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

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.

• Authors: Amy L Allan, Patricia L Gladstone, Melissa L P Price, Stephanie A Hopkins, Jose C Juarez, Fernando Doñate, Robert J Ternansky, David E Shaw, Bruce Ganem, Yingbo Li, Weiru Wang, Steven Ealick
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 26 Pg. 7807-15 (Dec 28 2006) ISSN: 0022-2623 [Print] United States
• PMID: 17181163 (Publication Type: Evaluation Study, Journal Article)

Chemical References

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

Topics

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