| Abstract | Thymidine phosphorylase (TP) is over-expressed in various tumour types and plays an important role in tumour angiogenesis, growth, invasion and metastasis. The enzymatic activity of TP is required for the angiogenic effect of TP, therefore, inhibitors of TP are of significant interest in cancer chemotherapy. A series of xanthine oxidase (XO) activated prodrugs of known inhibitors of TP have been designed and synthesized with the ultimate intent of improving tumour selectivity and pharmacokinetic characteristics. These prodrugs were not inhibitors of TP, but were selectively oxidized by XO at C-2 and/or C-4 of the uracil ring moiety to generate the desired TP inhibitor. Molecular modelling of both the TP inhibitors and XO-activated prodrugs rationalized their binding in the active site of the human TP crystal structure. |
| Authors | Philip Reigan, Abdul Gbaj, Ian J Stratford, Richard A Bryce, Sally Freeman
(Affiliation: School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Oxford Road, Manchester M13 9PL, UK.)
|
| Journal | European journal of medicinal chemistry
(Eur J Med Chem)
Vol. 43
Issue 6
Pg. 1248-60
(Jun 2008)
ISSN: 0223-5234 France |
| PMID | 17870212
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Enzyme Inhibitors
- Prodrugs
- Xanthine Oxidase
- Thymidine Phosphorylase
|
| Topics |
- Enzyme Activation
- Enzyme Inhibitors
(pharmacokinetics)
- Humans
- Magnetic Resonance Spectroscopy
- Models, Molecular
- Prodrugs
(pharmacokinetics)
- Spectrophotometry, Infrared
- Thymidine Phosphorylase
(antagonists & inhibitors, chemistry)
- Xanthine Oxidase
(metabolism)
|
