Synthesis And Antitumor Activity Of Disulfide Derivatives Based On Substituted Phenacylmethylthio-1,3,4-thiadiazole

According to the current statistics,the incidence rate and mortality of cancer are increasing year by year.Now cancer is considered to be the second most common cause of deaths after cardiovascular disease,and it is also one of the major health problems in the world.At this stage,the most common and effective cancer treatment is chemotherapy,but its effect is still limited.Therefore,we urgently need to design new and effective antitumor drugs.Studies have shown that 1,3,4-thiadiazole is an important structural fragment in many natural and synthetic drugs,and has antibacterial,antiinflammatory,antioxidant,antiviral,antidiabetes,trypanocidal,antitumor as well as antitubercular biological activities.Disulfide derivatives have broad-spectrum biological activities,and their proliferation inhibition is closely related to the thioredoxin system in vivo,so they have attracted great interest.Based on the above biological activity characteristics,we designed and synthesized 28 disulfide derivatives containing substituted phenacylmethylthio-1,3,4-thiadiazole,and structural characterization of their by ~1H NMR,¹³C NMR,IR as well as HR-ESI-MS.Using 1-methylpropyl-2-imidazole disulfide（PX-12）and 5-fluorou-racil（5-FU）as positive control drugs,the antiproliferative activity in vitro of these compounds on human liver cancer cells（SMMC-7721）,human cervical cancer cells（He La）,human lung cancer cells（A549）and normal mouse cells（L929,normal cells）were determined by CCK-8 assay.The results show that compound 6a demonstrated the strongest antiproliferative activity on SMMC-7721 cells with IC₅₀ value of 1.62μmol/L.Compounds 6c,7g and8g displayed excellent antitumor activities against He La cells with IC₅₀ values of 3.65,3.59 and 3.21μmol/L,respectively.Compounds 6f,7c and 7e revealed efficient antitumor activities against A549 cells with IC₅₀ values of 3.22,2.25 and 2.85μmol/L,respectively.Meanwhile,most compounds showed lower cytotoxicity to L929 cells than the two positive control drugs.In conclusion,the 28 compounds synthesized have different degrees of antitumor activities against SMMC-7721,A549 and He La cells,and some compounds show low cytotoxicity to L929 cells.The above results lay a foundation for the study of the action mechanism and structure-activity relationship of these compounds.