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

J Med Chem. 2003 Jan 16;46(2):207-9. doi: 10.1021/jm020964w.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / chemical synthesis*
  • Angiogenesis Inhibitors / chemistry
  • Binding Sites
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Escherichia coli / chemistry
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Models, Molecular
  • Structure-Activity Relationship
  • Thymidine Phosphorylase / antagonists & inhibitors*
  • Thymidine Phosphorylase / chemistry
  • Uracil / analogs & derivatives*
  • Uracil / chemical synthesis*
  • Uracil / chemistry

Substances

  • Angiogenesis Inhibitors
  • Enzyme Inhibitors
  • Imidazoles
  • Uracil
  • Thymidine Phosphorylase