Abstract：
Several studies have indicated the potential therapeutic outcomes of combining selective COX-2 inhibitors with tubulin-targeting anticancer agents. In the current study, a novel series of thiazolidin-4-one-based derivatives (7a-q) was designed by merging the pharmacophoric features of some COXs inhibitors and tubulin polymerization inhibitors. Compounds 7a-q were synthesized and evaluated for their cytotoxic activity against MCF7, HT29, and A2780 cancer cell lines (IC50 = 0.02-17.02 μM). The cytotoxicity of 7a-q was also assessed against normal MRC5 cells (IC50 = 0.47-13.46 μM). Compounds 7c, 7i, and 7j, the most active in the MTT assay, significantly reduced the number of HT29 colonies compared to the control. Compounds 7c, 7i, and 7j also induced significant decreases in the tumor volumes and masses in Ehrlich solid carcinoma-bearing mice compared to the control. The three compounds also exhibited significant anti-HT29 migration activity in the wound-healing assay. They have also induced cell cycle arrest in HT29 cells at the S and G2/M phases. In addition, they induced significant increases in both early and late apoptotic events in HT29 cells compared to the control, where 7j showed the highest effect. On the other hand, compound 7j (1 μM) displayed weak inhibitory activity against tubulin polymerization compared to colchicine (3 μM). On the other hand, compounds 7a-q inhibited the activity of COX-2 (IC50 = 0.42-29.11 μM) compared to celecoxib (IC50 = 0.86 μM). In addition, 7c, 7i, and 7j showed moderate inhibition of inflammation in rats compared to indomethacin, with better GIT safety profiles. Molecular docking analysis revealed that 7c, 7i, and 7j have higher binding free energies towards COX-2 than COX-1. These above results suggested that 7j could serve as a potential anticancer drug candidate.
摘要：
一些研究已经表明了将选择性COX-2抑制剂与微管蛋白靶向抗癌剂组合的潜在治疗结果。在目前的研究中,通过融合一些COX抑制剂和微管蛋白聚合抑制剂的药理作用，设计了一系列基于噻唑烷-4-酮的新型衍生物（7a-q）。合成化合物7a-q并评价其对MCF7、HT29和A2780癌细胞系的细胞毒性活性(IC50=0.02-17.02μM)。还评估了7a-q对正常MRC5细胞的细胞毒性(IC50=0.47-13.46μM)。化合物7c,7i,7j,在MTT测定中最活跃，与对照相比,HT29菌落的数量显著减少。化合物7c,7i,与对照相比，7j和7j还在带有Ehrlich实体癌的小鼠中诱导了肿瘤体积和质量的显着减少。这三种化合物在伤口愈合试验中也表现出显著的抗HT29迁移活性。它们还在HT29细胞中在S和G2/M期诱导细胞周期停滞。此外,与对照组相比，它们在HT29细胞中诱导了早期和晚期凋亡事件的显着增加，其中7j显示出最高的效果。另一方面,与秋水仙碱(3μM)相比,化合物7j(1μM)对微管蛋白聚合显示弱抑制活性。另一方面,与塞来昔布(IC50=0.86μM)相比,化合物7a-q抑制COX-2(IC50=0.42-29.11μM)的活性。此外,7c,7i,与吲哚美辛相比，7j对大鼠的炎症有中等抑制作用，具有更好的GIT安全性。分子对接分析显示7c，7i,和7j具有比COX-1更高的对COX-2的结合自由能。上述结果表明7j可以作为潜在的抗癌药物候选物。
