| Summary: | Artemisinin, also known as qinghaosu, is a tetracyclic 1,2,4-trioxane occurring in Artemisia annua. Artemisinin and its derivatives are currently recommended as frontline antimalarials for regions experiencing�?�?�?�· P. falciparum resistance to traditional antimalarial drugs. In addition to their well-known antimalarial activity, artemisinin derivatives possess potent activity against cancer cells. A potential drawback with many of these derivatives is the presence of a metabolically susceptible C-lO acetal linkage; the aim of this thesis was to prepare metabolically stable artemisinin derivatives possessing potent antimalarial and anticancer activity. It has be~n noted that the replacement of oxygen at the C-IO position with carbon .produces compounds not only with greater hydrolytic stability but also with a longer half-' life and potentially lower toxicity. We have prepared a series of non-acetal C-lO carbalinked dimers, several of which show significant antimalarial and anticancer activity. For example, methyl phosphonate dimer 59 (ICso=O.04 nM vs. 3D7 P. falciparum) and amide dimer 83 (ICso=O.04 nM vs. 3D7 P. falciparum) are amongst the most potent antimalarials to have been prepared at the University of Liverpool and also demonstrate low nanomolar activity against human promyelocytic leukemia HL-60 cells. An alternative approach to increasing the metabolic stability of artemisinin derivatives involves incorporation of a phenyl group in place of the alkyl group of first generation analogues. Such modifications are expected to block oxidative metabolic formation of dihydroartemisinin in vivo. We have utilized both approaches to prepare artemisininamino acid derivatives which possess potent low nanomolar activity against a variety of P.falciparum strains. Different modes of action have been proposed by various groups to account for the action of artemisinin and its derivatives in treating malaria. Whilst the mode of action of artemisinin as an antimalarial has not been unequivocally established, it has been demonstrated that the endoperoxide is essential for activity. It is widely accepted that a molecular interaction occurs between the endoperoxide bridge and heme or ferrous iron, leading to the generation of cytotoxic carbon-centered free radicals that cause rapid death of the parasite. It has been suggested that the toxic free-radicals resulting from endoperoxide cleavage can form irreversible adducts with malaria parasite proteins. Several potential proteins have been proposed as targets for the artemisinins but it has not yet been established which protein targets are critical for artemisinin drug action and consequently the formal identification of these target proteins will be essential for systematically testing for such a role and probing the potential for the development of drug resistance. We have prepared two biotinylated-artemisinin bioprobes for use in a proteomics approach to explicitly identify the molecular targets of the artemisinins in P. falciparum and cancer cells. Both of these probes retain activity against malaria parasites and cancer cells. One of the major shortcomings with current cancer therapies is the non-selective delivery of chemotherapeutic agents to both cancer cells and healthy cells. We have prepared artemisinin-spermidine conjugates designed to selectively target cancer cells by virtue of the upregulated polyamine transport system present in many cancer cells.
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