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

Creek, Darren J.; Chiu, Francis Chi Keung; Prankerd, Richard J.; Charman, Susan A.; Charman, William N.

doi:10.1002/jps.20400

Cited by 43 publications

(38 citation statements)

References 46 publications

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“…Under these experimental conditions, the previously determined pseudo-first order rate constants (k) for 1a and artemisinin were 0.41 ± 0.02 h −126 and 0.054 ± 0.006 h −1 . 25 The weakly active 1b reacted considerably more rapidly (k = 1.77 ± 0.06 h −1 ) with iron(II) than did 1a confirming our previous observations [26][27] that chemically reactive peroxides do not necessarily possess high antimalarial activities. Trioxane 2b reacted with iron(II) at a rate (k = 0.12 ± 0.03 h −1 ) between that of 1a and artemisinin, whereas trioxepane 3b reacted much more slowly (k = 0.021 ± 0.006 h −1 ), and neither 2a nor 3a underwent statistically significant degradation over the 24 h time course studied (k = 0.011 ± 0.013 h −1 and 0.017 ± 0.012 h −1 , respectively).…”

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confidence: 78%

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Spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane pairs: Relationship between peroxide bond iron(II) reactivity, heme alkylation efficiency, and antimalarial activity

Wang

Creek

Schiaffo

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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supporting

confidence: 78%

“…25 In these experiments, pseudo-first order reaction rate constants for 1b, 2a, 2b, 3a, and 3b (0.03 mM) with FeSO 4 (3 mM) in 50% acetonitrile/water at 37 °C under an argon atmosphere were determined. These data (n = 3) were corrected for non-specific degradation in iron-free controls.…”

mentioning

confidence: 99%

Spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane pairs: Relationship between peroxide bond iron(II) reactivity, heme alkylation efficiency, and antimalarial activity

Wang

Creek

Schiaffo

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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“…Hemolysis, another condition related to severe manifestations of malaria, was reproduced in the present work by incubating the drug in erythrocyte lysate. Previous studies show that Fe(II), but not Fe(III), can decompose artemisinin (19,20) and that peroxidic antimalarials are stable in the presence of hemoglobin but react with free heme (21). In this work, further evidence of the role of Fe(II)-heme is that flushing RBC lysate with CO, which tightly binds Fe(II)-heme inhibiting its reactivity, moderated the effects on DHA activity.…”

Section: Discussionsupporting

confidence: 53%

Stability of the Antimalarial Drug Dihydroartemisinin under Physiologically Relevant Conditions: Implications for Clinical Treatment and Pharmacokinetic and In Vitro Assays

Parapini

Olliaro

Navaratnam

et al. 2015

Antimicrob Agents Chemother

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f Artemisinins are peroxidic antimalarial drugs known to be very potent but highly chemically unstable; they degrade in the presence of ferrous iron, Fe(II)-heme, or biological reductants. Less documented is how this translates into chemical stability and antimalarial activity across a range of conditions applying to in vitro testing and clinical situations. Dihydroartemisinin (DHA) is studied here because it is an antimalarial drug on its own and the main metabolite of other artemisinins. The behaviors of DHA in phosphate-buffered saline, plasma, or erythrocyte lysate at different temperatures and pH ranges were examined. The antimalarial activity of the residual drug was evaluated using the chemosensitivity assay on Plasmodium falciparum, and the extent of decomposition of DHA was established through use of high-performance liquid chromatography with electrochemical detection analysis. The role of the Fe(II)-heme was investigated by blocking its reactivity using carbon monoxide (CO). A significant reduction in the antimalarial activity of DHA was seen after incubation in plasma and to a lesser extent in erythrocyte lysate. Activity was reduced by half after 3 h and almost completely abolished after 24 h. Serum-enriched media also affected DHA activity. Effects were temperature and pH dependent and paralleled the increased rate of decomposition of DHA from pH 7 upwards and in plasma. These results suggest that particular care should be taken in conducting and interpreting in vitro studies, prone as their results are to experimental and drug storage conditions. Disorders such as fever, hemolysis, or acidosis associated with malaria severity may contribute to artemisinin instability and reduce their clinical efficacy.A rtemisinin derivatives have been the most potent antimalarials available to date; they are highly active against all Plasmodium species and parasite stages, including young gametocytes, and constitute the backbone of malaria case management for severe and uncomplicated malaria (as a component of artemisinin combination therapy [ACT]) (1). The emergence and spread of artemisinin resistance in Southeast Asia is, therefore, a serious threat to malaria control (2, 3).All artemisinin derivatives share a distinctive 1,2,4-trioxane pharmacophore, which confers their antimalarial activity (the corresponding acyclic analogues lacking the endoperoxide bridge are inactive) (4, 5) but also makes these molecules particularly highly reactive and thus difficult to quantify in plasma or blood. Of the various artemisinin-type compounds in use, dihydroartemisinin (DHA), the reduced lactol derivative of artemisinin, is an antimalarial compound on its own (currently coformulated with piperaquine) and the main bioactive metabolite of artesunate and artemether. DHA itself is chemically fragile and displays a marked propensity to undergo ring opening of the lactol and rearrangement under neutral conditions, leading to a new, biologically active peroxide, which in turn rapidly decays to the inert end product deoxyartemisi...

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“…The supernatant was removed and stored at 4°C for up to 24 h prior to analysis. The stability of artemisinins and 1,2,4-trioxolanes was confirmed in the quenched solutions for up to 72 h. The concentration of peroxide antimalarial in each sample was determined by LC-MS as previously described (5,6), with the addition of diazepam as an internal standard to monitor the MS response. All reactions were performed in triplicate, and pseudo-first-order reaction rates were compared by one-way analysis of variance with a post hoc Tukey test.…”

Section: Methodsmentioning

confidence: 99%

Stability of Peroxide Antimalarials in the Presence of Human Hemoglobin

Creek

Ryan

Charman

et al. 2009

Antimicrob Agents Chemother

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Peroxide antimalarials, including artemisinin, are important for the treatment of multidrug-resistant malaria. These peroxides are known to react with iron or heme to produce reactive intermediates that are thought to be responsible for their antimalarial activities. This study investigated the potential interaction of selected peroxide antimalarials with oxyhemoglobin, the most abundant form of iron in the human body. The observed stability of artemisinin derivatives and 1,2,4-trioxolanes in the presence of oxyhemoglobin was in contrast to previous reports in the literature. Spectroscopic analysis of hemoglobin found it to be unstable under the conditions used for previous studies, and it appears likely that the artemisinin reactivity reported in these studies may be attributed to free heme released by protein denaturation. The stability of peroxide antimalarials with intact oxyhemoglobin, and reactivity with free heme, may explain the selective toxicity of these antimalarials toward infected, but not healthy, erythrocytes.

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

Cited by 43 publications

References 46 publications

Spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane pairs: Relationship between peroxide bond iron(II) reactivity, heme alkylation efficiency, and antimalarial activity

Spiroadamantyl 1,2,4-trioxolane, 1,2,4-trioxane, and 1,2,4-trioxepane pairs: Relationship between peroxide bond iron(II) reactivity, heme alkylation efficiency, and antimalarial activity

Stability of the Antimalarial Drug Dihydroartemisinin under Physiologically Relevant Conditions: Implications for Clinical Treatment and Pharmacokinetic and In Vitro Assays

Stability of Peroxide Antimalarials in the Presence of Human Hemoglobin

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