Design, synthesis, biological evaluation, and 3D-QSAR analysis of podophyllotoxin-dioxazole combination as tubulin targeting anticancer agents
| Autor: | Fu-Gen Yu, Han-Yue Qiu, Wen-Xue Sun, Z.H. Wang, Yan-Jun Pang, Jin-Liang Qi, Yong-Hua Yang, Gui-Hua Lu, Xiao-Ming Wang, Ya-Han Zhang, Xue Wang |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Quantitative Structure-Activity Relationship Antineoplastic Agents Apoptosis 01 natural sciences Biochemistry HeLa 03 medical and health sciences chemistry.chemical_compound Tubulin Microtubule Cell Line Tumor Neoplasms Drug Discovery medicine Humans Colchicine Podophyllotoxin Pharmacology Oxadiazoles biology 010405 organic chemistry Cell Cycle Organic Chemistry Cyclin-dependent kinase 2 Cell cycle biology.organism_classification Tubulin Modulators 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology chemistry Drug Design biology.protein Molecular Medicine Drug Screening Assays Antitumor Cyclin A2 medicine.drug |
| Zdroj: | Chemical Biology & Drug Design. 90:236-243 |
| ISSN: | 1747-0277 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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