The results of Fe(2+)-induced decomposition of the clinically used artemisinins, artemisone, other aminoartemisinins, 10-deoxoartemisinin, and the 4-fluorophenyl derivative have been compared with their antimalarial activities and their ability to inhibit the parasite SERCA PfATP6. The clinical artemisinins and artemisone decompose under aqueous conditions to give mixtures of C radical marker products, carbonyl compounds, and reduction products. The 4-fluorophenyl derivative and aminoartemisinins tend to be inert to aqueous iron(II) sulfate and anhydrous iron(II) acetate. Anhydrous iron(II) bromide enhances formation of the carbonyl compounds and provides a deoxyglycal from DHA and enamines from the aminoartemisinins. Ascorbic acid (AA) accelerates the aqueous Fe(2+)-mediated decompositions, but does not alter product distribution. 4-Oxo-TEMPO intercepts C radicals from a mixture of an antimalaria-active trioxolane, 10-deoxoartemisinin, and anhydrous iron(II) acetate to give trapped products in 73 % yield from the trioxolane, and 3 % from the artemisinin. Artemisone provides a trapped product in 10 % yield. Thus, in line with its structural rigidity, only the trioxolane provides a C radical eminently suited for intermolecular trapping. In contrast, the structural flexibility of the C radicals from the artemisinins allows facile extrusion of Fe(2+) and collapse to benign isomerization products. The propensity towards the formation of radical marker products and intermolecular radical trapping have no relationship with the in vitro antimalarial activities of the artemisinins and trioxolane. Desferrioxamine (DFO) attenuates inhibition of PfATP6 by, and antagonizes antimalarial activity of, the aqueous Fe(2+)-susceptible artemisinins, but has no overt effect on the aqueous Fe(2+)-inert artemisinins. It is concluded that the C radicals cannot be responsible for antimalarial activity and that the Fe(2+)-susceptible artemisinins may be competitively decomposed in aqueous extra- and intracellular compartments by labile Fe(2+), resulting in some attenuation of their antimalarial activities. Interpretations of the roles of DFO and AA in modulating antimalarial activities of the artemisinins, and a comparison with antimalarial properties of simple hydroperoxides and their behavior towards thapsigargin-sensitive SERCA ATPases are presented. The general basis for the exceptional antimalarial activities of artemisinins in relation to the intrinsic activity of the peroxide within the uniquely stressed environment of the malaria parasite is thereby adumbrated.

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The Fe2+-mediated decomposition, PfATP6 binding, and antimalarial activities of artemisone and other artemisinins: the unlikelihood of C-centered radicals as bioactive intermediates.

Development of artemisinin and its structurally simplified trioxane derivatives as antimalarial drugs.

Novel spiroanellated 1,2,4-trioxanes with high in vitro antimalarial activities.

Kinetics of iron-mediated artemisinin degradation: Effect of solvent composition and iron salt

Synthetic ozonides and tetraoxanes were shown to have high cytotoxicity in vitro when tested on androgen-independent prostate cancer cell lines DU145 and PC3, which is in some cases was higher than that of doxorubicin, cisplatin, etoposide, artemisinin, and artesunate. Activity of ozonide stereoisomers differs from each other. This difference in activity and absence of correlation between activity of stereoisomers and their oxidative properties allow us to suggest existence of a quite specific mechanism of cytotoxicity of these endoperoxides different from a traditional mechanism based mainly on oxidative properties of peroxides.

Cyclic peroxides as promising anticancer agents: in vitro cytotoxicity study of synthetic ozonides and tetraoxanes on human prostate cancer cell lines

1,2,4-Trioxane is the essential segment of the new antimalarial agent qinghaosu 1, and hence its reduction is an important plausible process related to the bio-activity mode. An overview of its reduction and a careful examination of some reducing systems are presented herewith. Electrochemical reduction is a two-electron reduction, which is confirmed by the isolation of product deoxyqinghaosu. However, in the presence of a catalytic amount of FeII/III electrochemical reduction yields mainly the single-electron-reduction products, which are identified with the products from reduction of qinghaosu with one equivalent ferrous sulfate or a catalytical amount of FeII/III and excess of other reducing agents, such as ascorbic acid, or cysteine. These results mean that qinghaosu is reduced by ferrous ion and the resulting ferric ion is then reduced on the electrode to regenerate ferrous ion. In addition, qinghaosu could be reduced to deoxyqinghao by iodide, but not by bromide, and also could be reduced by the ascorbic acid–CuSO4 system to give free-radical reaction products.

Wen-Min Wu

Papers

Chemical and electro-chemical reduction of qinghaosu (artemisinin)

Selection and characterization of bispecific aptamers against malachite green and leucomalachite green.

Chemical and Electro‐Chemical Reduction of Qinghaosu (Artemisinin).