Design, synthesis and in vitro drug release investigation of new potential 5-FU prodrugs

In order to identify new efficient prodrugs of 5-fluorouracil (5-FU) and to develop an original targeting approach using 2-fluoro-2-deoxyglucose (FDG) as a potential drug carrier, eight original 5-FU derivatives were synthesized: 5-FU was attached by the N1 position of the pyrimidinic ring to the C1 position of the FDG structure either by direct coupling (2a) or via various spacers (3, 6a–c, 10b and 19). A new sensitive high-performance liquid chromatography method was developed to simultaneously quantify 5-FU and its derivatives in human plasma and other relevant media at physiological temperatures. Half-lives were determined from the degradation profiles of these conjugates. Slow degradation of compounds 2a, 3, 10b and 19 was observed in vitro at 37 °C, but no 5-FU release was noticed. By contrast, the in vitro drug release profiles of compounds 6a–c followed pseudo-first-order kinetics, and 5-FU was found in all the media. The antiproliferative activity of the eight compounds was assessed in vitro by a fluorometric assay against two human solid cancer cell lines and one healthy cell line. A correlation was found between the activities of the compounds and their ability to release 5-FU efficiently.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Eight original FDG-coupled 5-FU derivatives were synthesized and characterized. ► Investigation of their stability by HPLC-UV in three different media. ► Estimation of their half-lives from their degradation profiles. ► In vitro stability studies of 5-FU carbamoyl derivatives showed 5-FU release. ► Good correlation between biological activity and ability to release 5-FU.