A 5‑FU Precursor Designed to Evade Anabolic and Catabolic Drug Pathways and Activated by Pd Chemistry In Vitro and In Vivo Adam, Catherine Rubio Ruiz, Belén We 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 (H2020MSCA-IF-2014-658833, ChemoBOOM) for financial support. A.U.-B. and D.J.B. thank Medical Research Scotland (PHD-1046-2016) for funding. We acknowledge support from the MRC Confidence in Concept scheme (MRC/CIC6/52) and EPSRC Impact Acceleration Account (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. 2022-02-02T09:08:00Z 2022-02-02T09:08:00Z 2022-01-03 info:eu-repo/semantics/article J. Med. Chem. 2022, 65, 1, 552–561. [https://doi.org/10.1021/acs.jmedchem.1c01733] http://hdl.handle.net/10481/72604 10.1021/acs.jmedchem.1c01733 eng info:eu-repo/grantAgreement/EC/H2020/658833 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España American Chemical Society