Triple coumarin-based 5-fluorouracil prodrugs, their synthesis, characterization, and release kinetics

Abstract

5-Fluorouracil (5-FU) has been commonly used as a chemotherapy medication in cancer management. However, owing to its substantial side effects, limited selectivity, and tumor resistance, therapeutic usage of 5-FU has been called into doubt. In order to alter the physicochemical properties of 5-FU and improve its targeting, a coumarin-based-esterase-sensitive prodrug system was used to create nine 5-FU prodrugs, which were divided into three series of compounds, A, B, and C. The chemical structures of these prodrugs are confirmed by using FTIR, 1H-NMR, 13C-NMR, and mass spectrophotometers. The chemical stability of these prodrugs in simulated gastric and intestinal fluids as well as their release in human serum were measured spectrophotometrically. The outcomes showed that the synthetic prodrugs had extraordinary stability in the two stimulated fluids with relatively high half-lives, indicating that they can transit through the upper GIT portions without being harmed. The half-lives of the produced prodrugs in human serum vary from 391.30 to 517.94 min, demonstrating their ability to enter their target tissues undamaged and release their active components in pseudo-first-order kinetics. These components include 5-FU, coumarin or one of its derivatives, and one of the 5-FU biochemical modifiers, which are legumain-specific tripeptide, dichloroacetate, or leucovorin. In conclusion, It is hypothesized that the prepared triple coumarin-based 5-FU prodrugs offer several advantages, including improving the physicochemical properties of the parent drug, potentiating its anticancer activity, minimizing its toxic effects, boosting its oral bioavailability, and providing the capacity for specific targeting.