Synthesis And Anti-tumor Activity Of Shikonin Carboxylate

Nowadays, cancer is becoming one of the critical illnesses that threaten people’s health and ultimately lead to death. Drug treatment is one of the main measures of treating such diseases currently, among which drugs derived from natural products occupy a big proportion (such as paclitaxel, camptothecin, etc.). In recent years, studies have shown that active naphthoquinone components isolated from traditional Chinese medicine lithospermum-shikonin also has significant anti-tumor activity in vivo and in vitro. Thus, researches that consider shikonin as a lead compound and structurally modify it emerge in endlessly, which aims to overcome its deficiencies in solubility, toxicity and other aspects. Tubulin has been verified to be the target for many natural products, naphthoquinone has been improved to be effective enzyme inhibitors of tubulin, and shikonin has a typical structure of naphthoquinone nucleus. Therefore, we treated tubulin as a target and shikonin as a lead compound to obtain novel active molecular and further verified the biological activity. Introduction of bioactive intermediate drug and drugs gave shikonin stronger and better biological activity. We found an active molecular— shikonin-ibuprofen ester (S10) showed selectively significant inhibitory activity to Hepatoma cell line (HepG2) (IC50 value is 2.136 μM,2.732μM,1.097 μM respectively for A549, Hela and HepG2 cells), while low toxic to normal liver cells (IC50 value is> 100 μM) in vitro. Apoptosis test demonstrates that shikonin-ibuprofen ester effectively promotes apoptosis in HepG2 cells in a concentration-dependent manner. When HepG2 cells were handled with certain concentration of shikonin-ibuprofen ester, we found the compound could arrest the majority of cells at the G2/M transition and disorganize cytoskeletal microtubule. Docking results reveal that the compound can effectively combine with the colchicine active site of tubulin, which provided us an effective theoretical basis. Together, these data suggest that our study not only get efficient biologically active molecules of shikonin-pharmaceutical intermediates, and make a certain contribution for the study of anti-cancer mechanisms.