title: Potential tumor-selective nitroimidazolylmethyluracil prodrug derivatives: inhibitors of the angiogenic enzyme thymidine phosphorylase.
abstract: 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-aminoimidazolylmethyluracils (4b/4c) were very potent inhibitors of E. coli TP (IC50 approximately 20 nM). Contrastingly, the corresponding 2'-nitroimidazolylmethyluracil (as bioreductively activated) prodrugs (3b/3c) were 1000-fold less active (IC50 22-24 microM). This approach may be used to selectively deliver TP inhibitors into hypoxic regions of solid tumors where TP is overexpressed.
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Cole
authors.forename: Philip
authors.initials: P
authors.lastname: Reigan
authors.forename: Abdul
authors.initials: A
authors.lastname: Gbaj
authors.forename: Philip N
authors.initials: PN
authors.lastname: Edwards
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Douglas
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Stratford
authors.forename: Sally
authors.initials: S
authors.lastname: Freeman
authors.forename: Mohammed
authors.initials: M
authors.lastname: Jaffar
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D004926:Escherichia coli / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D014498:Uracil; D013939:Thymidine Phosphorylase