American Chemical Society
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Synthesis and Evaluation of Multisubstrate Bicyclic Pyrimidine Nucleoside Inhibitors of Human Thymidine Phosphorylase

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journal contribution
posted on 2006-12-28, 00:00 authored by 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
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.