5 years ago

Design, synthesis, biological evaluation, and 3D-QSAR analysis of podophyllotoxin–dioxazole combination as tubulin targeting anticancer agents

Design, synthesis, biological evaluation, and 3D-QSAR analysis of podophyllotoxin–dioxazole combination as tubulin targeting anticancer agents
Fu-Gen Yu, Ya-Han Zhang, Han-Yue Qiu, Xue Wang, Xiao-Ming Wang, Gui-Hua Lu, Wen-Xue Sun, Jin-Liang Qi, Yong-Hua Yang, Yan-Jun Pang, Zi-Zhen Wang
The advancement of cancer-fighting drugs has never been a simple linear process. Those drug design professionals begin to find inspiration from the nature after failing to find the ideal products by creative drug design and high-throughput screening. To obtain new molecules for inhibiting tubulin, podophyllotoxin was adopted as the leading compound and 1,3,4-oxadiazole was brought in to the C-4 site of podophyllotoxin in this research. A series of seventeen podophyllotoxin-derived esters have been achieved and then evaluated their antitumor activities against four different cancer cell lines: A549, MCF-7, HepG2, and HeLa. Among all the compounds, compound 7c showed the best antiproliferating properties with IC50 = 2.54 ± 0.82 μm against MCF-7 cancer cell line. It was obvious that the content of ROS grew significantly in MCF-7 in a way depending on the dosage. The time- and dose-dependent cell cycle assays revealed that compound 7c could apparently block cell cycle in the phase of G2/M along with the upregulation of cyclin A2 and CDK2 protein. According to further studies, confocal microscopy experiment has certified that compound 7c could restrain cancer from growing by blocking the polymerization of microtubule. Meanwhile, compound 7c could be ideally integrated with the colchicine site of tubulin. In future, it would be feasible to selectively design tubulin inhibitors with the help of 3D-QSAR. This means that it is hopeful to develop compound 7c as a potential agent against cancer due to its biological characteristics. It proves that compound 7c conjugated in the colchicine site of tubulin (1SA0) perfectly and cyclin A2 and CDK2 are involved in the cell cycle process induced by 7c.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/cbdd.12942

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