Karetnikov Georgy L, Vasilyeva Lilya A, Babayeva Gulalek, Pokrovsky Vadim S, Skvortsov Dmitry A, Bondarenko Oksana B
Chemistry Department and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119991, Russian Federation.
Research Institute of Molecular and Cellular Medicine, RUDN University, Moscow 117198, Russian Federation.
ACS Pharmacol Transl Sci. 2024 Jan 16;7(2):384-394. doi: 10.1021/acsptsci.3c00239. eCollection 2024 Feb 9.
Focusing on the molecular docking results, a series of 3,4-diarylisoxazoles, analogues of Combretastatin A4, bearing various substituents at the fifth position of the isoxazole ring and pharmacophore groups bioisosteric to methoxy substituent at ring B, were synthesized in good yields and high regioselectivity. Depending on the substituent at C5, three approaches were chosen for the construction of isoxazole ring, including nitrosation of gem-dihalocyclopropanes, nitrile oxide synthesis, and difluoromethoxylation of isoxazolone to afford 5-haloisoxazoles, 5-unsubstituted isoxazoles, and 5-difluoromethoxyisoxazoles, respectively. Isoxazoles and showed selective cytotoxicity and antitubulin inhibition properties , with pharmacodynamic profiles closely related to that of CA-4. Both of them slow down tumor growth (66-74%) in mouse xenografts and slightly exceed in effectiveness Combretastatin A4-phosphate itself.
基于分子对接结果，合成了一系列异恶唑环5位带有不同取代基且与B环甲氧基具有生物电子等排体药效基团的3,4-二芳基异恶唑类化合物，它们是康普瑞他汀A4的类似物，产率良好且区域选择性高。根据C5位的取代基，选择了三种构建异恶唑环的方法，包括偕二卤代环丙烷的亚硝化、腈氧化物的合成以及异恶唑酮的二氟甲氧基化，分别得到5-卤代异恶唑、5-未取代异恶唑和5-二氟甲氧基异恶唑。异恶唑 和 显示出选择性细胞毒性和抗微管蛋白抑制特性，其药效学特征与CA-4密切相关。它们均可减缓小鼠异种移植瘤的生长（66-74%），且有效性略高于磷酸康普瑞他汀A4本身。
