Potential Tumor-Selective Nitroimidazolylmethyluracil Prodrug Derivatives:  Inhibitors of the Angiogenic Enzyme Thymidine Phosphorylase

• Published in: Journal of medicinal chemistry 2003-01, Vol.46 (2), p.207-209
• Main Authors: Cole, Christian, Reigan, Philip, Gbaj, Abdul, Edwards, Philip N, Douglas, Kenneth T, Stratford, Ian J, Freeman, Sally, Jaffar, Mohammed
• Format: Article
• Language: English
• Subjects: Angiogenesis Inhibitors - chemical synthesis; Angiogenesis Inhibitors - chemistry; Antineoplastic agents; Binding Sites; Biological and medical sciences; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Escherichia coli - chemistry; General aspects; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Medical sciences; Models, Molecular; Nitroimidazolylmethyluracil; Pharmacology. Drug treatments; Structure-Activity Relationship; Thymidine Phosphorylase - antagonists & inhibitors; Thymidine Phosphorylase - chemistry; Uracil - analogs & derivatives; Uracil - chemical synthesis; Uracil - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020964w

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 ∼ 20 nM). Contrastingly, the corresponding 2‘-nitroimidazolylmethyluracil (as bioreductively activated) prodrugs (3b/3c) were 1000-fold less active (IC50 22−24 μM). This approach may be used to selectively deliver TP inhibitors into hypoxic regions of solid tumors where TP is overexpressed.