Design,Synthesis And Biological Evaluation Of Artemisinin Derivatives Containing Fluorine Atoms As Anticancer Agents

Over the past decades,the incidence of cancer has rised constantly,especially breast cancer,lung cancer,melanoma,etc,which seriously threaten human health.Currently,traditional medicine,surgery,radiation therapy and chemotherapy are the most commom methods used in the treatment of cancer,but all of them are not particularly effective.Traditional treatments may also damage normal cells while killing tumor cells,followed by a series of side effects such as hair loss and liver toxicity.Therefore,It is urgent to seek a novel drug with high efficiency and low toxicity.Artemisinin and its derivatives have been widely used in clinical practice due to their high antimalarial activities.A large number of studies have showned that artemisinin plays an important role in anti-tumor,anti-schistosomiasis,anti-pregnancy,anti-arrhythmia and so on.In addition,fluorine was characterized by its small size and high electronegativity.The introduction of fluorine atoms into chemical molecules can improve its chemical and biological properties,including stability,lipophilicity and bioavailability.Herein,using artemisinin as a lead compound,we have designed and synthesized a series of artemisinin derivatives containing fluorine atoms,in order to obtain compounds with better antitumor activity and to conduct a preliminary study on its mechanism of action.Based on the background,we synthesized 34 artemisinin derivatives,including 6 artemisinin ester derivatives,12 artemisinin ether derivatives and 16 artemisinin amine derivatives.The in vitro cytotoxicity of artemisinin derivatives against U87MG,SH-SY5Y,MCF-7,MDA-MB-231,A549 and A375 cancer cell lines was evaluated by MTT assay.Most of artemisinin derivatives exhibited greater anti-tumor activity compared with artemisinin.Among them,compound 11p showed the most potent anti-proliferative agent against the human breast cancer MCF-7 cells and displayed lower cytotoxicity on normal hepatic L02 cells than doxorubicin.Thence,we further studied the mechanism of action of compound 11p.The quantitative analysis of MCF-7 cells apoptosis was monitored by using Annexin V-FITC/PI double staining through flow cytometry.Compound 11p caused significant inhibitory effect with a concentration-dependent manner on tested cells.MCF-7 cells were incubated with lip and then stained with Hoechst 33258 to investigate the nuclear morphological changes.Compound lip treatment induced marked apoptotic morphological alterations,including cell shrinkage and granular apoptotic body formation.We also examined the effect of compound lip on cell cycle distribution,the result showed that compound lip arrested cell cycle at G1 phase in MCF-7 cells.Based on the above studies,it can be seen that compound lip exhibited excellent activity in anti-breast cancer,which facilitate the development of new antitumor candidates.