Synthesis And Activity Evaluation Of Artemisinin-based Immunosuppressants

Object:The immunosuppressive agents currently available for the treatment of autoimmune diseases have serious side effects and cost high,thus,to develop new lower cost immunosuppressive agents with higher therapeutic efficiency and lower toxicity is a medical need.Artemisinin derivatives,in addition to their antimalarial and anti-tumor activities,have been found shown notable immunosuppressive activities.Since it is a very safe class of compound,artemisinin has potential to become the leading compound for developing drug to treat the autoimmune diseases.However,due to the unique peroxyacetal lactone structure motif,the structure modification can only be focused on the position 10 of dihydroartemisnin.The objective of this study was to synthesize a series of artemisinin ethers with the emphasis to improve the water solubility of artemisinin core while maintain or improve their immunosuppressive activity.Method:Monosaccharides,disaccharides,tartaric acid,Kojic acid and 3,5-dihydroxybenzoate were selected as the substrates,various synthetic methods were screened to etherificate dihydroartemisinine at position 10.Trichloroacetonitrile was used as the activate reagent of saccharides,and under the catalysis of BF₃-Et₂O,a series of dihydroartemisinin-glycosides?Compounds 1-8?were synthesized.In addition,the conjugates of dihydroarteamisinine with tartaric acids?compounds 9-10?,Kojic acid?compound 11?and 3,5-dihydroxybenzoate?compounds 12-13?were synthesized under the similar condition.The immunosuppressive activities of compounds 1-13 were assessed with human T cells,and their effects on IFN-?secretion were also measured.Results:Thirteen water soluble artemisinin derivatives were synthesized.Among them,compounds 3-13 are new compounds.Their immunosuppressive activity were evaluated with human T cells and their effects on cytokines IFN-?secretion were also measured,it was found that all compounds shown notable immunosuppressive activities,while compound 12 has the best inhibitory effect.Conclusion:The immunosuppressive activities of thirteen water soluble artemisinin derivatives were preliminarily evaluated.Compound 12 has the best immunosuppress-ive activity and worth for further assessment.