A 5-FU precursor designed to evade anabolic and catabolic drug pathways and activated by Pd chemistry in vitro and in vivo

Adam, C., Bray, T. L., Pérez-López, A. M., Tan, E. H., Rubio-Ruiz, B., Baillache, D. J., Houston, D. R., Salji, M. J. , Leung, H. Y. and Unciti-Broceta, A. (2022) A 5-FU precursor designed to evade anabolic and catabolic drug pathways and activated by Pd chemistry in vitro and in vivo. Journal of Medicinal Chemistry, 65(1), pp. 552-561. (doi: 10.1021/acs.jmedchem.1c01733) (PMID:34979089)

Abstract

5-Fluorouracil (5-FU) is an antineoplastic antimetabolite that is widely administered to cancer patients by bolus injection, especially to those suffering from colorectal and pancreatic cancer. Because of its suboptimal route of administration and dose-limiting toxicities, diverse 5-FU prodrugs have been developed to confer oral bioavailability and increase the safety profile of 5-FU chemotherapy regimens. Our contribution to this goal is presented herein with the development of a novel palladium-activated prodrug designed to evade the metabolic machinery responsible for 5-FU anabolic activation and catabolic processing. The new prodrug is completely innocuous to cells and highly resistant to metabolization by primary hepatocytes and liver S9 fractions (the main metabolic route for 5-FU degradation), whereas it is rapidly converted into 5-FU in the presence of a palladium (Pd) source. In vivo pharmokinetic analysis shows the prodrug is rapidly and completely absorbed after oral administration and exhibits a longer half-life than 5-FU. In vivo efficacy studies in a xenograft colon cancer model served to prove, for the first time, that orally administered prodrugs can be locally converted to active drugs by intratumorally inserted Pd implants.

• Item Type: Articles
• Additional Information: The authors are grateful to the EPSRC (EP/N021134/1) for funding. T.L.B. thanks the CMVM of the University of Edinburgh (Principal’s scholarship), and B.R.-R. thanks the EC (H2020- MSCA-IF-2014-658833, ChemoBOOM) for financial support. A.U.-B. and D.J.B. thank Medical Research Scotland (PHD1046-2016) for funding. We acknowledge support from the MRC Confidence in Concept scheme (MRC/CIC6/52) and EPSRC Impact Acceleration Account (PIII024).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Tan, Dr Ee and Leung, Professor Hing and Salji, Dr Mark
• Authors: Adam, C., Bray, T. L., Pérez-López, A. M., Tan, E. H., Rubio-Ruiz, B., Baillache, D. J., Houston, D. R., Salji, M. J., Leung, H. Y., and Unciti-Broceta, A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Medicinal Chemistry
• Publisher: American Chemical Society
• ISSN: 0022-2623
• ISSN (Online): 1520-4804
• Published Online: 03 January 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Journal of Medicinal Chemistry 65(1): 552-561
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
174350		Palladium-activated prodrug therapy: a novel focal therapy for localised cancers of unmet need	Hing Leung	Engineering and Physical Sciences Research Council (EPSRC)	EP/N021134/1	CS - Clinical Trials Research