Yakkala Prasanna A, Panda Samir R, Naidu Vegi G M, Shafi Syed, Kamal Ahmed
Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Assam 781101, India.
ACS Med Chem Lett. 2023 Feb 16;14(3):260-269. doi: 10.1021/acsmedchemlett.2c00475. eCollection 2023 Mar 9.
A library of pyridine-based 1,2,4-triazolo-tethered indole conjugates were designed, synthesized, and evaluated for anti-proliferative activity against a panel of six human cancer cell lines. All the synthesized conjugates (-) were found to be effective against the HT-29 cell line. Particularly conjugates , , and exhibited promising cytotoxicity, with IC values of 1 μM, 2.4 μM, and 3.6 μM, respectively, compared to the standard 5-fluorouracil (IC = 5.31 μM). Cell cycle arrest at the G0/G1 phase was observed with these compounds, the mitochondrial membrane potential was interrupted, and the total ROS production was enhanced. Western blot and immunofluorescence experiments illustrated that these compounds inhibit the expression of markers that are involved in β-catenin and PI3K pathways. Molecular dynamics simulations demonstrated that compound has major hydrophobic interactions and few H-bonding interactions with both PI3K and tankyrase proteins.
设计、合成了一系列基于吡啶的1,2,4-三唑连接的吲哚共轭物，并评估了它们对六种人类癌细胞系的抗增殖活性。发现所有合成的共轭物（-）对HT-29细胞系均有效。特别是共轭物 、 和 表现出有前景的细胞毒性，与标准的5-氟尿嘧啶（IC = 5.31 μM）相比，其IC值分别为1 μM、2.4 μM和3.6 μM。观察到这些化合物使细胞周期停滞在G0/G1期，线粒体膜电位被中断，并且总活性氧生成增加。蛋白质印迹和免疫荧光实验表明，这些化合物抑制参与β-连环蛋白和PI3K途径的标志物的表达。分子动力学模拟表明，化合物 与PI3K和端锚聚合酶蛋白均有主要的疏水相互作用和少量氢键相互作用。
