The Synthesis Of Thio And Sulfonyl Substituted Fused Heterocyclic Compound And Their Antitumor Application

Objective:The sulfur and sulfonyl-containing compounds are widely used in organic chemistry,material chemistry,pharmaceutical industry and pesticides.Meanwhile,the nitrogen-containing fused heterocycles present diverse biological activities,and are usually applied in drug molecules.The combination of sulfur and sulfonyl groups with the nitrogen-containing heterocycles is helpful to improve the druggability of compounds according to the principle of drug splicing.Thus,it is very necessary to develop an efficient and green method for the construction of novel nitrogen-containing fused heterocycles with sulfur groups and sulfonyl groups.Based on our previous work,new visible-light-catalyzed methods for the synthesis of thio-and sulfonyl-substituted nitrogen-containing fused heterocycles were developed.Then,the thio-and sulfonyl-substituted nitrogen-containing fused heterocycles were screened for in vitro antitumor activity by MTT method,and it is looking forward to find compounds with good activity.Methods:Thiosulfonate was induced to generate sulfur and sulfonyl radicals catalyzed by Na₂-Eosin Y under the irradiation of 30 W white light in acetonitrile,then,the radicals underwent cascade addition with 1-allyl-2-phenylethynyl-benzimidazole and 1-（2-isocyanophenyl）-propenone to provide a series of novel thio-and sulfonyl-substituted nitrogen-containing fused ring compounds.The antitumor activity of the new obtained compounds against T-24（human bladder cancer cells）,MGC-803（human gastric cancer cells）,He La（human cervical cancer cells）,and LO2（human normal hepatocytes）was study by the MTT method.Results:24examples of pyrrolo[1,2-a]benzimidazoles and 17 examples of benzo[d][1,3]oxazines were synthesized through the new developed methods,the structures of the obtained products were determined by NMR,HRMS and other instruments.And the reaction mechanism was investigated by controlled experiments.The MTT method showed that some of the obtained benzo[d][1,3]oxazine compounds present good in vitro antitumor activity,among them,3b’,3e’and 3m’exhibited most antitumor effects.The IC₅₀ values of compound 3b’for MGC-803 and Hela were 6.6±0.5μM and 8.7±0.7μM,respectively.The IC₅₀ values of compound 3e’for MGC-803 and Hela were 12.5±1μM and 4.1±0.5μM,respectively.The IC₅₀ value of compound 3m’for Hela was 2.7±0.5μM.Conclusions:A new visible-light-catalyzed radical tandem reaction of thiosulfonates was developed,which provided a series of novel thio-and sulfonyl-substituted nitrogen-containing fused-ring compounds.The method present some advantages such as simple operation,good atom economy and ect.The obtained benzo[d][1,3]oxazine compounds exihibited good in vitro antitumor activity,the antitumor activity study of these new compounds will contribute to discover lead compounds.