Inhibition of thymidine phosphorylase (PD-ECGF) from SD-lymphoma by phosphonomethoxyalkyl thymines

• Published in: Biochemical pharmacology 2005-05, Vol.69 (10), p.1517-1521
• Main Authors: Votruba, Ivan, Pomeisl, Karel, Tloušt’ová, Eva, Holý, Antonín, Otová, Berta
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Enzyme Inhibitors - pharmacology; Escherichia coli; FPMPT; Lymphoma, T-Cell - enzymology; Medical sciences; Organophosphonates - pharmacology; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Stereoisomerism; Structure-Activity Relationship; Thymidine Phosphorylase - antagonists & inhibitors; Thymidine phosphorylase inhibition; Thymine - analogs & derivatives; Thymine - pharmacology; Thymine acyclic nucleoside phosphonates; Thymopoietins - pharmacology
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2005.03.003

A series of thymine phosphonomethoxyalkyl derivatives were evaluated for their ability to inhibit thymidine phosphorylase (dThdPase) purified from rat spontaneous T-cell lymphoma. A kinetic study of thymidine phosphorolysis catalyzed by dThdPase was performed with thymidine and/or inorganic phosphate as substrates. Data show that the substantial inhibitory effect of these acyclic nucleotide analogues is decreasing in the order of ( R)-FPMPT > ( S)-FPMPT ≥ ( R)-HPMPT > ( S)-PMPT > ( S)-HPMPT > PMET ≥ ( R)-PMPT. The inhibitory potency ( K i/ dThd K m) of the most efficient inhibitors from this series against T-cell lymphoma enzyme is 0.0026 for ( R)-FPMPT and 0.0048 for ( S)-FPMPT. The studied compounds do not inhibit Escherichia coli and human enzyme and possess lower inhibitory potency against rat liver thymidine phosphorylase.