Synthesis And Biological Activity Evaluation Of Sesamin-like Analogs

Natural products are an important source for the discovery of various lead compounds.More than 50%of marketed drugs contain fragments of natural products,or are directly derived from natural products.Natural products provide a wide variety of structures that can be used as templates to synthesize new drugs with enhanced biological activity and improved pharmacological properties through structural modification.Sesamin is a lignan natural product isolated from sesame seeds,which has a variety of biological activities,such as antioxidant,anti-inflammatory,anti-tumor and so on.Due to the poor solubility seriously affects the further research and development of sesamin,how to obtain sesamin analogs with enhanced biological activity and solubility is of great significance.Most of the drugs in clinical use contain nitrogen heterocyclic structures（as of 2018,the proportion of nitrogen-containing heterocyclic structures in small molecule drugs is about 61%）,which can be used to synthesize water-soluble salts or quaternary ammonium compounds,so we plan to synthesize the tetrahydropyrrole-containing sesamin analogs.In this paper,17 new sesamin-like analogs were synthesized by sesamin ring-opening reaction,Mitsunobu reaction and Suzuki reaction using sesamin as raw material,and the ring-opening mechanism of sesamin was studied.Using the ring-opening product 10 as the raw material,four new compounds were obtained through hydrolysis reaction,Dess-Martin oxidation and Mitsunobu reaction.All compounds were characterized by NMR and HRMS,and the configurations of compounds 8 and 10 were confirmed by 2D NMR and X-ray.Subsequently,the synthesis compounds were evaluated for their antifungal and antitumor activities by micro-broth dilution method and MTT method,and it was found that some compounds had inhibitory activity on the growth of fungi and hepatoma cell（Hep G2）.Among them,compounds 19k,22 and 25 have both antifungal and antitumor activities.From the anti-tumor evaluation results of 17sesamin-like analogs,compounds 19c and 19k have antitumor activity with IC₅₀values of 6.492μM and 4.727μM,respectively.It can be seen from the evaluation results of 17b,22 and 25 that obtained from compound 10 have anti-tumor activities,and the IC₅₀ values of 17b,22 and 25 are 1.758μM,4.690μM and 3.987μM,respectively.The results of this paper show that some sesamin analogs have inhibitory activity against fungi and tumor cells,which provides a new idea for further research on sesamin.