Aminoimidazolylmethyluracil analogues as potent inhibitors of thymidine phosphorylase and their bioreductive nitroimidazolyl prodrugs

Philip Reigan, Philip N. Edwards, Abdul Gbaj, Christian Cole, Simon T. Barry, Ken M. Page, Susan E. Ashton, Richard W A Luke, Kenneth T. Douglas, Ian J. Stratford, Mohammed Jaffar, Richard A. Bryce, Sally Freeman

    Research output: Contribution to journalArticlepeer-review


    Thymidine phosphorylase (TP) is an important target enzyme for cancer chemotherapy because it is expressed at high levels in the hypoxic regions of many tumors and inhibitors of TP have been shown in animal model studies to inhibit angiogenesis and metastasis, and to promote tumor cell apoptosis. The 5-halo-6-[(2′-aminoimidazol-1′-yl)methyl]uracils (3, X = Cl, Br) are very potent inhibitors of E. coli and human TP with IC50 values of ∼20 nM when the enzyme concentration is ∼40 nM. Their 4′-aminoimidazol-1′-yl analogues (4, X = Cl, Br) are >350-fold less active with IC50 values of ∼7 μM. The 5-unsubstituted analogues (3 and 4, X = H) were both less active than their 5-halo derivatives. Determination of pKa values and molecular modeling studies of these compounds in the active site of human TP was used to rationalize their activities. The finding that 3, X = Br has a poor pharmacokinetic (PK) profile in mice, coupled with the desire for tumor selectivity, led us to design prodrugs. The corresponding 2′-nitroimidazol-1′-ylmethyluracils (5, X = Cl, Br) are >1000-fold less active (IC50 22-24 μM) than their 2′-amino analogues and are reduced to the 2′-amino inhibitors (3, X = Cl, Br) by xanthine oxidase (XO). As XO is also highly expressed in many tumors, the 2′-nitro prodrugs have the potential to selectively deliver the potent 2′-aminoimidazol-1′-yl TP inhibitors into hypoxic solid tumors.
    Original languageEnglish
    Pages (from-to)392-402
    Number of pages10
    JournalJournal of Medicinal Chemistry
    Issue number2
    Publication statusPublished - 27 Jan 2005


    Dive into the research topics of 'Aminoimidazolylmethyluracil analogues as potent inhibitors of thymidine phosphorylase and their bioreductive nitroimidazolyl prodrugs'. Together they form a unique fingerprint.

    Cite this