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

Robert S. Klein, Michelle Lenzi, Timothy H. Lim, Kylie A. Hotchkiss, Phyllis Wilson, Edward L. Schwartz

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Abstract

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 Ki 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.

Original languageEnglish (US)
Pages (from-to)1257-1263
Number of pages7
JournalBiochemical Pharmacology
Volume62
Issue number9
DOIs
StatePublished - Nov 1 2001

Fingerprint

Thymidine Phosphorylase
Angiogenesis Inhibitors
Uracil
Cell Movement
Assays
Endothelial cells
Human Umbilical Vein Endothelial Cells
Uridine Phosphorylase
Cells
Purine-Nucleoside Phosphorylase
Deoxyribonucleosides
Angiogenesis Inducing Agents
Thymidine
Vascular Endothelial Growth Factor A
Tumors
Catalyst activity
Colon

Keywords

  • Angiogenesis
  • Endothelial cells
  • Thymidine phosphorylase

ASJC Scopus subject areas

  • Pharmacology

Cite this

Novel 6-substituted uracil analogs as inhibitors of the angiogenic actions of thymidine phosphorylase. / Klein, Robert S.; Lenzi, Michelle; Lim, Timothy H.; Hotchkiss, Kylie A.; Wilson, Phyllis; Schwartz, Edward L.

In: Biochemical Pharmacology, Vol. 62, No. 9, 01.11.2001, p. 1257-1263.

Research output: Contribution to journalArticle

Klein, Robert S. ; Lenzi, Michelle ; Lim, Timothy H. ; Hotchkiss, Kylie A. ; Wilson, Phyllis ; Schwartz, Edward L. / Novel 6-substituted uracil analogs as inhibitors of the angiogenic actions of thymidine phosphorylase. In: Biochemical Pharmacology. 2001 ; Vol. 62, No. 9. pp. 1257-1263.
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