Department of Pharmaceutical Chemistry, KLE College of Pharmacy (A Constituent Unit of KLE Academy of Higher Education & Research-Belagavi), Rajajinagar, Bengaluru, Karnataka, India-, 560010.
Cellular Characterization and Biorepository Core Facility, Border Biomedical Research Center, Department of Biological Sciences, College of Science, The University of Texas at El Paso, 500 West University Avenue, El Paso, TX 79968-0519, USA.
Chem Biodivers. 2023 Sep;20(9):e202300843. doi: 10.1002/cbdv.202300843. Epub 2023 Aug 9.
A novel series of pyrazole-oxindole conjugates were prepared and characterized as potential cytotoxic agents by FT-IR, NMR and HR-MS. The cytotoxic activity of these compounds was tested in the Jurkat acute T cell leukemia, CEM acute lymphoblastic leukemia, MCF10 A mammary epithelial and MDA-MB 231 triple negative breast cancer cell lines. Among the tested conjugates, 5-methyl-3-((3-(1-phenyl)-3-(p-tolyl)-1H-pyrazol-4-yl)methylene)indolin-2-one 6h emerged as the most cytotoxic with a CC of 4.36+/-0.2 μM against Jurkat cells. The mechanism of cell death induced by 6h was investigated through the Annexin V-FITC assay via flow cytometry. Reactive oxygen species (ROS) accumulation, mitochondrial health and the cell cycle progression were also evaluated in cells exposed to 6h. Results demonstrated that 6h induces apoptosis in a dose-response manner, without generating ROS and/or altering mitochondrial health. In addition, 6h disrupted the cell cycle distribution causing an increase in DNA fragmentation (Sub G0-G1), and an arrest in the G0-G1 phase. Taken together, the 6h compound revealed a strong potential as an antineoplastic agent evidenced by its cytotoxicity in leukemia cells, the activation of apoptosis and restriction of the cell cycle progression.
我们合成了一系列新型吡唑并吲哚类化合物，并通过傅里叶变换红外光谱（FT-IR）、核磁共振（NMR）和高分辨质谱（HR-MS）对其进行了结构表征，将其鉴定为具有潜在细胞毒性的化合物。我们在 Jurkat 急性 T 淋巴细胞白血病、CEM 急性淋巴细胞白血病、MCF10A 乳腺上皮细胞和 MDA-MB-231 三阴性乳腺癌细胞系中测试了这些化合物的细胞毒性。在测试的化合物中，5-甲基-3-((3-(1-苯基)-3-(对甲苯基)-1H-吡唑-4-基)亚甲基)吲哚啉-2-酮 6h 对 Jurkat 细胞的 CC 为 4.36+/-0.2 μM，表现出最强的细胞毒性。通过流式细胞术的 Annexin V-FITC 检测，我们研究了 6h 诱导细胞死亡的机制。还评估了细胞内 ROS 积累、线粒体健康和细胞周期进展。结果表明，6h 以剂量依赖性方式诱导细胞凋亡，而不会产生 ROS 和/或改变线粒体健康。此外，6h 破坏了细胞周期分布，导致 DNA 片段化增加（Sub G0-G1），并使细胞周期停滞在 G0-G1 期。综上所述，6h 化合物具有很强的抗肿瘤潜力，其在白血病细胞中的细胞毒性、凋亡的激活和细胞周期进程的限制都证明了这一点。
