Department of Medicinal Chemistry, Faculty of Pharmacy, Drug Design and Development Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran.
Department of Toxicology and Pharmacology, Faculty of Pharmacy and Poisoning Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Drug Res (Stuttg). 2021 May;71(5):284-290. doi: 10.1055/a-1306-0202. Epub 2020 Dec 7.
The microtubule is composed of αβ tubulin heterodimers and is an attractive target for the design of anticancer drugs. Over the years, various compounds have been developed and their effect on tubulin polymerization has been studied. Despite a great efforts to make an effective drug, no drug has been introduced which inhibit Colchicine binding site.
In the current work a series of pyrimidine derivatives were designed and synthesized. Furthermore their cytotoxic activities were evaluated and molecular docking studies were performed. Twelve compounds of pyrimidine were synthesized in 3 different groups. In the first group, 4,6-diaryl pyrimidine was connected to the third aryl group via thio-methylene spacer. In the second group, this linker was substituted by sulfoxide-methylene moiety and in the third group sulfone-methylene group was used as spacer.
The cytotoxic activity of these compounds were evaluated against 3 different cancerous cell lines (HT-29, MCF-7, T47D) as well as normal cell line (NIH3T3). Compounds in group 2 showed the best cytotoxicity and compound 7D: showed the most potent cytotoxic activity against all cell lines. Molecular modelling studies revealed that compound 7D: could strongly bind to the colchicine binding site of tubulin.
Altogether, with respect to obtained results, it is attractive and beneficial to further investigation on pyrimidine scaffold as antimitotic agents.
微管由αβ-微管蛋白异二聚体组成，是设计抗癌药物的理想靶点。多年来，已经开发出各种化合物，并研究了它们对微管聚合的影响。尽管为了制造有效的药物付出了巨大的努力，但仍没有一种药物能够抑制秋水仙素结合位点。
在目前的工作中，设计并合成了一系列嘧啶衍生物。此外，评估了它们的细胞毒性活性并进行了分子对接研究。合成了 12 种嘧啶类化合物，分为 3 组。在第一组中，将 4,6-二芳基嘧啶通过硫代亚甲基间隔基连接到第三芳基上。在第二组中，该连接基团被亚砜亚甲基部分取代，在第三组中，亚砜亚甲基基团被用作间隔基。
这些化合物的细胞毒性活性针对 3 种不同的癌细胞系（HT-29、MCF-7、T47D）以及正常细胞系（NIH3T3）进行了评估。第 2 组的化合物表现出最好的细胞毒性，化合物 7D：对所有细胞系表现出最强的细胞毒性。分子建模研究表明，化合物 7D：可以与微管蛋白的秋水仙素结合位点强烈结合。
总之，鉴于获得的结果，嘧啶骨架作为抗有丝分裂剂具有吸引力和有益性，值得进一步研究。
