A 5-FU Precursor Designed to Evade Anabolic and Catabolic Drug Pathways and Activated by Pd Chemistry In Vitro and In Vivo
| Autor: | Catherine Adam, Thomas L. Bray, Ana M. Pérez-López, Ee Hong Tan, Belén Rubio-Ruiz, Daniel J. Baillache, Douglas R. Houston, Mark J. Salji, Hing Y. Leung, Asier Unciti-Broceta |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Antimetabolites
Antineoplastic 010405 organic chemistry 010402 general chemistry HCT116 Cells 01 natural sciences Xenograft Model Antitumor Assays 0104 chemical sciences 3. Good health Rats Mice Liver Drug Discovery Hepatocytes Molecular Medicine Animals Humans Prodrugs Fluorouracil Biotransformation Metabolic Networks and Pathways Palladium Half-Life Protein Binding |
| Zdroj: | Adam, C, Bray, T, Perez-Lopez, A, Tan, E H, Rubio Ruiz, B, Baillache, D, Houston, D R, Salji, M J, Leung, H Y & 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, vol. 65, no. 1, pp. 552-561 . https://doi.org/10.1021/acs.jmedchem.1c01733 |
| ISSN: | 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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