Synthesis and biological evaluation of novel chalcone derivatives as a new class of microtubule destabilizing agents.
A series of novel chalcone derivatives were designed and synthesized as potential antitumor agents. Structures of target molecules were confirmed by1H NMR,13C NMR and HR-MS, and evaluated for their in vitro anti-proliferative activities using MTT assay. Among them, compound 12k displayed potent activity against the test tumor cell lines including multidrug resistant human cancer lines, with the IC50values ranged from 3.75 to 8.42 μM. In addition, compound 12k was found to induce apoptosis in NCI-H460 cells via the mitochondrial pathway, including an increase of the ROS level, loss of mitochondrial membrane potential, release of cytochrome c, down-regulation of Bcl-2, up-regulation of Bax, activation of caspase-9 and caspase-3, respectively. Moreover, the cell cycle analysis indicated that 12k effectively caused cell cycle arrest at G2/M phase. The results of tubulin polymerization assay displayed that 12k could inhibit tubulin polymerization in vitro. Furthermore, molecular docking study indicated that 12k can be binding to the colchicine site of tubulin.
Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
Xiaochao
X
Huang
Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
Rizhen
R
Huang
Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China.
Lingxue
L
Li
Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, China. Electronic address: sgou@seu.edu.cn.
Shaohua
S
Gou
State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, China. Electronic address: whengshan@163.com.
Hengshan
H
Wang
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D006801:Humans; D020128:Inhibitory Concentration 50; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology*
D000970:Antineoplastic Agents; D047188:Chalcones; D050257:Tubulin Modulators
Anti-tumor activity; Apoptosis; Chalcone; Molecular modeling; Tubulin