Design,Synthesis And Antitumor Activity Of Artemisinin Derivatives Containing Piperazine And Fluorine Groups

Currently,cancer is still one of the high-risk diseases facing by humans,and the number of cancer patients is increasing year by year,which seriously threatens human health.Current methods for treating cancer include chemotherapy,radiotherapy,surgery,targeted therapy,and immunotherapy.These traditional methods of treating cancer still have certain defects,so it is necessary to find new anticancer therapies.In the past two decades,the drug research community has developed a large number of cancer drugs,but among the existing drugs,most drugs for treating cancer have shown poor stability and targeting under physiological conditions,causing toxic side effects on normal tissues or organs.Therefore,it is necessary to actively develop new anticancer drugs with high targeting and no drug resistance.Artemisinin,active substance extracted from Artemisia,contains a unique new structure of peroxy bridge.Long-term studies on artemisinin and its derivatives have revealed that quercetin compounds have a variety of biological activities,such as anti-malarial,anti-tumor,anti-schistosomiasis,anti-viral,anti-bacterial,anti-diabetic and anti-obesity activities,which encourages a large number of researchers have further explored it.Piperazine is a commonly used nitrogen heterocycle.The introduction of piperazine into drug molecules can effectively change the pharmacokinetic properties of the drug,adjust the acid-base equilibrium constant,the lipid-water partition coefficient of the drug,and it can improve the biological activity of the drug by forming hydrogen bonds or ionic bonds.A bond or ionic bond that improves the biological activity of the drug.Studies on piperazines have found that these drugs have the advantages of small side effects,fast onset,low toxicity,and no addiction.The introduction of a fluorine atom or a fluorine-containing group in a drug molecule can also effectively change the pKa,conformation,membrane permeability,pharmacodynamics,metabolic pathway and pharmacokinetic properties of tlhe molecule,increase the stability of drug metabolism,and affect drug toxicity.Therefore,we use artemisinin as the matrix and combine artemisinin,piperazine and fluorine-containing groups according to the principle of active structure splicing to obtain a compound with better activity and to improve the solubility and the like.This project designed and synthesized 32 artemisinin derivatives,including 16 six-mem'bered ring artemisinin derivatives and 16 five-membered ring artemisinin derivatives.The cytotoxic effects of artemisinin derivatives on tumor cells such as PC12,SH-SY5Y.,U87MG,U118MG,MCF-7 and A549 were examined by MTT assay.The experimental results show that the antitumor activity of the derivatives is enhanced compared with artemisinin and dihydroartemisinin.Among them,compound 12g has good activity against MCF-7.,PC12,SH-SY5Y and U118MG,with IC50 of 6.08,2.11,0.29 and 26.15 ?M,respectively.Its activity against neuroblastoma SH-SY5Y is comparable to that of doxorubicin.We will conduct a study on the related anti-tumor mechanism of compound 12g.