N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation; National Research University Higher School of Economics (HSE), 20 Myasnitskaya Street, 101000 Moscow, Russian Federation.
N. D. Zelinsky Institute of Organic Chemistry RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation.
Bioorg Med Chem Lett. 2020 Dec 1;30(23):127608. doi: 10.1016/j.bmcl.2020.127608. Epub 2020 Oct 7.
The ability of monomethoxy-substituted o-diphenylisoxazoles 2a-d to interact with the colchicine site of tubulin was predicted using computational modeling, docking studies, and calculation of binding affinity. The respective molecules were synthesized in high yields by three steps reaction using easily available benzaldehydes, acetophenones, and arylnitromethanes as starting material. The calculated antitubulin effect was confirmed in vivo in a sea urchin embryo model. Compounds 2a and 2c showed high antimitotic microtubule destabilizing activity compared to that of CA4. Isoxazole 2a also exhibited significant cytotoxicity against human cancer cells in NCI60 screen. For the first time, isoxazole-linked CA4 derivatives 2a and 2c with only one methoxy substituent were identified as potent antimitotic microtubule destabilizing agents. These molecules could be considered as promising structures for further optimization.
使用计算建模、对接研究和结合亲和力计算，预测了单甲氧基取代邻二苯异恶唑 2a-d 与微管蛋白秋水仙碱结合位点相互作用的能力。分别通过三步反应以高收率合成了相应的分子，使用易得的苯甲醛、苯乙酮和芳基硝基甲烷作为起始原料。在海胆胚胎模型中体内验证了计算出的抗微管蛋白作用。与 CA4 相比，化合物 2a 和 2c 表现出较高的抗有丝分裂微管去稳定化活性。异恶唑 2a 在 NCI60 筛选中对人类癌细胞也表现出显著的细胞毒性。首次鉴定出具有仅一个甲氧基取代基的异恶唑连接 CA4 衍生物 2a 和 2c 作为有效的抗有丝分裂微管去稳定剂。这些分子可以被认为是进一步优化的有前途的结构。
