Discovery of 5-substituted-6-chlorouracils as efficient inhibitors of human thymidine phosphorylase
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 π-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 μM (Ki/ dThdKm = 0.0017) for thymidine phosphorylase expressed in V79 cells and Ki = 0.29 ± 0.04 μM (Ki/ dThdKm = 0.0024) for the enzyme purified from placenta.
Nencka, Radim,Votruba, Ivan,H?ebabecky, Hubert,Jansa, Petr,Tlou?t'ová, Eva,Horská, Květa,Masojídková, Milena,Holy, Antonín
p. 6016 - 6023
(2008/09/17)
Chemo- and regioselective functionalization of uracil derivatives. Applications to the synthesis of oxypurinol and emivirine
A novel route for the synthesis of 4,5-difunctionalized uracils using a chemo- and regioselective bromine/magnesium exchange reaction on 5-bromo-4-halogeno-2,6-dimethoxypyrimidines has been developed. Applications to the synthesis of pharmaceuticals such as oxypurinol and emivirine are reported.
Boudet, Nadege,Knochel, Paul
p. 3737 - 3740
(2007/10/03)
Metallation of diazines. III. New synthesis of analogues of trimethoprim and of bacimethrin
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Ple,Turck,Fiquet,Queguiner
p. 283 - 288
(2007/10/02)
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