Synthesis And Antitumor Activity Research Of Disubstituted Shikonin Phenoxy Acid Derivatives

Shikonin is a specific naphthoquinone natural active molecules in comfrey, with sterilization, anti-inflammatory, anti-oxidation, anti-HIV and anti-tumor activity. From the early anti-bacterial, anti-oxidation to the current anti-cancer research which is more in-depth, we found that shikonin is a promising anti-tumor natural leading compounds. Numerous research concentrates on the shikonin active functional molecules to carry out, at the same time a little number of studies consider natural shikonin esters as a leading compound, which is published activity validation papers. The structural modification of shikonin which starts from the molecular structure is an important issue to resolve its toxicity, solubility. Thus, after separation to obtain a shikonin natural product, we introduced the biocompatibility of the active pharmaceutical intermediates phenoxy carboxylic acid into its molecular structure, to thereby obtain a structure of a novel series of shikonin derivatives. Tumor cells in vitro inhibition activity (A875 cell line, HepG2 cell line, Hela cell line) shows that this series of derivatives compared to the shikonin have significant anti-tumor activity. The compound 4-shikonin phenoxy phenylacetic ester showes significant inhibitory activity to A875, Hela and HepG2cell lines (IC50 value is 1.239 μM/L,4.314 μM/L, 0.426 μM/L). Apoptosis and cell cycle experiments also verify a high concentration (> 10μM/L) phenoxy phenylacetic acid ester can effectively promote the apoptosis of HepG2 cells. At the same time, as the growth over time, between the tumor cells and drugs have a siginficant concentration-dependent. Docking simulation results also show that the compound with the vinblastine active site of tubulin can effectively combine, which also proved vinblastine the active site of tubulin is the compound effective role in the target. Thus, this study not only get efficient shikonin phenoxy acid esters inhibitors, also laid a solid foundation for further study, at the same time, the corresponding mechanisms of inhibition of tumor cell to explore shikonin derivatives makes a corresponding contribution.