Novel Shikonin Derivatives Targeting Tubulin as Anticancer Agents

• Published in: Chemical biology & drug design 2014-11, Vol.84 (5), p.603-615
• Main Authors: Guo, Jing, Chen, Xiao-Feng, Liu, Jing, Lin, Hong-Yan, Han, Hong-Wei, Liu, Hong-Chang, Huang, Shou-Cheng, Shahla, Baloch K., Kulek, Andrew, Qi, Jin-Liang, Wang, Xiao-Ming, Ling, Li-Jun, Yang, Yong-Hua
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; apoptosis; Apoptosis - drug effects; Binding Sites; confocal microscopy; Dose-Response Relationship, Drug; Hep G2 Cells - drug effects; Humans; Hydrogen Bonding; Microtubules - drug effects; molecular docking; Molecular Docking Simulation; Molecular Targeted Therapy; Naphthoquinones - chemistry; shikonin derivatives; tubulin; Tubulin - metabolism; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Vinblastine - metabolism
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12353

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. A series of shikonin‐phenoxyacetic acid derivative were prepared; among them, compound 16 potently inhibited the function of microtubules, inducing cell growth inhibition and apoptosis of HepG2 cells. Analysis of microtubules with confocal microscopy demonstrated that 16 altered the microtubule architecture and exhibited a significant reduction in microtubule density.