Synthesis and evaluation of multisubstrate bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase

J Med Chem. 2006 Dec 28;49(26):7807-15. doi: 10.1021/jm060428u.

Abstract

A series of novel, multisubstrate, bicyclic pyrimidine nucleoside inhibitors of human thymidine phosphorylase (TP) is described. Thymidine phosphorylase has been implicated in angiogenesis and plays a significant role in tumor progression and metastasis. The presence and orientation of the phosphonate moiety (acting as a phosphate mimic) in these derivatives were critical for inhibitory activity. The most active compounds possessed a phosphonate group in an endo orientation. This was consistent with molecular modeling results that showed the endo isomer protein-ligand complex to be lower in energy than the exo complex.

Publication types

  • Evaluation Study

MeSH terms

  • Bridged Bicyclo Compounds, Heterocyclic / chemical synthesis*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Pyrimidine Nucleosides / chemical synthesis*
  • Pyrimidine Nucleosides / chemistry
  • Pyrimidine Nucleosides / pharmacology
  • Structure-Activity Relationship
  • Thymidine Phosphorylase / antagonists & inhibitors*

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Enzyme Inhibitors
  • Pyrimidine Nucleosides
  • Thymidine Phosphorylase