Bailey, C., Carvalho, S., Patterson, S., Fyfe, J. W. B., Semenova, O., Wrigley, S. K., Hopkins, E., Manohar, R., Drake, C., Kokubun, T., Boyle, J., Kvaerno, L., Lees, K., Hoffmann, K. F., Forde-Thomas, J., Wyllie, S., Steele, J., Gilbert, I. H., & Tarver, G. J. (2025). Use of P450 Enzymes for Late-Stage Functionalization in Drug Discovery. Journal of Medicinal Chemistry, 68(20), 21479-21488. https://doi.org/10.1021/acs.jmedchem.5c01467

@article{10b0dfe001954e178cebc23713717a0b,

title = "Use of P450 Enzymes for Late-Stage Functionalization in Drug Discovery",

abstract = "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.",

keywords = "Neglected Diseases, Biotransformation, Drug discovery, Cytochrome P450s, Late-stage functionalisation",

author = "Vincent Poon and Christopher Bailey and Sandra Carvalho and Stephen Patterson and Fyfe, \{James W. B.\} and Olga Semenova and Wrigley, \{Stephen K.\} and Emily Hopkins and Ravi Manohar and Christopher Drake and Tetsuo Kokubun and John Boyle and Lisbet Kvaerno and Kristin Lees and Hoffmann, \{Karl F.\} and Josephine Forde-Thomas and Susan Wyllie and Jonathan Steele and Gilbert, \{Ian H.\} and Tarver, \{Gary J.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors. Published by American Chemical Society",

year = "2025",

month = oct,

day = "23",

doi = "10.1021/acs.jmedchem.5c01467",

language = "English",

volume = "68",

pages = "21479--21488",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

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Poon, V, Bailey, C , Carvalho, S , Patterson, S , Fyfe, JWB , Semenova, O, Wrigley, SK, Hopkins, E, Manohar, R, Drake, C, Kokubun, T, Boyle, J, Kvaerno, L, Lees, K, Hoffmann, KF, Forde-Thomas, J, Wyllie, S, Steele, J, Gilbert, IH & Tarver, GJ 2025, 'Use of P450 Enzymes for Late-Stage Functionalization in Drug Discovery', Journal of Medicinal Chemistry, vol. 68, no. 20, pp. 21479-21488. https://doi.org/10.1021/acs.jmedchem.5c01467

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.

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

SN - 0022-2623

VL - 68

SP - 21479

EP - 21488

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 20

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Application of Biotransformations To Neglected Tropical Disease Research (Joint with Industrial Partner)

Wellcome Centre for Anti-Infectives Research

Cite this

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Application of Biotransformations To Neglected Tropical Disease Research (Joint with Industrial Partner)

Wellcome Centre for Anti-Infectives Research

Cite this