The Role of the Iron Protoporphyrins Heme and Hematin in the Antimalarial Activity of Endoperoxide Drugs

Plasmodium has evolved to regulate the levels and oxidative states of iron protoporphyrin IX (Fe-PPIX). Antimalarial endoperoxides such as 1,2,4-trioxane artemisinin and 1,2,4-trioxolane arterolane undergo a bioreductive activation step mediated by heme (FeII-PPIX) but not by hematin (FeIII-PPIX), leading to the generation of a radical species. This can alkylate proteins vital for parasite survival and alkylate heme into hematin–drug adducts. Heme alkylation is abundant and accompanied by interconversion from the ferrous to the ferric state, which may induce an imbalance in the iron redox homeostasis. In addition to this, hematin–artemisinin adducts antagonize the spontaneous biomineralization of hematin into hemozoin crystals, differing strikingly from artemisinins, which do not directly suppress hematin biomineralization. These hematin–drug adducts, despite being devoid of the peroxide bond required for radical-induced alkylation, are powerful antiplasmodial agents. This review addresses our current understanding of Fe-PPIX as a bioreductive activator and molecular target. A compelling pharmacological model is that by alkylating heme, endoperoxide drugs can cause an imbalance in the iron homeostasis and that the hematin–drug adducts formed have strong cytocidal effects by possibly reproducing some of the toxifying effects of free Fe-PPIX. The antiplasmodial phenotype and the mode of action of hematin–drug adducts open new possibilities for reconciliating the mechanism of endoperoxide drugs and for malaria intervention.

Selenium-Catalyzed Reduction of Hydroperoxides in Chemistry and Biology

Among the chalcogens, selenium is the key element for catalyzed H2O2 reduction. In organic synthesis, catalytic amounts of organo mono- and di-selenides are largely used in different classes of oxidations, in which H2O2 alone is poorly efficient. Biological hydroperoxide metabolism is dominated by peroxidases and thioredoxin reductases, which balance hydroperoxide challenge and contribute to redox regulation. When their selenocysteine is replaced by cysteine, the cellular antioxidant defense system is impaired. Finally, classes of organoselenides have been synthesized with the aim of mimicking the biological strategy of glutathione peroxidases, but their therapeutic application has so far been limited. Moreover, their therapeutic use may be doubted, because H2O2 is not only toxic but also serves as an important messenger. Therefore, over-optimization of H2O2 reduction may lead to unexpected disturbances of metabolic regulation. Common to all these systems is the nucleophilic attack of selenium to one oxygen of the peroxide bond promoting its disruption. In this contribution, we revisit selected examples from chemistry and biology, and, by using results from accurate quantum mechanical modelling, we provide an accurate unified picture of selenium’s capacity of reducing hydroperoxides. There is clear evidence that the selenoenzymes remain superior in terms of catalytic efficiency.

Elucidating the Chemiexcitation of Dioxetanones by Replacing the Peroxide Bond with S-S, N-N and C-C Bonds

Dioxetanone is one of the prototypical cyclic peroxide intermediates in several chemiluminescent and bioluminescent systems, in which thermolysis reactions allow for efficient singlet chemiexcitation. While the chemiexcitation mechanism of dioxetanone...

ELECTROCATALYSIS INVOLVING AMORPHOUS METAL ELECTRODES

The effect of chemical composition of amorphous metal electrodes with different elemental composition (i.e. Al87.0Y5.0Ni8.0, Fe80.0Si6.0B14.0, Fe78,5Ni1.0Mo0.5Si6.0B14.0, Fe81,0Ni1.0Nb0.5Mo0.5Si3.0B14.0, Fe73,1Cu1.0Nb3.0Si15.5B7.4) on their electrocatalytic activity in the reactions of the decomposition of peroxide –O–O– bonds in hydrogen peroxide H2O2 and organic oligoperoxide compounds based on vinyl acetate, 2-tert-butyl peroxy-2-methyl-5-hexen-3-yne and maleic anhydride was studied. The electrochemical reduction of H2O2 and organic oligoperoxsde on AMA-electrodes by cyclic voltammetry is investigated. The dependencies of the rate of electrocatalytic processes on the concentration of supporting electrolyte, the rate of scanning of potential, the concentration of depolarizer and the duration of the initial spontaneous (in the absence of external potential) interaction of the peroxides compounds with the electrode surface were investigated. The rate constants of the decomposition of –O–O– bonds in peroxides of different structure were determined. In the case of the electrocatalytic AMA electrode Al87.0Y5.0Ni8.0, the process of dissociation of –O–O– bonding by the reductive mechanism is the most probable: In the case of AMA electrodes based on Fe (especially Fe73,1Cu1.0Nb3.0Si15.5B7.4) the decomposition of –O–O– bonds follows preferential oxidation mechanism: . Due to their high absorption ability, oligoperoxide molecules can undergo conformational changes on the surface of the electrode. This affects the stability of the peroxide bond significantly. The functional groups of oligoperxides show affinity to localized electrons on the electrode surface. This leads to the elongation of the –O–O– bond and facilitates the fragmentation of the oligomers. The amorphous alloys Fe73,1Cu1.0Nb3.0Si15.5B7.4 and Fe81,0Ni1.0Nb0.5Mo0.5Si3.0B14.0 have a higher catalytical activity in decomposition of H2O2.

Electrochemical reduction of artemisinin: Chromatographic identification of bulk electrolysis products

Artemisinin is a naturally occurring sesquiterpene lactone with an endo-peroxide bond. This drug is used for treatment of many diseases including malaria. The reduction of this molecule on an electrode surface was carried out by cyclic voltammetry as well as amperometry. Cyclic voltammetry of artemisinin generated one prominent peak wave at -1.0 V and another, smaller one at -0.3 V vs Ag/AgCl reference electrode. The bulk electrolysis of artemisinin on a carbon electrode generated two other irreversible peak waves at around -0.7 and -0.1 V. The concentration of the products was dependent on the time of electrolysis. LC-MS was used to determine the bulk electrolysis products of artemisinin. Initially dihydroartemisinin was generated as the main reduction product. Other reduction products were formed after further reduction of dyhidroartemisinin.

Crystal structure of rubidium peroxide ammonia disolvate

The title compound, Rb2O2·2NH3, has been obtained as a reaction product of rubidium metal dissolved in liquid ammonia and glucuronic acid. As a result of the low-temperature crystallization, a disolvate was formed. To our knowledge, only one other solvate of an alkali metal peroxide is known: Na2O2·8H2O has been reported by Grehlet al.[Acta Cryst.(1995), C51, 1038–1040]. We determined the peroxide bond length to be 1.530 (11) Å, which is in accordance with the length reported by Bremm & Jansen [Z. Anorg. Allg. Chem.(1992),610, 64–66]. One of the ammonia solvate molecules is disordered relative to a mirror plane, with 0.5 occupancy for the corresponding nitrogen atom.