title: Design, Synthesis and Antitumor Activity of Novel link-bridge and B-Ring Modified Combretastatin A-4 (CA-4) Analogues as Potent Antitubulin Agents.
abstract: A series of 12 novel acylhydrazone, chalcone and amide-bridged analogues of combretastatin A-4 were designed and synthesized toward tubulin. All these compounds were determined by elemental analysis, (1)H NMR, and MS. Among them, compound 7 with acylhydrazone-bridge, bearing a benzyl at the indole-N position, was identified as a potent antiproliferative agent against a panel of cancer cell lines with IC50 values ranging from 0.08 to 35.6 μM. In contrast, its cytotoxic effects on three normal human cells were minimal. Cellular studies have revealed that the induction of apoptosis by compound 7 was associated with a collapse of mitochondrial membrane potential, accumulation of reactive oxygen species, alterations in the expression of some cell cycle-related proteins (Cyclin B1, Cdc25c, Cdc2, P21) and some apoptosis-related proteins (Bax, PARP, Bcl-2, Caspase3). The docking mode showed the binding posture of CA-4 and compound 7 are similar in the colchicine-binding pocket of tubulin, as confirmed by colchicine-tubulin competitive binding assay, tubulin polymerization inhibitory activity, extracellular protein expression determination assay and confocal immunofluorescence microscopy. In vivo study, compound 7 effectively inhibited A549 xenograft tumor growth without causing significant loss of body weight suggesting that compound 7 is a promising new antimitotic agent with clinical potential.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, 163 Xianlin Road, P. R. China.
authors.forename: Yong-Tao
authors.initials: YT
authors.lastname: Duan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, 163 Xianlin Road, P. R. China.|Guangxi University for Nationalities, Nanning 530006, People's Republic of China.
authors.forename: Ruo-Jun
authors.initials: RJ
authors.lastname: Man
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, 163 Xianlin Road, P. R. China.
authors.forename: Dan-Jie
authors.initials: DJ
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, 163 Xianlin Road, P. R. China.
authors.forename: Yong-Fang
authors.initials: YF
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, 163 Xianlin Road, P. R. China.
authors.forename: Xiang-Xiang
authors.initials: XX
authors.lastname: Tao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, 163 Xianlin Road, P. R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, 163 Xianlin Road, P. R. China.
authors.forename: Xin-Yi
authors.initials: XY
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, 163 Xianlin Road, P. R. China.
authors.forename: Jigar A
authors.initials: JA
authors.lastname: Makawana
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Mei-Juan
authors.initials: MJ
authors.lastname: Zou
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, 163 Xianlin Road, P. R. China.
authors.forename: Zhong-Chang
authors.initials: ZC
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, 163 Xianlin Road, P. R. China.|Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hai-Liang
authors.initials: HL
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002599:Chalcone / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D006835:Hydrazones / Q000737:chemistry; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; D013267:Stilbenes; D014404:Tubulin; D050257:Tubulin Modulators; D002599:Chalcone; C058728:fosbretabulin