Discovery of 5-substituted-6-chlorouracils as efficient inhibitors of human thymidine phosphorylase

作者：Nencka Radim^*; Votruba Ivan; Hrebabecky Hubert; Jansa Petr; Tloust'ova Eva; Horska Kevta; Masojidkova Milena; Holy Antonin

来源：Journal of Medicinal Chemistry, 2007, 50(24): 6016-6023.

DOI：10.1021/jm070644i

Thymidine phosphorylase plays an important role in angiogenesis, which is an attractive target for therapy of 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 exhibit significant inhibitory activity against this enzyme. The most potent compounds bear a five- or six-membered cyclic substituent containing a pi-electron system at C5 and a chlorine atom attached at C6. 6-Chloro-5cyclopent-1-en-1-yluracil 7a is the most efficient derivative in this study, with K-i = 0.20 +/- 0.03 mu M (K-i /K-dThd(m), = 0.0017) for thymidine phosphorylase expressed in V79 cells and K-i = 0.29 +/- 0.04 mu M (K-i /K-dThd(m), = 0.0024) for the enzyme purified from placenta.

• 出版日期2007-11-29