Synthesis And Application Of 5-hydroxy-3-selenyl-2H-chromenones And 5-selenium Pyrimidines

Objective:Organoselenium compounds and heterocyclic compounds have biological activities.From the perspective of drug design and the principle of drug combination,the selenium functional group combined with the heterocyclic skeleton is effective to obtain a heterocyclic selenium compound with pharmacological activity.Base on the researches of our group,we have developed a simple and efficient new method for the synthesis of 5-hydroxy-3-selenyldihydrochromanone and 5-selenium pyrimidine,and a series of organic selenium compounds have been synthesized by using the new method,and MTT method was used to screen the anti-tumor activity of the synthesized organic selenium compounds in vitro,and further studied the mechanism of the compounds with better pharmacological activity,so as to enrich the variety of heterocyclic selenium compounds and provide the source for screening the candidate drugs of organic selenium.Methods:Diphenyl diselenyl ether was used as raw material to react with alkyne-tethered cyclohexadienones and uracils respectively to obtain the target products.Under the irradiation of visible light,radical cascade cyclization reaction took place in the former,which resulted in the formation of5-hydroxy-3-selenyl-chromenones.The structures of the obtained compound were characterized by ¹H NMR,¹³C NMR and HRMS,The MTT method was used to detect T-24（human bladder cancer cells）,MGC-803（human gastric cancer cells）,Hep G-2（human liver cancer cells）,SK-OV-3（human ovarian cancer cells）and WI-38（human embryonic lung cells）in vitro anti-tumor activity,and 5-fluorouracil（5-FU）was used as a positive control.The antitumor mechanism of MGC-803 cells in vitro by compound 3e was studied.In the latter,the electrophilic substitution reaction was carried out by electrochemical method,and the corresponding 5-selenium uracils were obtained.The structures of the resulting compounds were also characterized by ¹H NMR,¹³C NMR and HRMS.Results:Thirty novel5-hydroxy-3-selenyl-2H-chromenones and nineteen 5-selenium pyrimidine heterocyclic compounds were synthesized,and their structures were characterized.The results of antitumor activity showed that some selenyl-chromenones were cytotoxic,and compounds 3e and 3q had significant effects.The IC₅₀ values of compound 3e were 5.6±0.9μM（T-24）,5.0±1.1μM（MGC-803）,and 5.5±0.9μM（Hep G-2）,respectively.The IC₅₀ values of compound 3q were 8.1±0.4μM（T-24）and 7.2±1.7μM（MGC-803）,respectively.The study of antitumor mechanism showed that compound 3e could change the morphology of MGC-803 cells,change the concentration of ROS,induce apoptosis and block the cell cycle in G1 phase.Conclusions:A total of forty nine heterocyclic selenium compounds were synthesized,of which nine selenyl-chromenone compounds have pharmacological activities,especially the compounds 3e and 3q have good pharmacological effects on some tumor cell lines.Compound 3e was used to study the antitumor mechanism of MGC-803 cells.It was found that compound 3e could change the cell morphology,increase the concentration of reactive oxygen species and induce apoptosis.With the increase of compound concentration,the apoptosis rate gradually increased,and block the cell cycle in G1 phase,so as to effectively inhibit cell proliferation.