title: Design, synthesis, biological evaluation and molecular modeling study of novel macrocyclic bisbibenzyl analogues as antitubulin agents.
abstract: A series of macrocyclic bisbibenzyls with novel skeletons was designed, synthesized, and evaluated for antiproliferative activity against five anthropic cancer cell lines. Among these novel molecules, compound 47 displayed excellent anticancer activity against HeLa, k562, HCC1428, HT29 and PC-3/Doc cell lines, with IC50values ranging from of 1.51 μM-5.51 μM, which were more potent than the parent compound, marchantin C. Compounds 44 and 55 with novel bisbibenzyl skeletons also exhibited significantly improved antiproliferative potency. Structure-activity relationship (SAR) analyses of these synthesized compounds were also performed. In addition, compound 47 effectively inhibited tubulin polymerization in HCC1482 cells and induced HCC1482 cell cycle arrest at the G2/M phase in a concentration-dependent manner. The binding mode of compound 47 to tubulin was also investigated utilizing a molecular docking study. In conclusion, the present study discovered several potent antitubulin compounds with novel bisbibenzyl skeletons, and our systematic studies revealed new scaffolds that target tubulin and mitosis and provide progress towards the discovery of novel antitumor drugs discovery.
authors.affiliation: National Glycoengineering Research Center, Shandong University, Jinan 250012, PR China; Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China.
authors.forename: Bin
authors.initials: B
authors.lastname: Sun
authors.affiliation: Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China.
authors.forename: Qing-Wen
authors.initials: QW
authors.lastname: Hu
authors.affiliation: Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China.
authors.forename: Hong-Bo
authors.initials: HB
authors.lastname: Zheng
authors.affiliation: Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Tang
authors.affiliation: School of Medicine, Shandong University, Jinan 250012, PR China.
authors.forename: Huan-Min
authors.initials: HM
authors.lastname: Niu
authors.affiliation: School of Medicine, Shandong University, Jinan 250012, PR China.
authors.forename: Hui-Qing
authors.initials: HQ
authors.lastname: Yuan
authors.affiliation: National Glycoengineering Research Center, Shandong University, Jinan 250012, PR China; Key Laboratory of Natural Products & Chemical Biology, Ministry of Education, Shandong University, Jinan, 250012, PR China. Electronic address: louhongxiang@sdu.edu.cn.
authors.forename: Hong-Xiang
authors.initials: HX
authors.lastname: Lou
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001632:Bibenzyls / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D047028:Macrocyclic Compounds; D014404:Tubulin; D050257:Tubulin Modulators
keywords: Anticancer; Bisbibenzyls; Molecular modeling; Tubulin polymerization inhibitors