Design,Synthesis And Bioactivity Evaluation Of Coumarin Shikonin Carboxylic Acid Esters Derivatives

Due to soil,water and air pollution is increasing,and work pressure increased gradually and low immunity caused by body function transform,the cancer become one of the important diseases of a serious threat to human health.As a result,more efficient low toxicity of antitumor drugs design and synthesis of research more and more get the attention of the researchers.Tumor cells is a kind of strong proliferation ability and its fast growth and the change of volume was maintained by ultra high level mitosis,if the formation of the spindle is restrained,mitosis process will be stopped,then cells will die.And tubulin is mitosis process play an important role in the protein,according to a report in the literature,based on the tubulin depolymerization or polymerization inhibitor drugs or molecules were showed highly effective inhibition of mitosis,inducing cancer cell apoptosis,therefore,microtubule protein has become a kind of antitumor drug development important targets.Studies have confirmed that shikonin is a kind of natural products has significant antitumor effect.With its display for many reactive molecules leads to obtain superior solubility and cytotoxic,And coumarin molecule is a class of small molecules with antitumor activity,and coumarin has low cytotoxicity,simple structure,the introduction of reactive molecules can significantly reduce the toxicity and drug resistance,based on this,we use the Discovery Studio molecular docking simulation software for a series of coumarin schiff base class filtered shikonin carboxylic acid esters derivatives,and the preparation of a series of coumarin schiff base class shikonin carboxylic acid esters derivatives(PMMB-229—PMMB-229),and active functional verification.Studies have shown that compounds PMMB-232 has the strongest inhibitory activity on Hela,IC50 is 6.25 μM,effection is obviously better than that of shikonin(Hela:IC50=15.50μM),compound PMMB-232 in human embryonic kidney cells,IC50 is 63.80μM,cytotoxicity significantly less than the 10.52μM of shikonin.Further,we found that PMMB-232 tubulin polymerization experiment molecular agree with colchicine mechanism,which can effectively promote the depolymerization of tubulin,and inhibit the tubulin assembly.Further experiments showed that PMMB-232 can effectively induce apoptosis and cell cycle arrest in G2/M phase,has the good time and the concentration dependence.Mitochondrial fluorescence staining and Western blot experiments show that the two can be through the mitochondrial pathway and caspase pathway induced apoptosis.Therefore,this topic of shikonin derivatives is a kind of high-efficiency,reactive molecules,PMMB-232 revealed a significant tubulin inhibitory activity,has deep research significance.