Design And Synthesis Of Furoxan Derivatives Targeting Trematodes TGR And Anticancer Activity Of Artemisinin Derivatives

1.Design and synthesis of furazan derivatives targeting trematodes TGR.The disease of trematodes are caused by the internal and external parasites of the monogonimoclass,scutellar subclass and compound subclass of the phylum trematodes,which belongs to the phylum trematodes.The trematodes of the first two subclasses are mainly parasitic on amphibians,reptiles,molluscs and crustaceans,while the trematode of the last subclass is mainly parasitic on mammals.After asexual reproduction with freshwater snails?including small nest snails,radish snails,ear radish snails,trapezoid snails and vertebral snails,etc.?,they parasitic on mammals finally,more than 30 species of which are parasitic on human beings.The disease of trematodes are endemic epidemic in the world,and its transmission is greatly affected by natural conditions.for example,fascioliasis occurs frequently during the rainy season,and there is no snail distribution in northern of China,so there is almost no occurrence of schistosomiasis.The disease of trematodes is seriously harmful to human health and economic development,but at present,the drugs for the treatment are still limited,and the development of therapeutic drugs is slow.For example,so far,the first drug for schistosomiasis is still praziquantel.The drug of Fasciola gigantica is still trichlorobendazole,and existing serious drug resistance.In eukaryotes,there is a redox system to remove toxic reactive oxygen produced by their own metabolism,so as to maintain the oxygen balance of the body.It has been found that trematodes have a different redox system,it's a single enzyme that responsible for maintaining the redox balance of trematodes,it is called TGR,and so it can be a target for drug research on TGR.In the early stage,researchers targeted TGR of Schistosoma mansoni.Through extensive screening,they found that furoxan not only had a good inhibitory effect on TGR of Schistosoma mansoni,but also had significantly insecticidal ability of Schistosoma mansoni.After that,they carried out structural modification on this basis,and found that these derivatives had strong anti-TGR activity and insecticidal ability.Therefore,the structural modification of oxadiazole-2-oxide is one of the important strategies for the development of anti-TGR drugs.In this paper,we regard furoxan as the lead compound and trematodes TGR as the target,29new oxadiazole-2-oxide derivatives were designed and synthesized by introducing piperazine groups and fluorine atoms on the basis of the previous work of our group.The structures of these new compounds were determined by ¹H NMR and ¹³C NMR,HR-MS,and were used to determine the activity of recombinant TGR of Fasciola gigantica.2.Research on anticancer activity of Artemisinin DerivativesSince the 21st century,the rapid development of global economy and science and technology has led to the rapid improvement of people's living standards.But so far,cancer is still the biggest killer that threatens the lives of people around the world.Each year,the number of deaths caused by cancer far exceeds that caused by AIDS,tuberculosis and malaria.At present,although there are many commercial drugs for the treatment of cancer,most of them have strong toxic and side effects,and even multidrug resistance,so it is still an urgent problem to find and develop new anticancer drugs with high efficiency and low toxicity.Artemisinin and its derivatives are well known for their anti-malarial activity,but subsequent studies on the anticancer activity of artemisinin compounds have found that they also have significant anti-tumor activity,which brings dawn for people.In this paper,MTT method was used to detect the anti-proliferation effects of 24 new artemisinin derivatives which designed and synthesized in our laboratory on 7 tumor cell lines and normal liver epithelial cells,and the compound D-21 with good activity and high selectivity was selected for further study to explore the preliminary mechanism of apoptosis of human acute lymphoblastic leukemia cells induced by D-21.After the cancer cells were treated with compound D-21,we observed the morphology of cancer cells,Hoechst 33258staining,Annexin V-FITC and PI staining and mitochondrial membrane potential staining,all of those experiments proved that compound D-21 could induce apoptosis of cancer cells through mitochondrial membrane potential apoptosis pathway in the concentration-and time-dependent manners.The results provide a reliable experimental basis for future clinical experimental research,and compound D-21 could be a candidate for new anticancer drugs.