title: Synthesis and biological evaluation of novel millepachine derivatives as a new class of tubulin polymerization inhibitors.
abstract: Twenty-one novel derivatives of millepachine were synthesized and evaluated for their in vitro antiproliferative activity. Among them, 8 exhibited the most potent activity, with IC50 values of 8-27 nM against panel of cancer cell lines and retained full activity in multidrug resistant cancer cells. Treated cells were arrested in G2/M phase and resulted in cellular apoptosis. Microtubule dynamics confirmed 8 was a novel tubulin polymerization inhibitor by binding at the colchicine site. 8 also exhibited antivascular activity because it concentration dependently reduced the cell migration and disrupted capillary like tube formation in HUVEC cells. Furthermore, the hydrochloride salt of 8 (8·HCl) significantly improved the bioavailability up to 47% while retaining the antiproliferative activity. Importantly, 8·HCl significantly inhibited tumor growths in four xenograft models including resistance tumor-cell-bearing mice models without causing significant loss of body weight, suggesting that 8 is a promising new orally anticancer agent to be developed.
authors.affiliation: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University , Chengdu, China.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Yang
authors.forename: Wenshuang
authors.initials: W
authors.lastname: Wu
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Luyuan
authors.initials: L
authors.lastname: Li
authors.forename: Jianhong
authors.initials: J
authors.lastname: Yang
authors.forename: Guangcheng
authors.initials: G
authors.lastname: Wang
authors.forename: Dong
authors.initials: D
authors.lastname: Cao
authors.forename: Ronghong
authors.initials: R
authors.lastname: Zhang
authors.forename: Minghai
authors.initials: M
authors.lastname: Tang
authors.forename: Jiaolin
authors.initials: J
authors.lastname: Wen
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Wei
authors.initials: W
authors.lastname: Xiang
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Ma
authors.forename: Mingli
authors.initials: M
authors.lastname: Xiang
authors.forename: Jingsong
authors.initials: J
authors.lastname: You
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D005455:Fluorescent Antibody Technique; D056945:Hep G2 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047188:Chalcones; D050257:Tubulin Modulators; C583284:millepachine