Abstract
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.
Keywords:
G2/M phase arrest; cell apoptosis; quinoxaline derivatives; reactive oxygen species; tubulin polymerization inhibitors.
© 2019 John Wiley & Sons A/S.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Binding Sites
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Cell Line, Tumor
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Dose-Response Relationship, Drug
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G2 Phase Cell Cycle Checkpoints / drug effects
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Humans
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Membrane Potential, Mitochondrial / drug effects
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Molecular Docking Simulation
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Protein Structure, Tertiary
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Quinoxalines / chemistry*
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Quinoxalines / metabolism
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Quinoxalines / pharmacology
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Reactive Oxygen Species / metabolism*
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Structure-Activity Relationship
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Tubulin / chemistry*
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Tubulin / metabolism
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Tubulin Modulators / chemical synthesis*
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Tubulin Modulators / metabolism
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Tubulin Modulators / pharmacology
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Up-Regulation / drug effects
Substances
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Antineoplastic Agents
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Cyclin-Dependent Kinase Inhibitor p21
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Quinoxalines
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Reactive Oxygen Species
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Tubulin
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Tubulin Modulators