title: Design, synthesis, biological evaluation, and 3D-QSAR analysis of podophyllotoxin-dioxazole combination as tubulin targeting anticancer agents.
abstract: 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.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing, China.|Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, China.
authors.forename: Zi-Zhen
authors.initials: ZZ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing, China.|Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, China.
authors.forename: Wen-Xue
authors.initials: WX
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing, China.|Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing, China.|Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, China.
authors.forename: Ya-Han
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing, China.|Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, China.
authors.forename: Han-Yue
authors.initials: HY
authors.lastname: Qiu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing, China.|Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, China.
authors.forename: Jin-Liang
authors.initials: JL
authors.lastname: Qi
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing, China.
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Pang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing, China.|Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, China.
authors.forename: Gui-Hua
authors.initials: GH
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing, China.|Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing, China.
authors.forename: Fu-Gen
authors.initials: FG
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, NJU-NJFU Joint Institute of Plant Molecular Biology, Nanjing University, Nanjing, China.|Co-Innovation Center for Sustainable Forestry in Southern China, Nanjing Forestry University, Nanjing, China.
authors.forename: Yong-Hua
authors.identifier: 0000-0003-1826-1252
authors.initials: YH
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011034:Podophyllotoxin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010069:Oxadiazoles; D014404:Tubulin; D050257:Tubulin Modulators; C583463:1,3,4-oxadiazole; D011034:Podophyllotoxin
keywords: 1,3,4-dioxazole; antitubulin; antitumor; podophyllotoxin