Cerecetto Hugo, González Mercedes, Onetto Silvia, Saenz Patricia, Ezpeleta Olga, De Ceráin Adela López, Monge Antonio
Departamento de Química Orgánica, Facultad de Química - Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
Arch Pharm (Weinheim). 2004 May;337(5):247-58. doi: 10.1002/ardp.200300782.
New 1, 2, 4-Triazine N-oxide and N, N'-dioxide derivatives were synthesized in order to obtain compounds as selective hypoxic cell cytotoxins. The starting heterocycles have been prepared using a standard microwave oven in a clean and good-yielded process. The reactivity of methyl-1, 2, 4-triazine N(4)-oxide and N(1), N(4)-dioxide with different electrophilic agents has been studied. The desired products were obtained only when iminium electrophiles were employed. The regioselectivity of this process has been studied by means of experimental and theoretical (at ab initio level) procedures. Theoretically was expected that the most stable intermediates where the benzylic-like anion from position 5. A fact which agreed with the experimental observed regioselectivity. The new compounds were tested for their cytotoxicity in oxia and hypoxia. Some of them proved to be less active in hypoxic conditions than tirapazamine, 3-amino-benzo[1, 2-e]1, 2, 4-triazine N(1), N(4)-dioxide. Derivative 19, 6-methyl-5-[2-(5-nitrothienyl)ethenyl)-1, 2, 4-triazine N(4)-oxide, was the most cytotoxic compound, but it was non-selective.
为了获得作为选择性乏氧细胞细胞毒素的化合物，合成了新型的1, 2, 4-三嗪N-氧化物和N, N'-二氧化物衍生物。起始杂环已使用标准微波炉通过清洁且产率良好的过程制备。研究了甲基-1, 2, 4-三嗪N(4)-氧化物和N(1), N(4)-二氧化物与不同亲电试剂的反应活性。仅当使用亚胺鎓亲电试剂时才获得所需产物。通过实验和理论（从头算水平）方法研究了该过程的区域选择性。理论上预期最稳定的中间体是来自5位的苄基样阴离子。这一事实与实验观察到的区域选择性一致。对新化合物在有氧和乏氧条件下的细胞毒性进行了测试。其中一些在乏氧条件下的活性比替拉扎明（3-氨基-苯并[1, 2-e]1, 2, 4-三嗪N(1), N(4)-二氧化物）低。衍生物19，6-甲基-5-[2-(5-硝基噻吩基)乙烯基]-1, 2, 4-三嗪N(4)-氧化物是细胞毒性最强的化合物，但它没有选择性。
