Synthesis Of New Artemisinin Derivatives And Evaluation Of Their In Vitro Antitumor Activities

Artemisinin and it’s derivatives have shown to exhibit antitumor, antivirus aswell as immunoregulating activities besides antimalarial effect. Their antitumormechanism is different from those of traditional chemotherapeutic agents. Studiesshowed that free radicals formed by Fe2+-catalysed breakage of the endoperoxidebridge of artemisinin can cause damage to biomolecules, apopotosis in tumor cells orinhibition of angiogenesis. Because Fe2+is much richer in tumor cells than in normalones, artemisinin and it’s derivatives show high selectivity for tumor cells with lowcytoxity to normal tissues. Furthermore, they have wide anti-tumour spectrumwithout any cross-resistance with the traditional anti-cancer drugs and can reversemultidrug resistance in cancer cells. Synthesis and screening of novel antitumorartemisinin derivatives has become one of the hot topics in the field of medicinalchemistry of antitumor drugs.This work mainly includes the following two parts:1. Artemisinin was reduced to dihydroartemisinin with NaBH4. A series ofdihydroartemisinin-derived esters was then obtained by acylation ofdihydroartemisinin with corresponding substituted cinnamic acid chloride orsubstituted benzoic acid chloride. Their antiproliferative effect against Bel-7402andA549cells was determined by MTT assay. The two most effective compounds(dihydroartemisinin3,4-dimethoxy-cinnamic acid ester and dihydroartemisininp-methoxybenzoic acid ester) were further applied to various tumor cell lines andshowed inhibition against tumor cells from different tissue resources. Finally，Western Blot was used to check the key proteins in A549cell apoptosis induced bydihydroartemisinin3,4-dimethoxy-cinnamic ester. The results indicate thatdihydroartemisinin3,4-dimethoxy-cinnamic ester can induce dose-dependentdissection of pro-caspase3and PARP in A549cells. pro-caspase3and PARP weredissected markedly when the dose was10μM.2. Three dihydroartemisinin-derived hybrid drugs were designed andsynthesized according to combination principles. Dihydroartemisinin N,N-bis(2-chloroethyl)carbamate was prepared by treating dihydroartemisinin withchlormethine chloroformate; Both dihydroartemisinin-oleanolic acid conjugate anddihydroartemisinin-genistein conjugate were prepared with succinic anhydride as thecoupling reagent. Their IC50values against Bel-7402and A549cells weredetermined by MTT assay. The results showed that the anti-tumor effect of the hybid drugs is much better than that of dihydroartemisinin.