Synthesis And In Vitro Antiproliferative Evaluation Of 1,3,4-Thiadiazole Disulfide Derivatives Bearing Substituted Mercapto

Cancer is the second leading cause of death in humans.Despite significant advances in cancer treatment,the discovery and development of effective anti-cancer drugs remains one of the thorniest health problems in the world.As a result,people are increasingly looking for new targets for cancer treatment.The thioredoxin system is closely related to the development of cancer,which has gradually become a new target for tumor therapy.The antitumor activity of disulfides is closely related to the thioredoxin system in vivo and shows a broad spectrum of biological activities such as antibacterial,antifungal,anti-HIV activity,attracting a great deal of attention.As an important leading molecule in the design of bioactive agents,1,3,4-thiadiazole derivatives have many biological activities such as anticancer,bactericidal,anti-inflammatory,antituberculosis,antivirus and anticonvulsant drugs,becoming the research hotspot of azole compounds.Based on the above analysis,33 nonsymmetrical 1,3,4-thiadiazole disulfide derivatives bearing substitutedmercapto were designed and synthesized in this paper.The structures of the target compounds were characterized by ¹HNMR,¹³C NMR,IR and HR-ESI-MS.Meanwhile,the antiproliferation of A549?human lung cancer cell?,Hela?human cervical cancer cell?and SMMC-7721C?human liver cancer cell?was determined by CCK-8 assay using 5-FU?5-fluorouracil?and PX-12?1-methylpropyl 2-imidazolyl disulfide?as positive control drugs,as well as to the cytotoxicity to L929?mouse fibroblasts?.The test results showed that the target compounds showed different degrees of proliferation inhibitory activity on A549,Hela and SMMC-7721 tumor cells,and showed low toxicity on normal cell L929.In A549 cells,compounds 6c,6e,6h,7e,7h and 8e all showed better antiproliferative activity than the positive control drugs 5-FU and PX-12,and compound 6e showed the best proliferation inhibitory activity with an IC₅₀0 value of3.62?mol/L.In Hela cells,compounds 6i,7a,7g,8a and 8b all showed potent antiproliferative activity with IC₅₀ values of 3.88,3.76,3.59,3.38 and 3.12?mol/L,respectively.Compounds6a,6e,6g,6i,7a,8a and 8e all exhibited superior bioactivity to the control drugs PX-12against SMMC-7721 cells.Among them,compounds 6a,7a,8a displayed good antiproliferative activity with IC₅₀ values of 2.54,2.69 and 2.31?mol/L,respectively.In addition,most compounds displayed weak cytotoxic effect against the L929 cell lines.In summary,the 33 target compounds synthesized in this study displayed different degrees of anti-proliferative activity on A549,Hela and SMMC-7721 tumor cells,while showing lower cytotoxicity against normal cells.This result provides an important basis for the development of such compounds as effective antitumor lead compounds.