Synthesis And Anti-tumor Activity Evaluation Of Compounds Based On Coumarin Skeleton

Cancer is a serious threat to human health and the second leading cause of death after cardiovascular diseases.Its morbidity and mortality will continue to rise for a long time.So far,many anti-cancer drugs have been affected by restrictive factors such as narrow therapeutic window,drug resistance,non-specificity,etc.,making the development demand for new anti-cancer drugs increasing.Natural products are one of the important sources for the development of new anti-cancer drugs.Compounds containing coumarin and or isoflavone skeletons have been confirmed to have potential anti-cancer activities in vivo and in vitro.Based on the previous work of the research group,based on the framework of coumarin and isoflavones,three new series of coumarin or isoflavone derivatives were designed and synthesized,and a variety of tumor cell anti-proliferative activity evaluation experiments were carried out.Preliminary study on the mechanism of action.The specific work is as follows:1.Through the structural modification of the coumarin and isoflavone cores,three series of 88 coumarin and isoflavone derivatives were designed and synthesized,including 50 coumarin derivatives and 38 isoflavone derivatives.The structure was confirmed by ¹H NMR,¹³C NMR,and MS,and the structure of 73 compounds has not been reported in the literature.2.Explore the synthesis method of key intermediate 5a-5o in seriesⅠcompound,and improve the yield of the target product.Exploring the post-treatment method of the isoflavone cyclization in the compounds in series III has increased the yield of the target compound by nearly 50%.3.The anti-proliferative activity of the target compound on 4 kinds of tumor cells was evaluated.Most of the compounds showed good inhibitory activity.Among them,compound 5c showed the best inhibitory activity on PC-3 and MGC-803 cells,and its IC₅₀ was respectively 0.14±0.01μM and 1.02±0.04μM,and preliminary exploration of their mechanism of action,found that compound 5c can inhibit the migration of PC-3 and MGC-803 cells and the ability of cell colony formation.Flow cytometry detection showed that compound 5c can induce apoptosis of PC-3 cells.Western Blot experiment showed that the mechanism of compound 5c inducing apoptosis may be through the cysteine-containing aspartate proteolytic enzyme（Caspase）Enzyme-dependent apoptosis.