title: Biological evaluation and molecular modelling study of podophyllotoxin derivatives as potent inhibitors of tubulin polymerization.
abstract: Microtubules are considered as important targets of anticancer therapy. Podophyllotoxin and its structural derivative are major microtubule-interfering agents with potent anticancer activity. In this study, we reported the anticancer effects of 10 representative podophyllotoxin derivatives on a panel of four human cancer cell lines. Deoxypodophyllotoxin (6b) and β-apopicropodophyllotoxin (6g) elicited strong antiproliferative effects (IC₅₀) at a range of 0.0073-0.14 μM. Direct tubulin depolymerization assay in vitro was also performed. Results showed that that the two compounds can inhibit microtubule polymerization. Experimental measurements were also supported by molecular dynamic simulations, which showed that the two active compounds formed interactions with the colchicine-binding site of the tubulin protein. Our results helped us understand the nature of tubulin binding and determine the core design of a new series of potent inhibitors of tubulin polymerization.
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Yaqiong
authors.initials: Y
authors.lastname: Ma
authors.forename: Senbiao
authors.initials: S
authors.lastname: Fang
authors.forename: Huanhuan
authors.initials: H
authors.lastname: Li
authors.forename: Chao
authors.initials: C
authors.lastname: Han
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Yonglong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yingqian
authors.initials: Y
authors.lastname: Liu
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhao
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000633:toxicity; D001665:Binding Sites; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004365:Drugs, Chinese Herbal; D006367:HeLa Cells; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D062105:Molecular Docking Simulation; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000633:toxicity; D013816:Thermodynamics; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D004365:Drugs, Chinese Herbal; D014404:Tubulin; D050257:Tubulin Modulators; C014451:deoxypodophyllotoxin; D011034:Podophyllotoxin