Alcina A, Fresno M, Alarcón B
Centro de Biología Molecular (CSIC-UAM), Universidad Autónoma, Madrid, Spain.
Antimicrob Agents Chemother. 1988 Sep;32(9):1412-5. doi: 10.1128/AAC.32.9.1412.
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.
P536是一种UDP - 葡萄糖类似物，先前被描述为一种抗病毒剂（M. J. 卡马拉萨、P. 费尔南德斯·雷萨、M. T. 加西亚·洛佩斯、F. G. 德拉斯·埃拉斯、P. P. 门德斯 - 卡斯特里隆、B. 阿拉孔和L. 卡拉斯科，《药物化学杂志》28:40 - 46, 1985年），在体外对克氏锥虫的细胞内和细胞外阶段具有强大且选择性的活性。对于在J774G8巨噬细胞样细胞内生长的克氏锥虫细胞外培养形式（前鞭毛体），其50%抑制浓度小于5微克/毫升，对于克氏锥虫细胞内形式（无鞭毛体）则为25微克/毫升。相比之下，对于培养的哺乳动物细胞，50%抑制浓度为100微克/毫升或更高，对于小鼠脾淋巴细胞的增殖，50%抑制浓度为180微克/毫升。此外，向感染克氏锥虫的J774G8细胞中添加P536（50微克/毫升）可治愈被感染的巨噬细胞，使其能够正常生长和发挥功能。对该药物作用机制的研究表明，它抑制了克氏锥虫前鞭毛体将[35S]甲硫氨酸、[3H]胸苷、[3H]甘露糖、[14C]-N - 乙酰葡糖胺和[3H]尿苷掺入大分子中，其中最后一种最为敏感。
