title: Synthesis and biological evaluation of a series of podophyllotoxins derivatives as a class of potent antitubulin agents.
abstract: A series of eight novel podophyllotoxin derivatives were designed, synthesized and evaluated for biological activities. The antiproliferative activities were tested against a panel of human cancer cell lines (K562, SGC, Hela and HepG) and the inhibition of tubulin polymerization was also evaluated. Compound 8e displayed significant antiproliferative activities for all four cell lines and strong levels of tubulin polymerization inhibition effect. Combined with cell apoptosis and cell cycle analysis, it demonstrated that compound 3e that effectively interfere with tubulin dynamics prevent mitosis in cancer cells, leading to cell cycle arrest and, eventually dose dependent apoptosis. All experimental measurements were also supported by molecular docking simulations of colchicine binding site, which revealed the governing forces for the binding behavior and a good relationship with anti-tubulin activity and antiproliferative activities. The synthesis and biological studies provided an interesting new class of antitubulin agents for development of lead compounds and also a direction for further structure modification to obtain more potent anti-cancer drugs.
authors.affiliation: School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
authors.forename: Yingqian
authors.initials: Y
authors.lastname: Liu
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Wei
authors.forename: Yonglong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Weidong
authors.initials: W
authors.lastname: Cheng
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Yaqiong
authors.initials: Y
authors.lastname: Ma
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Chao
authors.initials: C
authors.lastname: Han
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Wei
authors.forename: Huiming
authors.initials: H
authors.lastname: Cao
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhao
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D020014:K562 Cells; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011034:Podophyllotoxin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014404:Tubulin; D050257:Tubulin Modulators; D011034:Podophyllotoxin