Potential tumor-selective nitroimidazolylmethyluracil prodrug derivatives: Inhibitors of the angiogenic enzyme thymidine phosphorylase

Thymidine phosphorylase (TP) is an angiogenic growth factor and a target for anticancer drug design. Molecular modeling suggested that 2'-aminoimidazolylmethyluracils would be potent inhibitors of TP. The novel 5-halo-2-amino-imidazolylmethyluracils (4b/4c) were very potent inhibitors of E. coli TP (IC50 similar to 20 nM). Contrastingly, the corresponding 2'-nitroimidazolylmethyluracil (as bioreductively activated) prodrugs (3b/3c) were 1000-fold less active (IC50 22-24 muM). This approach may be used to selectively deliver TP inhibitors into hypoxic regions of solid tumors where TP is overexpressed.