Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cervical cancer treatment. In this study, we designed and synthesized a series of benzimidazole derivatives and evaluated their anti-cervical cancer activity. Compound exhibited strong antiproliferative activity in different cervical cancer cell lines HeLa, SiHa and Ca Ski, and relative lower cytotoxicity to normal hepatic and renal cell lines LO2 and HEK-293t (IC values were at 21.08 μM and 23.96 μM respectively). Its IC value was at 3.38 μM to the SiHa cells. Further mechanistic studies revealed that induced apoptosis, arrested cell cycle in G2/M phase, suppressed PI3K/Akt/mTOR pathway and inhibit the polymerization of tubulin. Molecular docking study suggested that formed key H-bonds action with PI3Kα (PDB ID:) and tubulin (PDB ID:). Zebrafish acute toxicity experiments showed that high concentrations of did not cause death or malformation of zebrafish embryos. All these results demonstrated that would be a promising lead candidate for further development of novel PI3K and tubulin dual inhibitors in cervical cancer treatment.

中文翻译：

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通过 PI3K/Akt/mTOR 通路和微管蛋白抑制作为抗宫颈癌药物的新型苯并咪唑衍生物的设计、合成和生物学评价

磷脂酰肌醇3激酶（PI3K）是宫颈癌治疗中最有吸引力的治疗靶点之一。在本研究中，我们设计并合成了一系列苯并咪唑衍生物并评估了它们的抗宫颈癌活性。化合物对不同宫颈癌细胞系HeLa、SiHa和Ca Ski表现出较强的抗增殖活性，对正常肝细胞系LO2和肾细胞系HEK-293t具有相对较低的细胞毒性（IC50值分别为21.08 μM和23.96 μM）。其对 SiHa 细胞的 IC 值为 3.38 μM。进一步的机制研究表明，诱导细胞凋亡，将细胞周期阻滞在 G2/M 期，抑制 PI3K/Akt/mTOR 通路并抑制微管蛋白的聚合。分子对接研究表明与 PI3Kα (PDB ID:) 和微管蛋白 (PDB ID:) 形成关键的氢键作用。斑马鱼急性毒性实验表明，高浓度并不会导致斑马鱼胚胎死亡或畸形。所有这些结果表明，这将是进一步开发新型 PI3K 和微管蛋白双重抑制剂治疗宫颈癌的有希望的先导候选药物。