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Studies on the molecular mechanism of action of artemisinins

Authors Fan, Kit Man
Issue Date 2008
Summary The causes and chemotherapies of malaria are briefly discussed. Among those treatments for malaria, artemisinins, the Chinese peroxidic sesquiterpene quinghaosu, is of special interest. The history, development, and particularly, mechanism of action of artemisinins are reviewed. Despite the fact that artemisinin and its derivatives have been used to treat malaria for years, the mode of action of this compound class is still not understood, and highly controversial. In order to probe the antimalarial activity in relation one hypothesis for mechanism of action, namely binding to the calcium pump PfATP. it is appropriate to evaluate the binding of the enantiomer of artemisinin, and of artemisone, the new derivative which inhibits the pump at nanomolar level. Therefore, a preliminary study on the total synthesis of the unnatural enantiomer of artemisinin has been carried out. The methodology is based on a total synthesis of artemisinin reported in the literature, but which uses enantiomers of the starting materials and intermediates. Cyclization of S-(-)-citronellal by the Prins reaction affords isopulegol which then is hydroborated and selectively protected at the primary hydroxyl group by triisopropylsilyl group. This was converted to the Robinson annelation precursor, (1S,3S,4R,8S)-9- [(triisopropylsilyl)oxy]- p-menthol after the Swern oxidation. However, unexpected difficulties arose in the course of conducting the conjugate addition. Different unsaturated acceptors, including methyl vinyl ketone and its α-trimethylsilyl derivative have been tried. The triisopropylsilyl protecting group was replaced by benzyl group, but still very low yields of conjugate adducts were obtained. Other means of alkylating the precursor, by using halide alkylating equivalent of MVK were briefly explored. The idea that artemisinins may exert their activity by accelerating the consumption of crucial biomolecules involved in essential redox or cellular processes in parasites is examined. The reactions of artemisinin and its derivatives with cysteine, reduced glutathione, and other hydride donors such as NADH in the presence of electron-deficient compounds such as Methylene Blue for instance, have been monitored spectrophotometrically. Effect of artemisinins on the reduction of desferrioxamine-ferric iron complex and ferrioxamine E in the presence of ferrous iron chelating agent, BPS, are tested. Efforts to demonstrate the effect of artemisinins on redox systems including naphthoquinones and glutathione reductase have been made. In the presence of artemisinins, an intriguing finding has been shown on the spontaneous oxidation of leuco Methylene Blue. An advance in understanding the mechanism of action could be made by the observation that BNAH, a model of the crucial enzyme co-factor NADH, can be oxidized in the presence of both ferrous sulfate and tert-butyl hydroperoxide. However, artemisinin in the presence of ferrous sulfate was ineffective.
Note Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2008
Language English
Format Thesis
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