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.

DOI: 10.1016/j.ejmech.2011.04.010

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@article{Daumar2011DesignSA, title={Design, synthesis and in vitro drug release investigation of new potential 5-FU prodrugs.}, author={Pierre Daumar and Caroline Decombat and Jean-Michel Chezal and Eric D{\'e}biton and Michel Madesclaire and Pascal Coudert and M. J. Galmier}, journal={European journal of medicinal chemistry}, year={2011}, volume={46 7}, pages={2867-79} }