Sedenkova Kseniya N, Leschukov Denis N, Grishin Yuri K, Zefirov Nikolay A, Gracheva Yulia A, Skvortsov Dmitry A, Hrytseniuk Yanislav S, Vasilyeva Lilja A, Spirkova Elena A, Shevtsov Pavel N, Shevtsova Elena F, Lukmanova Alina R, Spiridonov Vasily V, Markova Alina A, Nguyen Minh T, Shtil Alexander A, Zefirova Olga N, Yaroslavov Alexander A, Milaeva Elena R, Averina Elena B
Department of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.
Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia.
Pharmaceuticals (Basel). 2023 Oct 21;16(10):1499. doi: 10.3390/ph16101499.
Tubulin-targeting agents attract undiminished attention as promising compounds for the design of anti-cancer drugs. Verubulin is a potent tubulin polymerization inhibitor, binding to colchicine-binding sites. In the present work, a series of verubulin analogues containing a cyclohexane or cycloheptane ring 1,2-annulated with pyrimidine moiety and various substituents in positions 2 and 4 of pyrimidine were obtained and their cytotoxicity towards cancer and non-cancerous cell lines was estimated. The investigated compounds revealed activity against various cancer cell lines with IC down to 1-4 nM. According to fluorescent microscopy data, compounds that showed cytotoxicity in the MTT test disrupt the normal cytoskeleton of the cell in a pattern similar to that for combretastatin A-4. The hit compound (-(4-methoxyphenyl)-,2-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine) was encapsulated in biocompatible nanocontainers based on Ca or Mg cross-linked alginate and it was demonstrated that its cytotoxic activity was preserved after encapsulation.
微管蛋白靶向剂作为抗癌药物设计的有前景的化合物一直备受关注。Verubulin是一种有效的微管蛋白聚合抑制剂，可与秋水仙碱结合位点结合。在本研究中，我们合成了一系列含有与嘧啶部分稠合的环己烷或环庚烷环以及嘧啶2位和4位各种取代基的Verubulin类似物，并评估了它们对癌细胞系和非癌细胞系的细胞毒性。所研究的化合物对各种癌细胞系显示出活性，IC值低至1-4 nM。根据荧光显微镜数据，在MTT试验中显示细胞毒性的化合物以与康普瑞他汀A-4相似的模式破坏细胞的正常细胞骨架。命中化合物（-（4-甲氧基苯基）-，2-二甲基-5,6,7,8-四氢喹唑啉-4-胺）被封装在基于钙或镁交联藻酸盐的生物相容性纳米容器中，并且证明其细胞毒性活性在封装后得以保留。
