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

The anticancer mechanism of the disulfides derivatives are associated with thioredoxin system in the body, and PX-12 is the most typical representative, it can inhibit thioredoxin activity, thereby inhibiting the growth of tumor cells, and has been identified to possess good anticancer, antibacterial effects.1,3,4-thiadiazole derivatives are associated with many types of biological properties, The anticancer, antibacterial effects was widely used for studying drug intermediate in the present.And 1,3,4-thiadiazole structures are connected with electron donating element S, which can affect its biological activity by enhancing the affinity between the receptor and the ligand.Finally, it can significantly enhance the activity of the compound.Based on the above structures inciding the 1,3,4-thiadiazole and disulfides, PX-12 was used as the lead compound, 23 substituted disulfides-1,3,4- thiadiazole derivatives were designed and synthesized. The new target compound combine the disulfides and the1,3,4-thiadiazole structures. In order to find out novel potent antitumor agents, it can enhance effectiveness without adding side effects.For SMMC-7721 cells, the newly synthesized compounds all exhibited antiproliferation with different degrees. Meanwhile, Most of the compounds showed better activity than5-fluorouracil(IC50=5.62μmol/L) did. Among the chemical compounds of 2- substituted disulfides-5- substituted phenyl-1,3,4-thiadiazole(7a-7n), It displayed that electron donating substituent of phenyl ring including trimethoxy 、 methoxy 、 methyl had better antitumor activity than other groups.For MCF-7 cells, Only the compounds 7j displayed lower antitumor activity than that5-fluorouracil(IC50=14.26μmol/L) did. We were surprised that compound 2i showed the best inhibitory effect with IC50 values of 1.78μmol/L, its activity is obviously better than control.For A549 cells, all the target compounds of 2-amino-5- substituted disulfides-1,3,4-thiad iazole(2a-2i) displayed better antitumor activity than 5-fluorouracil, showed better cytotoxicity. But among the target compounds of 2-substituted disulfides-5- substituted phenyl-1,3,4-thiadiazole(7a-7n), only a part of compounds displayed better antitumor activity than 5-fluorouracil(IC50=8.13μmol/L) did. The compound bearing a 4-amino phenyl substituent showed the better inhibitory effect than 5-fluorouracil.In summary, the introduction of 1,3,4-thiadiazole had a significant impact to biological activity of disulfides derivatives.Therefore, the results laid a foundation for further improving the potency of this series of compounds.