Antimitotic agents: structure-activity studies with some pyridine derivatives.
Antimitotic agents: structure-activity studies with some pyridine derivatives.
复制标题
抗有丝分裂剂：一些吡啶衍生物的结构活性研究。
DOI：
10.1021/jm00098a014
复制
发表时间：
1992
影响因子：
7.3
通讯作者：
Noker,PE
中科院分区：
文献类型：
--
作者：
TempleJr,C;Rener,GA;Waud,WR;Noker,PE
在小鼠中观察到先前报道的乙基[6-氨基-4-[（1-甲基-2-苯基-2-氧代乙基）氨基]-5-硝基吡啶-2-基]氨基甲酸酯（8）的肟和几种相关化合物的抗肿瘤活性。这些化合物是活性吡啶并[3，4-b]吡嗪-7-基氨基甲酸乙酯（如4）的前体，后者是有效的抗有丝分裂剂。在5-硝基吡啶系列中，通过用酮基或醇基取代肟部分以及通过用氢取代侧链的1-甲基，降低了整体生物活性。将侧链含醇的5-硝基吡啶的硝基还原为相应的5-氨基吡啶可提高生物活性。初步研究表明，5-硝基吡啶肟作为抗有丝分裂剂的效力远低于吡啶吡嗪，并且前者在体内显然不会转化为后者。5-硝基吡啶肟的另一种可能的作用方式是抑制嘧啶核苷向DNA和RNA中的转化。许多具有不同结构的化合物，如考布他汀A-4（1），1安非他明（2），1 4（3#）-喹唑酮3，2和1，2-二氢吡啶并[3，4-6]吡啶（S）-4，已知3与秋水仙素竞争微管蛋白上的结合位点（图I）。这种作用方式干扰微管蛋白聚合形成微管，因此这些药物对小鼠实验性肿瘤显示出抗癌活性。另一种微管抑制剂，顺式-tubulazole（5），但不是反式异构体，也在小鼠中显示出活性。4在NCI药物合成与化学分支的指导下，在（RS）-4的再合成中，5-硝基吡啶前体在小鼠中显示出与目标化合物相似的活性。这一结果促使人们在以前制备的吡啶中间体中寻找生物活性。另一个目的是确定吡啶化合物是否是抗有丝分裂剂，以及这种活性是否是代谢转化为1，2-二氢吡啶并[3，4-6]吡嗪的结果。
Antitumor activity in mice was observed for the oxime of the previously reported ethyl [6-amino-4-[(l-methyl-2-phenyl-2-oxoethyl) amino]-5-nitropyridin-2-yl] carbamate (8) and several related compounds. These compounds are precursors of the active ethyl pyrido [3, 4-6] pyrazin-7-ylcarbamates (eg, 4), which are potent antimitotic agents. In the 5-nitropyridine series overall biological activity was reduced by replacement of the oxime moiety with a keto or alcohol group and by replacement of the 1-methyl group of the side chain with hydrogen. Reductionof the nitro group of the 5-nitropyridines containing an alcohol in the side chain tothe corresponding 5-aminopyridines increased biological activity. Preliminary studies showed that the 5-nitropyridine oximes were considerably less potent than the pyridopyrazines as antimitotic agents and that the former are apparently not converted to the latter in vivo. The inhibition of the incorporationof pyrimidine nucleosides into DNA and RNA was identified sis another possible mode of action of the 5-nitropyridine oximes.A number of compounds with diverse structures, com-bretastatin A-4 (l), 1 amphethinile (2), 1 the 4 (3#)-quinazolone 3, 2 and the l, 2-dihydropyrido [3, 4-6] pyridine (S)-4, 3 are known to compete with colchicine for binding sites on tubulin (Chart I). This mode of action interferes with the polymerization oftubulin to give microtubules, and as a result these agents have shown anticancer activity against experimental tumors in mice. Another microtubule inhibitor, c/s-tubulazole (5) but not the trans isomer, has also shown activity in mice. 4 In the resynthesis of (RS)-4, under thedirection of the Drug Synthesis and Chemistry Branch, NCI, a 5-nitropyridine precursor showed activity in mice similar to that observed for the target compound. This result prompted the search for biological activity in previouslyprepared pyridine inter-mediates. Another objective was to determine if the pyridine compounds were antimitotic agents and if this activity was a result of metabolic transformation to 1, 2-dihydropyrido [3, 4-6] pyrazines.