Xanthine oxidase-activated prodrugs of thymidine phosphorylase inhibitors.
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.
Reigan
Philip
P
School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Oxford Road, Manchester M13 9PL, UK.
Gbaj
Abdul
A
Stratford
Ian J
IJ
Bryce
Richard A
RA
Freeman
Sally
S
D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011355:Prodrugs / Q000493:pharmacokinetics*; D013055:Spectrophotometry, Infrared; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014969:Xanthine Oxidase / Q000378:metabolism*
D004791:Enzyme Inhibitors; D011355:Prodrugs; D014969:Xanthine Oxidase; D013939:Thymidine Phosphorylase