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-5-cyclopent-1-en-1-yluracil 7a is the most efficient derivative in this study, with Ki = 0.20 +/- 0.03 microM (Ki/dThdKm = 0.0017) for thymidine phosphorylase expressed in V79 cells and Ki = 0.29 +/- 0.04 microM (Ki/dThdKm = 0.0024) for the enzyme purified from placenta.

Gilead Sciences and IOCB Research Centre Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Centre for New Antivirals and Antineoplastics Flemingovo nam 2 Prague 6 Czech Republic

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$a Discovery of 5-substituted-6-chlorouracils as efficient inhibitors of human thymidine phosphorylase / $c R. Nencka, I. Votruba, H. Hřebabecký, P. Jansa, E. Tloušt'ová, K. Horská, M. Masojídková, A. Holý

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$a Gilead Sciences & IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Centre for New Antivirals and Antineoplastics, Flemingovo nam. 2, Prague 6, Czech Republic. nencka@uochb.cas.cz

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$a 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-5-cyclopent-1-en-1-yluracil 7a is the most efficient derivative in this study, with Ki = 0.20 +/- 0.03 microM (Ki/dThdKm = 0.0017) for thymidine phosphorylase expressed in V79 cells and Ki = 0.29 +/- 0.04 microM (Ki/dThdKm = 0.0024) for the enzyme purified from placenta.

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