72826-63-2Relevant articles and documents
THERMAL DECOMPOSITION PRODUCTS OF DIHYDROARTEMISININ (DIHYDROQINGHAOSU)
Lin, Ai Jeng,Theoharides, Anthony D.,Klayman, Daniel L.
, p. 2181 - 2184 (1986)
Dihydroartemisinin (2), a sodium borohydride reduction product of artemisinin (1), undergoes thermolysis at 190 deg C to give desoxyartemisinin (3) and a preponderant decomposition product (4) consisting of 2 epimers 4a, (2S, 3R, 6S)-2-(3-oxobutyl)-3-methyl-6--cyclohexanone, and 4b, (2S, 3R, 6R)-2-(3-oxobutyl)-3-methyl-6--cyclohexanone.
Fourier transform infrared investigation of non-heme Fe(III) and Fe(II) decomposition of artemisinin and of a simplified trioxane alcohol
Kapetanaki,Varotsis
, p. 3150 - 3156 (2001)
Fourier transform infrared spectra are reported for the Fe(III)- and Fe(II)-mediated activation of the antimalarial agents artemisinin I and its simplified synthetic analogue, trioxane alcohol 2. By monitoring the frequencies of the newly established marker lines in the FTIR spectra, the products of the Fe(II) and Fe(III) reactions have been characterized. In both reactions, artemisinin is activated giving a product mixture of a ring-contracted tetrahydrofuran acetatal 3, C4-hydroxy deoxyartemisinin 4, and deoxyartemisinin 5. These data illustrate that the oxidation state of the iron places no restrictions on the endoperoxide reduction mechanism. The FTIR difference (light - dark) spectra indicate that the endoperoxide moiety of artemisinin is photolabile and that the resulted products have the same vibrational characteristics as those observed in the reactions with Fe(II) and Fe(III). The use of 18O-18O enriched endoperoxide in 2 has allowed us to identify two oxygen sensitive modes in the reactions with Fe(II). The reduction of the peroxide bond by Fe(II) in trioxane alcohol 2 follows both the C - C cleavage and 1,5-H shift pathways and produces a ring-contracted tetrahydrofuran acetal 6 which is converted to tetrahydrofuran aldehyde 7 and C4-hydroxy deoxytrioxane alcohol 8, respectively. The cleavage of the O - O bond in 1 and 2 by iron and the ability to correlate vibrational properties of the reaction products with structural properties of the isolated products suggest that infrared spectroscopy is an appropriate tool to study the mode of action of antimalarial endoperoxides.
Reactions of Antimalarial Peroxides with Each of Leucomethylene Blue and Dihydroflavins: Flavin Reductase and the Cofactor Model Exemplified
Haynes, Richard K.,Cheu, Kwan-Wing,Tang, Maggie Mei-Ki,Chen, Min-Jiao,Guo, Zu-Feng,Guo, Zhi-Hong,Coghi, Paolo,Monti, Diego
experimental part, p. 279 - 291 (2012/01/12)
Flavin adenine dinucleotide (FAD) is reduced by NADPH-E.coli flavin reductase (Fre) to FADH2 in aqueous buffer at pH7.4 under argon. Under the same conditions, FADH2 in turn cleanly reduces the antimalarial drug methylene blue (MB) to leucomethylene blue. The latter is rapidly re-oxidized by artemisinins, thus supporting the proposal that MB exerts its antimalarial activity, and synergizes the antimalarial action of artemisinins, by interfering with redox cycling involving NADPH reduction of flavin cofactors in parasite flavin disulfide reductases. Direct treatment of the FADH2 generated from NADPH-Fre-FAD by artemisinins and antimalaria-active tetraoxane and trioxolane structural analogues under physiological conditions at pH7.4 results in rapid reduction of the artemisinins, and efficient conversion of the peroxide structural analogues into ketone products. Comparison of the relative rates of FADH2 oxidation indicate optimal activity for the trioxolane. Therefore, the rate of intraparastic redox perturbation will be greatest for the trioxolane, and this may be significant in relation to its enhanced invitro antimalarial activities. 1HNMR spectroscopic studies using the BNAH-riboflavin (RF) model system indicate that the tetraoxane is capable of using both peroxide units in oxidizing the RFH2 generated insitu. Use of the NADPH-Fre-FAD catalytic system in the presence of artemisinin or tetraoxane confirms that the latter, in contrast to artemisinin, consumes two reducing equivalents of NADPH. None of the processes described herein requires the presence of ferrous iron. Ferric iron, given its propensity to oxidize reduced flavin cofactors, may play a role in enhancing oxidative stress within the malaria parasite, without requiring interaction with artemisinins or peroxide analogues. The NADPH-Fre-FAD system serves as a convenient mimic of flavin disulfide reductases that maintain redox homeostasis in the malaria parasite. Antimalarial peroxides and flavin reductase: NADPH-E.coli flavin reductase (Fre) reduces FAD to FADH2, which in turn rapidly reduces artemisinins and antimalarial peroxides to deoxy or ketone products under physiological conditions. Thus, antimalarial activity is due to perturbation of intraparasitic redox homeostasis by oxidation of FADH2 in critical flavoenzymes with consequent sequestration of NADPH. The tetraoxane uses both peroxide units in consuming two equivalents of NADPH in the NADPH-Fre-FAD system.
Interaction of qinghaosu (artemisinin) with cysteine sulfhydryl mediated by traces of non-heme iron
Wu, Yikang,Yue, Zheng-Yu,Wu, Yu-Lin
, p. 2580 - 2582 (2007/10/03)
The antimalarial action of 1,2,4-trioxanes such as qinghaosu (QHS) may take place through the mechanism shown schematically: In the presence of cysteine traces of non-heme iron (FeSO4) may cleave the peroxy bond of QHS rapidly, and the transien
