Structural diversity of nucleoside phosphonic acids as a key factor in the discovery of potent inhibitors of rat T-cell lymphoma thymidine phosphorylase

• Published in: Bioorganic & medicinal chemistry letters 2010-02, Vol.20 (3), p.862-865
• Main Authors: Kočalka, Petr, Rejman, Dominik, Vaněk, Václav, Rinnová, Markéta, Tomečková, Ivana, Králíková, Šárka, Petrová, Magdalena, Páv, Ondřej, Pohl, Radek, Buděšínský, Miloš, Liboska, Radek, Točík, Zdeněk, Panova, Natalya, Votruba, Ivan, Rosenberg, Ivan
• Format: Article
• Language: English
• Subjects: Animals; Dose-Response Relationship, Drug; Humans; Inhibitory Concentration 50; Lymphoma, T-Cell - enzymology; Nucleosides - chemistry; Nucleosides - pharmacology; Nucleotide analogues; Organophosphonates - chemistry; Organophosphonates - pharmacology; Phosphonate; Pyrrolidine; Rat T-cell lymphomas; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thymidine phosphorylase; Thymidine Phosphorylase - antagonists & inhibitors; Thymidine Phosphorylase - metabolism
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.12.081

Potent inhibitors of the rat T-cell lymphoma thymidine phosphorylase with IC 50 values within 11–45 nM. Structurally diverse, sugar-modified, thymine-containing nucleoside phosphonic acids were evaluated for their ability to inhibit thymidine phosphorylase (TP, EC 2.4.2.4) purified from spontaneous T-cell lymphomas of an inbred Sprague-Dawley rat strain. From a large set of tested compounds, among them a number of pyrrolidine-based derivatives, 10 nucleotide analogues with IC 50 values below 1 μM were selected. Out of them, four compounds strongly inhibited the enzyme with IC 50 values lying in a range of 11–45 nM. These most potent compounds might be bi-substrate analogues.