Synthesis And Anti-tumor Activities Of Dl-shikonin Oxime Derivatives

Zicao is a traditional Chinese medicine in China with a long history of clinical application. The medicinal ingredients of Zicao are shikonin and its enantiomer Alkonin together with their esters. Shikonin has potent anti-tumor effects,but as an anticancer drug in clinical applications it still has a long way to go. This is mainly causedbyits cytotoxicity along withthe poor selectivity. While suppressing the growth of tumor cells, it may cause the death of a large number of normal cells. Therefore, how to reduce the cytotoxicity of shikonin to normal tissues and to increase its selectivity towards cancer cells will be the urgent issues to be solved in further development.In order to find an anticancer drug with more efficiency to cancer cells and low toxicity to normal cells, we modified the chemical structure of Shikonin. We designed a series of racemic Shikonin oxime derivatives and prepared intermediates of racemic shikonin. After the racemic Shikonin side chain hydroxyl been esterified or etherified,and followed oxidation of ammonium cerium nitrate, we got 2 and 6 dicarbonyl dimethoxy side chain hydroxyl esterified or etherified shikonin. At last,naphthalene ring nucleus carbonyl base conducted oxime modification, and we got racemic Shikonin derivatives(Referred to as shikonin oxime derivatives in the text)The in vitro inhibitory activity of Shikonin oxime compounds were measured by MTT assay,of which we choose three kinds of cell lines namely, Mcf-7, K-562 and DU-145. In vitrostudy show that the oxime series of shikonin derivatives have good inhibitory activity to Mcf-7 and K-562 cell lines, but exhibited less inhibitory activity against DU-145 cell line. The results demonstrated that this series of Shikonin oxime compounds have certain selectivity. When 5,8-oxygen dimethyl shikonin carbonyl modified to oxime the antitumor activity increased. The activity sequence is:1,4- dicarbonyl group of oxime(bis oxime)> 1- carbonyl oxime(Monooxime)> dicarbonyl compounds. From the aspect of in vitro activity of oxime derivatives precursor quinine we inferred that Oxime is not quinine prodrug.Besides,after carbonyl group being modified to oxime,the side chains have great impact on the activity. When the side chain was esterfied, the anticancer activity was significantly improved.But the etherified product show poor activity. When the side chain was esterfied with isovalerate,it demonstrated the activity to MCF-7and K562 and their IC50 value was 12.7 μM and 1.3 μM respectively.We chose this compound 2-DMSAKO-5conducted in vivo research.In vivo study showed that 2-DMSAKO-5 at 12 mg/kg, I.P. once daily for 8 days has significant inhibiting activity on mice bearing CT26 and mice bearing EMT6 with more than 45.9% and 41.4% respectively,which are higher than 5-FU group at dose of 25 mg/kg.But the group bearing S180 showed poor activity compared with 5-FU group.At the same time the weight of 2-DMSAKO-5 group increased obviously and did not show side effects. The detailed antitumor mechanism of this compound needs further experimental verification.