Synthesis And Antitumor Activity Of1,3,4-thiadiazole Derivatives Based On Benzisoselenazolone

Benzisoselenazolones can mimic the features of glutathione peroxidase(GSH-Px),andebselen is one of the most well-known mimetic agent of GSH-Px, which can enhance theantioxidant capacity for tissue, and has been identified to possess good anticancer,antibacterial effects. Moreover, the selenium in ebselen is not bioavailable. This is probablythe reason for its low toxicity.1,3,4-thiadiazole derivatives are associated with many types of biological properties,including anticancer, antioxidant, antibacterial effects. Moreover, the introduction of differentheterocyclic backbone to the thiadiazole nucleus affects its biological activity, and thus hasdrawn widespread attention.Based on the above ideas, Ebselen was used as the lead compound,13substitutedsulfur-1,3,4-thiadiazole derivatives based on benzisoselenazolone were designed andsynthesized.The structure of all the target compounds were confirmed by IR,1H NMR,13CNMR, ESI-MS and elemental analysis. In order to find out novel potent antitumor agents,these target compounds were evaluated for their cytotoxicity in vitro against human cancercell A549, SMMC-7721and MCF-7by CCK-8assay.For SMMC-7721cells, the newly synthesized compounds8a-m all exhibitedantiproliferation with different degrees. Meanwhile, Most of the compounds showed betteractivity than lead compound ebselen (IC50=18.33μmol/L) did. As compared with compound8b（IC50=19.82μmol/L）with no substituent at the phenyl ring of benzoylmethylthio-moiety,compounds8c,8e,8g and8k bearing electron-donating substituents all exhibited theenhanced antitumor effects against SMMC-7721cells. These results suggest that the presenceof electron-donating group at the phenyl ring is favorable for improving the potency.However, the influence of electron-drawing group on the antiproliferative activity has notbeen fully understood.For MCF-7cells, most of the compounds8a-m showed higher activities than thatebselen (IC50=15.02μmol/L) did. We were surprised that compound8e bearing a4-methylsubstituent showed the best inhibitory effect with IC50values of2.89μmol/L, which wassuperior to compound8b (IC50=3.26μmol/L).For A549cells, most of the compounds8a-m displayed lower antitumor activity thanthat ebselen (IC50=3.75μmol/L) did. Compared with compound8b, the majority of thecompounds exhibited the enhanced antitumor effects. Especially, compounds7e,7i and7ldisplayed highly effective antitumor activities with IC50values of2.33,2.33and3.51μmol/L,and showed stronger activity than ebselen did.In summary, the introduction of1,3,4-thiadiazole had a significant impact to biologicalactivity of benzisoselenazolone.Therefore, the results laid a foundation for further improvingthe potency and the selectivity of this series of compounds.