title: Synthesis, in vitro and in vivo evaluation of new hybrids of millepachine and phenstatin as potent tubulin polymerization inhibitors.
abstract: In this paper, a series of millepachine derivatives were synthesized and evaluated as tubulin polymerization inhibitors. The optimal compound 5i, (3-hydroxy-4-methoxyphenyl)(5-methoxy-2,2-dimethyl-2H-chromen-8-yl)methanone, displayed the highest cytotoxicity toward a series of cancer cells (ranging from 18 to 45 nM of IC50). Further investigation revealed that 5i significantly repressed the multidrug resistant cells (A549/CDDP, A2780/TAX) and had little cytotoxicity towards human normal cells (HLF, BJ). Cellular mechanism studies demonstrated that 5i induced G2/M phase arrest and apoptosis, which was associated with the collapse of the mitochondrial membrane potential (MMP). Additionally, western blot analysis showed that 5i could change the levels of cell cycle-related proteins (e.g. Cyclin B1, Cdc25c, Cdc2) and some apoptosis-related proteins (e.g. Bax, Bad, Bcl-2, Bcl-xl). Finally, 5i effectively inhibited the growth of xenograft tumours of A549 cells in nude mice.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. lixsh@mail.sysu.edu.cn.
authors.forename: Baijiao
authors.initials: B
authors.lastname: An
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. lixsh@mail.sysu.edu.cn.
authors.forename: Shun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. lixsh@mail.sysu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. lixsh@mail.sysu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. lixsh@mail.sysu.edu.cn.
authors.forename: Xingshu
authors.identifier: http://orcid.org/0000-0002-1880-6200
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001577:Benzophenones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D058105:Polymerization / Q000187:drug effects; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001577:Benzophenones; D047188:Chalcones; D014404:Tubulin; C583284:millepachine; C000612885:phenstatin