Synthesis And Anticancer Activity Of Disulfide Derivatives Based On 1,2,4-triazole[3,4-b]-1,3,4-thiadiazole

The prevention and treatment of cancer has became the public health problem to be solved in our country.There are various kinds of anticancer drugs on the market at present,but the traditional anticancer drugs often have obvious side effects,low bio-availability and resistance.The discovery of new targets in tumor cells and the application of targeted drugs have opened up a wider field for the design and development of new anti-tumor drugs.Heterocyclic compounds 1,2,4-triazole and 1,3,4-thiadiazole have been used in many fields,especially in the field of medicine,which have attracted wide attention.Therefore,the anticancer drugs designed with 1,2,4-triazole[3,4-b]-1,3,4-thiadiazole as structure unit which have potential application prospects.Thioredoxin?Trx?has been found highly expressed in many kinds of tumor cells,which has become a new target for cancer treatment.At present,there is no international market for anticancer drugs targeting Trx.Therefore,based on this strategy,molecular construction plays an important role in finding new anti-tumor drugs.As the disulfide has the characteristics of targeting thioredoxin,disulfide derivatives have become the focus of the design anticancer drugs.We has designed and synthesised 23 nonsymmetrical disulfide derivatives based on1,2,4-triazole[3,4-b]-1,3,4-thiadiazole.All newly compounds were characterized by IR,¹H NMR,¹³C NMR and HR-ESI-MS.5-Fluorouracil?5-FU?and 1-methylpropyl-2-imidazolyl disulfide?PX-12?were used as positive controls,for assessing their in vitro antiproliferative activities against human cancer cell lines A549,Hela,SMMC-7721 and fibroblast cell line L929 by CCK-8 assay.The experimental results showed that,in A549,compound 8b,8l,8n and 8p showed effective inhibitory effect,with IC50 values of 3.84,2.67,3.08 and 3.14?mol/L,and their activity is better than that of the control PX-12 and 5-FU.In Hela,compound 8d,8l,8n,8s and 8v showed very good anti-proliferative effect,with IC50 values of 2.23,2.84,3.34,3.41and 3.42?mol/L,and their activity is better than that of the control PX-12 and 5-FU.In SMMC-7721,compound 8a,8d,8g,8l and 8w,with IC₅₀0 values of 1.64,1.74,2.29,1.61 and2.11?mol/L,showed significant anti-tumor activity,and their activity is better than that of the control PX-12 and 5-FU.In L929,all compounds showed lower cytotoxicity of 5-FU control.In summary,23 compounds showed potent antiproliferative activity on cell lines A549,Hela and SMMC-7721.All compounds showed lower cytotoxicity to L929 compared with the positive control drug 5-FU.The above results lay a foundation for the study of its anticancer mechanism and other more broad-spectrum biological activities.