title: Novel shikonin derivatives targeting tubulin as anticancer agents.
abstract: In this study, we report the identification of a new shikonin-phenoxyacetic acid derivative, as an inhibitor of tubulin. A series of compounds were prepared; among them, compound 16 [(R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 2-(4- phenoxyphenyl) acetate] potently inhibited the function of microtubules, inducing cell growth inhibition, apoptosis of cancer cell lines in a concentration and time-dependent manner. Molecular docking involving 16 at the vinblastine binding site of tubulin indicated that a phenoxy moiety interacted with tubulin via hydrogen bonding with asparaginate (Asn) and tyrosine (Tyr). Analysis of microtubules with confocal microscopy demonstrated that 16 altered the microtubule architecture and exhibited a significant reduction in microtubule density. Cell cycle assay further proved that HepG2 cells were blocked in G2/M phase. Our study provides a new, promising compound for the development of tubulin inhibitors by proposing a new target for the anticancer activity of shikonin.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Chen
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Lin
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Han
authors.forename: Hong-Chang
authors.initials: HC
authors.lastname: Liu
authors.forename: Shou-Cheng
authors.initials: SC
authors.lastname: Huang
authors.forename: Baloch K
authors.initials: BK
authors.lastname: Shahla
authors.forename: Andrew
authors.initials: A
authors.lastname: Kulek
authors.forename: Jin-Liang
authors.initials: JL
authors.lastname: Qi
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Wang
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Ling
authors.forename: Yong-Hua
authors.initials: YH
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D008870:Microtubules / Q000187:drug effects; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D009285:Naphthoquinones / Q000737:chemistry*; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000737:chemistry* / Q000494:pharmacology*; D014747:Vinblastine / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D014404:Tubulin; D050257:Tubulin Modulators; C016101:shikonin; D014747:Vinblastine
keywords: apoptosis; confocal microscopy; molecular docking; shikonin derivatives; tubulin