Synthesis And Antitumor Activity Of Disulfide Derivatives Based On 1,3,4-Oxadiazole

Cancer is considered to be the second most common cause of deaths after cardiovascular disease in the world.In recent years,despite significant progress has been achieved in anticancer therapy,the treatment of malignancies in humans is still one of the most intractable worldwide health problems.Therefore,it is important to find effective drugs and new targets for the treatment of cancer.The thioredoxin redox system plays an important role in proliferation,apoptosis and metastasis of neoplastic cells,and has become a novel target for development of cancer therapeutics.As an important active functional group of sulfur element,disulfides possess a wide range of biological activities including anticancer,antibacterial,antifungal and anti-inflammatory.Among them,PX-12(1-methylpropyl-2-imidazolyl disulfde)is a typical representative of this series of compounds,which has been found to exhibit broad spectrum of antitumor activities targeting thioredoxin redox system.1,3,4-oxadiazole is a versatile lead molecule for designing potential bioactive agent,and its derivatives are associated with many types of biological properties such as anticancer,antioxidant,antibacterial,antifungal,anticonvulsant and anti-inflammatory activities.Based on the above analysis,15 nonsymmetrical disulfides bearing the 1,3,4-oxadiazole moiety were synthesized and reported for the first time by optimizing reaction conditions,and their structures were characterized by IR,1H NMR,13 C NMR and HRMS.Meanwhile,their vitro antiproliferative activities were evaluated against A549(human lung cancer cell),Hela(human cervix adenocarcinoma)and SMMC-7721(human liver cancer cell)cells by CCK-8assay with 5-fluorouracil(5-FU)as a positive control.The preliminary bioassay results demonstrated that all tested compounds exhibited antiproliferation with different degrees,and some compounds showed better effects than positive control 5-fluorouracil against various cancer cell lines.In A549 cells,except compounds 9c and 9h,which displayed moderate antitumor activities,with IC50 values of 17.89μmol/L and 17.14μmol/L respectively.The other compounds exhibited better antiproliferative effects with IC50 values range from 6.26 to8.31μmol/L,12 of these compounds inhibited the proliferation better than 5-fluorouracil.In Hela cells,except compound 9n,which displayed moderate antitumor activities,with IC50 values of 19.72μmol/L,the other compounds exhibited better antiproliferative effects with IC50 values range from 4.26 to 10.07μmol/L,all of these compounds inhibited the proliferation better than 5-fluorouracil.In SMMC-7721 cells,the whole compounds exhibited better antiproliferative effects with IC50 values range from 3.40 to 5.80μmol/L,13 of these compounds inhibited the proliferation better than 5-fluorouracil.However,the influence of the sort of substituents on antitumor activity against various cancer cell lines did not show apparent regularity.In summary,most of the tested compounds 9a-9o exhibited better in vitro anti--proliferative activities against various cancer cell lines.Therefore,the results laid a foundation for further improving the potency of this series of compounds and researching action mechanism.