6-Substituted 5-fluorouracil derivatives as transition state analogue inhibitors of thymidine phosphorylase

A combination of mechanism-based and structure-based design strategies led to the synthesis of a series of 5- and 6-substituted uracil derivatives as potential inhibitors of thymidine phosphorlase/platelet derived endothelial cell growth factor (TP/PD-ECGF). Among those tested, 6-imidazolylmethyl-5- fluorouracil was found to be the most potent inhibitor with a K _i-value of 51 nM, representing a new class of 5-fluoropyrimidines with a novel mechanism of action.