Activity of P536, a UDP-glucose analog, against Trypanosoma cruzi.
P536, a UDP-glucose analog which was previously described as an antiviral agent (M. J. Camaraza, P. Fernández Resa, M. T. García López, F. G. de las Heras, P. P. Mendez-Castrillón, B. Alarcón, and L. Carrasco, J. Med. Chem. 28:40-46, 1985), has a potent and selective activity against the intracellular and extracellular stages of Trypanosoma cruzi in vitro. It had a 50% inhibitory concentration of less than 5 micrograms/ml for T. cruzi extracellular cultured forms (epimastigote) and of 25 micrograms/ml for T. cruzi intracellular forms (amastigote) growing inside J774G8 macrophagelike cells. In contrast, the 50% inhibitory concentration was 100 micrograms/ml or greater for cultured mammalian cells and 180 micrograms/ml for the proliferation of mouse spleen lymphocytes. Furthermore, the addition of P536 (50 micrograms/ml) to T. cruzi-infected J774G8 cells cured the infected macrophages, making them able to grow and function normally. Studies on the mechanism of action of this drug indicated that it inhibited incorporation of [35S]methionine, [3H]thymidine, [3H]mannose, [14C]-N-acetylglucosamine, and [3H]uridine into macromolecules by T. cruzi epimastigotes, the last being the most sensitive.
Alcina
A
A
Centro de Biología Molecular (CSIC-UAM), Universidad Autónoma, Madrid, Spain.
Fresno
M
M
Alarcón
B
B
D000818:Animals; D002478:Cells, Cultured; D003470:Culture Media; D008264:Macrophages / Q000187:drug effects; D012414:Rubidium Radioisotopes; D013450:Sulfones / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology
D003470:Culture Media; D012414:Rubidium Radioisotopes; D013450:Sulfones; C057536:P 536; D014529:Uridine