A 5‑FU Precursor Designed to Evade Anabolic and Catabolic Drug Pathways and Activated by Pd Chemistry In Vitro and In Vivo

• Published in: Journal of medicinal chemistry Vol. 65; no. 1; pp. 552 - 561
• Main Authors: Adam, Catherine, Bray, Thomas L, Pérez-López, Ana M, Tan, Ee Hong, Rubio-Ruiz, Belén, Baillache, Daniel J, Houston, Douglas R, Salji, Mark J, Leung, Hing Y, Unciti-Broceta, Asier
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13.01.2022
• Subjects: Animals; Antimetabolites, Antineoplastic - metabolism; Antimetabolites, Antineoplastic - toxicity; Biotransformation; Fluorouracil - analogs & derivatives; Fluorouracil - metabolism; Fluorouracil - toxicity; Half-Life; HCT116 Cells; Hepatocytes - drug effects; Hepatocytes - metabolism; Humans; Liver - metabolism; Metabolic Networks and Pathways - drug effects; Mice; Palladium - chemistry; Prodrugs - metabolism; Prodrugs - toxicity; Protein Binding; Rats; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c01733

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.