Synthesis and Evaluation of Multisubstrate Bicyclic Pyrimidine Nucleoside Inhibitors of Human Thymidine Phosphorylase
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- 作者：Amy L. Allan ; Patricia L. Gladstone ; Melissa L. P. Price ; Stephanie A. Hopkins ; Jose C. Juarez ; Fernando Doñ ; ate ; Robert J. Ternansky ; David E. Shaw ; Bruce Ganem ; Yingbo Li ; Weiru Wang ; Steven E
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：December 28, 2006
- 年：2006
- 卷：49
- 期：26
- 页码：7807 - 7815
- 全文大小：132K
- 年卷期：v.49,no.26(December 28, 2006)
- ISSN：1520-4804
文摘
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 significantrole in tumor progression and metastasis. The presence and orientation of the phosphonate moiety (actingas a phosphate mimic) in these derivatives were critical for inhibitory activity. The most active compoundspossessed a phosphonate group in an endo orientation. This was consistent with molecular modeling resultsthat showed the endo isomer protein-ligand complex to be lower in energy than the exo complex.