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

Bioorg Med Chem Lett. 2010 Feb 1;20(3):862-5. doi: 10.1016/j.bmcl.2009.12.081. Epub 2009 Dec 28.

Abstract

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 microM 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Humans
  • Inhibitory Concentration 50
  • Lymphoma, T-Cell / enzymology*
  • Nucleosides / chemistry*
  • Nucleosides / pharmacology
  • Organophosphonates / chemistry*
  • Organophosphonates / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Thymidine Phosphorylase / antagonists & inhibitors*
  • Thymidine Phosphorylase / metabolism

Substances

  • Nucleosides
  • Organophosphonates
  • Thymidine Phosphorylase