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 Ki-value of 51 nM, representing a new class of 5-fluoropyrimidines with a novel mechanism of action.
Kalman
Thomas I
TI
Department of Chemistry, University at Buffalo, Amherst, NY 14260, USA. tkalman@buffalo.edu
Lai
Li
L
D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D011743:Pyrimidines / Q000737:chemistry; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors*
C506202:6-imidazolylmethyl-5-fluorouracil; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011743:Pyrimidines; D013939:Thymidine Phosphorylase; D005472:Fluorouracil