Abstract
The oral use of 5-fluorouracil is being deserted in the last decades due to its atypical intestinal absorption, which is primarily attributed to the mutable activity of dihydropyrimidine dehydrogenase located in the gastrointestinal mucosa. In this work, a coumarin-based prodrug system was utilized to synthesize a novel mutual prodrug of 5-fluorouracil and 5-ethynyluracil. This prodrug was designed to afford a concurrent release of these two active drugs resulting in the improvement of the therapeutic efficacy of both. The synthetic pathway involved 7 linear steps starting from coumarin. The chemical structures of the intermediates and prodrug were established by analyzing their FTIR, 1H-NMR, and 13C-NMR spectra. The in vitro chemical stability of the synthesized prodrug was tested in the HCl buffer (pH 1.2) and phosphate-buffered saline (pH 6.8), while its ability to release the active moieties was studied in human serum. The outcomes of these in vitro studies revealed that the prodrug showed a significant stability in the HCl buffer and phosphate-buffered saline with half-lives of 33.19 h and 18.13 hr respectively, obeying pseudo-first-order kinetics. Also, the prodrug was able to release the two active components in human serum with a half-life of 4.62 h obeying zero-order kinetics. It is concluded that the synthesized prodrug represents a promising oral prodrug of 5-fluorouracil and 5-ethynyluracil to serve better in therapeutics.
Highlights
Since its ingenious design and synthesis in 1957, 5-fluorouracil (5-FU) has been authenticated for the management of many tumor phenotypes [1]
This study aims to employ the coumarin-based prodrug system for synthesizing a mutual oral prodrug
Rationalization of the prodrug design The synthesized mutual prodrug was designed in an attempt to optimize the clinical usefulness of 5
Summary
Since its ingenious design and synthesis in 1957, 5-fluorouracil (5-FU) has been authenticated for the management of many tumor phenotypes [1]. The functionality of this cytotoxic drug in the chemotherapy is being doubted because of its severe adverse effects, poor targetability, and mounting tumor resistance [2, 3] To handle these limitations, many approaches have been applied such as the modulation of the administration schedules [4], alteration of the metabolic pathways [5], development of new fluorinated pyrimidines [6], and synthesis of prodrugs [7]. As an oral antitumor agent, the use of 5-FU was deserted in the last decades due to its atypical intestinal absorption that results in irregular plasma levels with marked inter- and intra-individual variations [9] This is primarily attributed to the mutable activity of HDPD located in the gastrointestinal mucosa [10]
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