title: Synthesis and biological evaluation of heterocyclic carboxylic acyl shikonin derivatives.
abstract: A series of shikonin derivatives (1-13) that were acylated selectively by various thiophene or indol carboxylic acids at the side chain of shikonin were synthesized, and their biological activities were also evaluated as potential tubulin inhibitors. Among them, compound 3 ((R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 3-(1H-indol-3-yl)propanoate) and compound 8 ((R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 2-(thiophen-3-yl)acetate) exhibited good antiproliferative activity of A875 (IC50  = 0.005 ± 0.001 μm, 0.009  ± 0.002 μm) and HeLa (IC50  = 11.84 ± 0.64 μm, 4.62  ± 0.31 μm) cancer cell lines in vitro, respectively. Shikonin (IC50  = 0.46 ± 0.002 μm, 4.80 ± 0.48 μm) and colchicine (IC50  = 0.75 ± 0.05 μm, 17.79 ± 0.76 μm) were used as references. Meanwhile, they also showed the most potent growth inhibitory activity against tubulin (IC50 of 3.96  ± 0.13 μm and 3.05 ± 0.30 μm, respectively), which were compared with shikonin (IC50  =  15.20 ± 0.25 μm) and colchicine (IC50  = 3.50 ± 0.35 μm). Furthermore, from the results of flow cytometer, we found compound 3 can really inhibit HeLa cell proliferation and has low cell toxicity. Based on the preliminary results, compound 3 with potent inhibitory activity in tumor growth may be a potential anticancer agent.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210093, China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Wang
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Lin
authors.forename: Wen-Yao
authors.initials: WY
authors.lastname: Kong
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.forename: Shou-Cheng
authors.initials: SC
authors.lastname: Huang
authors.forename: Jin-Liang
authors.initials: JL
authors.lastname: Qi
authors.forename: Rong-Wu
authors.initials: RW
authors.lastname: Yang
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Gu
authors.forename: Yong-Hua
authors.initials: YH
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003078:Colchicine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C000592742:1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 2-(thiophen-3-yl)acetate; C000592741:1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 3-(1H-indol-3-yl)propanoate; D000970:Antineoplastic Agents; D007211:Indoles; D009285:Naphthoquinones; D013876:Thiophenes; D014404:Tubulin; D050257:Tubulin Modulators; C016101:shikonin; D003078:Colchicine
keywords: anticancer; indol carboxylic acids; shikonin derivatives; thiophene carboxylic acids