Synthesis And In Vitro Antiproliferative Evaluation Of Novel Nonsymmetrical 1,3,4-thiadiazole Disulfide Derivatives Bearing Urea Moiety

Cancer is considered to be one of the most common causes of deaths in the world.Therefore,it is important to indentify effective drugs and new targets for the treatment of cancer.Thioredoxin(Trx)is a low molecular weight redox protein,which is widely expressed in vorous biological tissues and organs.Trx,thioredoxin redutase(TrxR)and nicotinamide adenine dinucleotide phosphate(NADPH)comprise a thioredoxin system that is involved in many aspects of tumor physiology such as proliferation,apoptosis and metastasis and has become a novel attractive target for development of new cancer therapeutics.As an important sulfur-containing compound,disulfide derivatives displayedmany types of biological activities,such as anticancer,antibacterial.Particularly,the antitumor character of disulfide derivatives attracts great interests from medicinal chemists.1,3,4-thiadiazole is a privileged scaffold incorporated in many compounds presenting a wide range of pharmacological activities,such as antioxidant,antibacterial,antifungal,anticancer,anticonvulsant and anti-inflammatory activities.Considering the biological significance of 1,3,4-thiadiazole and disulfide derivatives,we report herein the synthesis of nonsymmetrical 1,3,4-thiadiazole disulfide derivatives bearing urea moiety.All newly synthesized compounds were characterized by IR,1H NMR,13 C NMR and High Resolution-Electrospray Ionization-Mass Spectrometer(HR-ESI-MS).1-methylpropyl 2-imidazolyl disulfide(PX-12)and 5-fluorouracil(5-FU)were used as positive controls,we evaluated for their in vitro antiproliferative activities againsthuman cancer cell lines SMMC-7721,Hela,A549 and normal cell line L929 by CCK-8 assay.The bioassay results demonstrated that all tested compounds exhibited antiproliferation with different degrees against the three human cancer cell lines.In A549 cell line,most of compounds displayed moderate antiproliferative activities,among these compounds,compound 1b and 5b exhibited better effects than positive control PX-12 and 5-FU,especially compound 1b exhibited the best inhibitory effect with IC50 value of 7.93μM;in Hela cell line,the majority of them showed better activities than positive control positive controls PX-12 and 5-FU,especially compound 2c showed significant antiproliferative activity with IC50 value of 2.84μM;in SMMC-7721 cell line,some of the compounds displayed higher activities than positive controls PX-12 and 5-FU.Among them,compounds 2c,7c showed potent biological activities,in particular,compound 7c displayed highly effectivebiological activity with IC50 value of 3.06 and 2.83μM,repectively;in L929 cell line,most of the tested compounds showed weak cytotoxic effect.In summary,27 target compounds displayed antiproliferative activities against human cancer cell lines A549,Hela and SMMC-7721,and most of compounds showed weak cytotoxic effect against the normal cell line L929.Therefore,the results laid a foundation for the structure-function relationship and action mechanism research of this series of compounds.