Prodrug of 5-Fluorouracil and 5-Ethynyluracil: Synthesis, Characterization, and Release Study

Abstract

The oral administration of the standard cytotoxic agent 5-fluorouracil is extensively limited in the last three decades. This limitation has owing to the inconsistent intestinal absorption of this drug because of the mutable activity of the enzyme housed in the intestinal mucosa named dihydropyrimidine dehydrogenase. In this report, a prodrug consists of 5-fluorouracil and 5-ethynyluracil was designed to providethe mutual release of these two active drugs using a lactonization-facilitated release method.The synthesis of the target prodrug was proceeded through seven subsequent steps using coumarin as a precursor. The spectra obtained from different spectrophotometers, including FTIR, ¹H-NMR, and ¹³C-NMR, were confirmed the chemical backbones of the synthetic intermediate compounds and the target prodrug. The chemical stability of the target prodrug was investigated chemically in the HCl- (pH 1.2) and phosphate-(pH 6.8) buffers. Also, the capacity of the prodrug to release its active portions was evaluated utilizinghuman serum. The results gathered from the chemical stability studies indicated that the targeted prodrug hassubstantial stability in the HCl-bufferwith t_1/2 of 33.18 hours, and in the phosphate-buffered saline with t_1/2 of 18.14 hours, adapting pseudo-first-order kinetics. Besides, the prodrug can free the two active drugswith t_1/2of 4.62 hr in human serum adapting zero-order kinetics. The authors concluded that the target prodrug may represent a potential applicant as a mutual prodrug for the oral intake ofthe 5-fluorouracil and 5-ethynyluracil.