Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500037, India.
Bioorg Med Chem. 2023 Jul 15;90:117297. doi: 10.1016/j.bmc.2023.117297. Epub 2023 May 1.
Herein, regiospecific nucleophilic ring-opening of spiroaziridine oxindoles has been established to afford 3-substituted-thiooxindole derivatives as anticancer agents. Among the new series, compounds 7d and 9c exhibited promising cytotoxic activity toward HCT-116 cells with IC values of 6.73 ± 0.36 and 6.64 ± 0.95 µM, respectively. Further, AO/EB, DCFDA, and DAPI staining studies were executed to establish the underlying apoptosis mechanism which displayed significant nuclear and morphological alterations. JC-1 staining and annexin V binding assay inferred the loss of mitochondrial membrane potential in HCT-116 cancer cells. Cell cycle analysis showed the treatment of 9c against HCT-116 cells, arrested the cell cycle in G2-M phase. In addition, tubulin binding assay revealed that compound 9c exhibited tubulin polymerase inhibition with IC value of 9.73 ± 0.18 μM. This inhibition of tubulin polymerase was further supported by binding interactions of 9c with tubulin through docking studies on PDB ID: 3E22.
在此，通过区域选择性亲核开环螺环氮茚并吲哚，建立了作为抗癌剂的 3-取代-硫代氧吲哚衍生物。在新系列中，化合物 7d 和 9c 对 HCT-116 细胞表现出有希望的细胞毒性活性，IC 值分别为 6.73±0.36 和 6.64±0.95µM。此外，进行了 AO/EB、DCFDA 和 DAPI 染色研究，以确定潜在的细胞凋亡机制，显示出明显的核和形态改变。JC-1 染色和膜联蛋白 V 结合实验推断 HCT-116 癌细胞中线粒体膜电位丧失。细胞周期分析表明，9c 对 HCT-116 细胞的处理使细胞周期停滞在 G2-M 期。此外，微管结合实验显示化合物 9c 对微管聚合酶具有抑制作用，IC 值为 9.73±0.18μM。通过对接研究进一步支持了 9c 与微管的结合相互作用，对接研究使用的 PDB ID：3E22。
