Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
Eur J Med Chem. 2022 Jul 5;237:114372. doi: 10.1016/j.ejmech.2022.114372. Epub 2022 Apr 16.
A novel series of diphenylamine derivatives were designed and synthesized, and their biological activities were evaluated. The anti-proliferative activities of the derivatives were tested against five human cancer cell lines (MCF-7, MDA-MB-231, A549, HeLa and HT29). Among them, compound 5f exhibited the promising anti-proliferative activity against HT29 cell lines with the IC value of 23 nM. Further biological studies depicted that compound 5f inhibited cancer cell migration, colony formation and angiogenesis. Besides, dynamics studies and molecular docking studies revealed that compound 5f inhibited tubulin polymerization which may be a result of the compound binding to the colchicine site of tubulin. Furthermore, compound 5f arrested HT29 cell cycle at G2/M phase, and induced HT29 cell apoptosis by upregulating cyclin B1, Bcl-2, Bax, Cleaved-caspase9, Cleaved-caspase3, PARP, Cleaved-PARP proteins, and downregulating p-cdc25c (S216), p-cdc2 (T15) proteins. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) were also determined to confirm the cell apoptosis process. Finally, compound 5f greatly inhibited the tumor growth in HT29 xenograft mice by 75.5% at 10 mg/kg. Meanwhile, compound 5f owned the good pharmacokinetic properties. All the results promised that 5f is of potential to act as an antitumor candidate and worthy of further investigation.
设计和合成了一系列新型的二苯胺衍生物，并对其生物活性进行了评价。对这些衍生物对五种人癌细胞系（MCF-7、MDA-MB-231、A549、HeLa 和 HT29）的抗增殖活性进行了测试。其中，化合物 5f 对 HT29 细胞系表现出有希望的抗增殖活性，IC 值为 23 nM。进一步的生物学研究表明，化合物 5f 抑制癌细胞迁移、集落形成和血管生成。此外，动力学研究和分子对接研究表明，化合物 5f 抑制微管蛋白聚合，这可能是由于该化合物结合到微管蛋白的秋水仙碱结合部位。此外，化合物 5f 将 HT29 细胞周期阻滞在 G2/M 期，并通过上调细胞周期蛋白 B1、Bcl-2、Bax、Cleaved-caspase9、Cleaved-caspase3、PARP、Cleaved-PARP 蛋白和下调 p-cdc25c（S216）、p-cdc2（T15）蛋白来诱导 HT29 细胞凋亡。还测定了线粒体膜电位（MMP）和活性氧（ROS）以确认细胞凋亡过程。最后，化合物 5f 在 10 mg/kg 时在 HT29 异种移植小鼠中使肿瘤生长抑制率达到 75.5%。同时，化合物 5f 具有良好的药代动力学性质。所有结果都表明 5f 具有作为抗肿瘤候选物的潜力，值得进一步研究。
