Temple C, Rener G A, Comber R N
Southern Research Institute, Birmingham, Alabama 35255-5305.
J Med Chem. 1989 Oct;32(10):2363-7. doi: 10.1021/jm00130a023.
The ethyl (1,2-dihydropyrido[3,4-b]pyrazin-7-yl)carbamates have been reported to bind with cellular tubulin, to produce an accumulation of cells at mitosis, and to exhibit cytotoxic activity against experimental neoplasms in mice. Studies on the disposition of ethyl (5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 -yl)carbamate (8) in mice showed that one metabolite was formed by cleavage of the ethyl carbamate moiety. Analogues with alterations in the carbamate group were prepared by transformations at the carbamate of 8, by reductive cyclization of nitropyridine intermediates, and by hydride reduction of the ring of heteroaromatic compounds. In vitro and in vivo evaluations of analogues indicated that a carbamate group was required for activity. No significant change in activity was observed when ethyl was replaced by methyl. However, activity was reduced when ethyl was replaced with bulky aliphatic groups and when ethoxy was replaced with a methylamino group. Also, the activity of 8 was decreased by acetylation of the 5-amino group and was destroyed by substitution of an amino group at the 8-position.
据报道，乙基（1,2 - 二氢吡啶并[3,4 - b]吡嗪 - 7 - 基）氨基甲酸酯可与细胞微管蛋白结合，使细胞在有丝分裂时积累，并对小鼠实验性肿瘤表现出细胞毒性活性。对乙基（5 - 氨基 - 1,2 - 二氢 - 2 - 甲基 - 3 - 苯基吡啶并[3,4 - b]吡嗪 - 7 - 基）氨基甲酸酯（8）在小鼠体内的代谢研究表明，一种代谢产物是由氨基甲酸乙酯部分的裂解形成的。通过对8的氨基甲酸酯进行转化、硝基吡啶中间体的还原环化以及杂环芳烃环的氢化物还原，制备了氨基甲酸酯基团发生改变的类似物。对类似物的体外和体内评估表明，活性需要氨基甲酸酯基团。当乙基被甲基取代时，未观察到活性有显著变化。然而，当乙基被庞大的脂肪族基团取代以及乙氧基被甲氨基取代时，活性降低。此外，8的活性因5 - 氨基的乙酰化而降低，并因在8位取代氨基而被破坏。
