Novel 6-substituted uracil analogs as inhibitors of the angiogenic actions of thymidine phosphorylase

Thymidine phosphorylase (TP) catalyzes the reversible phosphorolysis of thymidine and other pyrimidine 2′-deoxyribonucleosides. In addition, TP has been shown to possess angiogenic activity in a number of in vitro and in vivo assays, and its angiogenic activity has been linked to its catalytic activ...

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Bibliographic Details
Published in:Biochemical pharmacology 2001-11, Vol.62 (9), p.1257-1263
Main Authors: Klein, Robert S., Lenzi, Michelle, Lim, Timothy H., Hotchkiss, Kylie A., Wilson, Phyllis, Schwartz, Edward L.
Format: Article
Language:English
Subjects:
Angiogenesis
Angiogenesis Inhibitors - chemistry
Angiogenesis Inhibitors - pharmacology
Antineoplastic agents
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Cell Movement - drug effects
Dose-Response Relationship, Drug
Endothelial cells
Endothelium, Vascular - drug effects
Endothelium, Vascular - enzymology
Endothelium, Vascular - physiology
General aspects
Humans
Medical sciences
Neovascularization, Physiologic - drug effects
Pharmacology. Drug treatments
Recombinant Proteins - antagonists & inhibitors
Recombinant Proteins - metabolism
Structure-Activity Relationship
Thymidine phosphorylase
Thymidine Phosphorylase - antagonists & inhibitors
Thymidine Phosphorylase - metabolism
Thymidine Phosphorylase - physiology
Tumor Cells, Cultured
Uracil - analogs & derivatives
Uracil - chemistry
Uracil - pharmacology
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Summary:Thymidine phosphorylase (TP) catalyzes the reversible phosphorolysis of thymidine and other pyrimidine 2′-deoxyribonucleosides. In addition, TP has been shown to possess angiogenic activity in a number of in vitro and in vivo assays, and its angiogenic activity has been linked to its catalytic activity. A series of 5- and 6-substituted uracil derivatives were synthesized and evaluated for their abilities to inhibit TP activity. Among the most active compounds was a 6-amino-substituted uracil analog, 6-(2-aminoethyl)amino-5-chlorouracil (AEAC), which was a competitive inhibitor with a K i of 165 nM. The inhibitory activity of AEAC was selective for TP, as it did not inhibit purine nucleoside phosphorylase or uridine phosphorylase at concentrations up to 1 mM. Human recombinant TP induced human umbilical vein endothelial cell (HUVEC) migration in a modified Boyden chamber assay in vitro, and this action could be abrogated by the TP inhibitors. The actions of the inhibitors were specific for TP, as they had no effect on the chemotactic actions of vascular endothelial growth factor (VEGF). HUVEC migration was also induced when TP-transfected human colon and breast carcinoma cells were co-cultured in the Boyden chamber assay in place of the purified angiogenic factors, and a TP inhibitor blocked the tumor cell-mediated migration almost completely. These studies suggest that inhibitors of TP may be useful in pathological conditions that are dependent upon TP-driven angiogenesis.
ISSN:0006-2952
1873-2968
DOI:10.1016/S0006-2952(01)00783-3