Synthesis and biological evaluation of quinoxaline derivatives as tubulin polymerization inhibitors that elevate intracellular ROS and triggers apoptosis via mitochondrial pathway.
A series of novel quinoxaline derivatives were synthesized and evaluated for their antiproliferative activity in three human cancer cell lines. Compound 12 exhibited the most potent antiproliferative activity with IC50 in the range of 0.19-0.51 μM. The compound inhibited tubulin polymerization and disrupted the microtubule network, leading to G2/M phase arrest. Furthermore, compound 12 induced ROS production and malfunction of mitochondrial membrane potential. Compound 12 led to cancer cells apoptosis in a dose-dependent manner. Western blot analysis showed that compound 12 induced up-regulation of p21 and affected the expression of cell cycle-related proteins. The binding mode was also probed by molecular docking.
['Qi|Jianguo|J|0000-0002-8087-1169', 'Huang|Jing|J|', 'Zhou|Xiaomin|X|', 'Luo|Wen|W|', 'Xie|Jiaxin|J|', 'Niu|Linqiang|L|', 'Yan|Zhijie|Z|', 'Luo|Yang|Y|', 'Men|Yuhui|Y|', 'Chen|Yanan|Y|', 'Zhang|Yahong|Y|', 'Wang|Jianhong|J|']
D000970:Antineoplastic Agents D017209:Apoptosis D001665:Binding Sites D045744:Cell Line, Tumor D050759:Cyclin-Dependent Kinase Inhibitor p21 D004305:Dose-Response Relationship, Drug D059565:G2 Phase Cell Cycle Checkpoints D006801:Humans D053078:Membrane Potential, Mitochondrial D008928:Mitochondria D062105:Molecular Docking Simulation D017434:Protein Structure, Tertiary D011810:Quinoxalines D017382:Reactive Oxygen Species D013329:Structure-Activity Relationship D014404:Tubulin D050257:Tubulin Modulators D015854:Up-Regulation
quinoxaline derivatives tubulin polymerization inhibitors G2/M phase arrest cell apoptosis reactive oxygen species