El-Naggar Abeer M, Eissa Ibrahim H, Belal Amany, El-Sayed Amira A
Chemistry Department, Faculty of Science, Ain Shams University Abbassiya Cairo 11566 Egypt
Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University Cairo 11884 Egypt
RSC Adv. 2020 Jan 15;10(5):2791-2811. doi: 10.1039/c9ra10094f. eCollection 2020 Jan 14.
In recent years, suppressing tubulin polymerization has been developed as a therapeutic approach for cancer treatment. Thus, new derivatives based on thiazol-5(4)-ones have been designed and synthesized in an eco-friendly manner. The synthesized derivatives have the same essential pharmacophoric features of colchicine binding site inhibitors. The anti-proliferative activity of the new derivatives was evaluated on three human cancer cell lines (HCT-116, HepG-2, and MCF-7) using MTT assay procedure and colchicine was used as a positive control. Compounds 4f, 5a, 8f, 8g, and 8k showed superior antiproliferative activities against the three tested cell lines with IC values ranging from 2.89 to 9.29 μM. Further investigation for the most active cytotoxic agents as tubulin polymerization inhibitors was also performed in order to explore the mechanism of their anti-proliferative activity. Tubulin polymerization assay results were found to be comperable with the cytotoxicity results. Compounds 4f and 5a were the most potent tubulin polymerization inhibitors with an IC value of 9.33 and 9.52 nM, respectively. Further studies revealed the ability of 5a to induce apoptosis and arrest cell cycle growth at the G2/M phase. Molecular docking studies were also conducted to investigate possible binding interactions between the target compounds and the tubulin heterodimer active site. From these studies, it was concluded that inhibition of tubulin polymerization yields the reported cytotoxic activity.
近年来，抑制微管蛋白聚合已被开发为一种癌症治疗方法。因此，已以环保方式设计并合成了基于噻唑 - 5(4)-酮的新衍生物。合成的衍生物具有秋水仙碱结合位点抑制剂相同的基本药效基团特征。使用MTT测定法在三种人类癌细胞系（HCT - 116、HepG - 2和MCF - 7）上评估了新衍生物的抗增殖活性，并将秋水仙碱用作阳性对照。化合物4f、5a、8f、8g和8k对三种测试细胞系表现出优异的抗增殖活性，IC值范围为2.89至9.29μM。还对作为微管蛋白聚合抑制剂的最具活性的细胞毒性剂进行了进一步研究，以探索其抗增殖活性的机制。发现微管蛋白聚合测定结果与细胞毒性结果相当。化合物4f和5a是最有效的微管蛋白聚合抑制剂，IC值分别为9.33和9.52 nM。进一步研究揭示了5a诱导细胞凋亡并使细胞周期生长停滞在G2/M期的能力。还进行了分子对接研究，以研究目标化合物与微管蛋白异二聚体活性位点之间可能的结合相互作用。从这些研究得出结论，微管蛋白聚合的抑制产生了所报道的细胞毒性活性。
