A 5‑FU Precursor Designed to Evade Anabolic and Catabolic Drug Pathways and Activated by Pd Chemistry In Vitro and In Vivo
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J. Med. Chem. 2022, 65, 1, 552–561. [https://doi.org/10.1021/acs.jmedchem.1c01733]
SponsorshipUK Research & Innovation (UKRI) Engineering & Physical Sciences Research Council (EPSRC) EP/N021134/1; CMVM of the University of Edinburgh; European Commission European Commission Joint Research Centre H2020MSCA-IF-2014-658833; Medical Research Scotland PHD-1046-2016; UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MRC/CIC6/52 UK Research & Innovation (UKRI); Engineering & Physical Sciences Research Council (EPSRC) PIII024
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.