Discovery of 5-Substituted-6-chlorouracils as Efficient Inhibitors of Human Thymidine Phosphorylase

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• 作者：Radim Nencka ; Ivan Votruba ; Hubert Hebabeck ; Petr Jansa ; Eva Tlout'ová ; Kvta Horská ; Milena Masojí ; dková ; Antoní ; n Hol
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 29, 2007
• 年：2007
• 卷：50
• 期：24
• 页码：6016 - 6023
• 全文大小：257K
• 年卷期：v.50,no.24(November 29, 2007)
• ISSN：1520-4804

文摘

Thymidine phosphorylase plays an important role in angiogenesis, which is an attractive target for therapyof cancer and other diseases. In our continuous effort to develop novel inhibitors of thymidine phosphorylase,we have discovered that 6-halouracils substituted at position C5 by certain hydrophobic groups exhibitsignificant inhibitory activity against this enzyme. The most potent compounds bear a five- or six-memberedcyclic substituent containing a -electron system at C5 and a chlorine atom attached at C6. 6-Chloro-5-cyclopent-1-en-1-yluracil 7a is the most efficient derivative in this study, with K_i = 0.20 ± 0.03 M(K_i/^dThdK_m = 0.0017) for thymidine phosphorylase expressed in V79 cells and K_i = 0.29 ± 0.04 M(K_i/^dThdK_m = 0.0024) for the enzyme purified from placenta.