Enantiomeric 1,2,4‐Trioxanes Display Equivalent in vitro Antimalarial Activity Versus <i>Plasmodium falciparum</i> Malaria Parasites: Implications for the Molecular Mechanism of Action of the Artemisinins

O’Neill, Paul M.; Rawe, Sarah L.; Borstnik, Kristina; Miller, Alison; Ward, Stephen A.; Bray, Patrick G.; Davies, Jill; Oh, Chang Ho; Posner, Gary H.

doi:10.1002/cbic.200500048

Cited by 52 publications

(35 citation statements)

References 35 publications

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“…31 This observation is in contrast to the report that enantiomers of compounds possessing the same core as artemisnin (a 1,2,4-trioxane) display equivalent in vitro activity against malaria parasites. 32 …”

Section: Resultsmentioning

confidence: 99%

Five-Membered Ring Peroxide Selectively Initiates Ferroptosis in Cancer Cells

2016

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A 1,2-dioxolane (FINO2) was identified as a lead compound from a screen of organic peroxides. FINO2 does not induce apoptosis, but instead initiates ferroptosis, an iron-dependent, oxidative cell death pathway. Few compounds are known to induce primarily ferroptosis. In contrast to the perceived instability of peroxides, FINO2 was found to be thermally stable to at least 150 °C. FINO2 was more potent in cancer cells than nonmalignant cells of the same type. One of the enantiomers was found to be more responsible for the observed activity.

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Section: Resultsmentioning

confidence: 99%

Five-Membered Ring Peroxide Selectively Initiates Ferroptosis in Cancer Cells

2016

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“…The next 40 years witnessed the synthesis of a series of artemisinin derivatives (ARTs), including dihydroartemisinin (DHA, Fig. 1A), artesunate, artemether and so on 3456. Due to the poor bioavailability of original ART, some artemisinin derivatives became more frequently used under clinical settings 7.…”

Section: Introductionmentioning

confidence: 99%

Two distinct and competitive pathways confer the cellcidal actions of artemisinins

Sun¹,

Li²,

Cao³

et al. 2015

MIC

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The biological actions of artemisinin (ART), an antimalarial drug derived from Artemisia annua, remain poorly understood and controversial. Besides potent antimalarial activity, some of artemisinin derivatives (together with artemisinin, hereafter referred to as ARTs), in particular dihydroartemisinin (DHA), are also associated with anticancer and other antiparasitic activities. In this study, we used baker’s yeast Saccharomyces cerevisiae as cellular and genetic model to investigate the molecular and cellular properties of ARTs. Two clearly separable pathways exist. While all ARTs exhibit potent anti-mitochondrial actions as shown before, DHA exerts an additional strong heme-dependent, likely mitochondria-independent inhibitory action. More importantly, heme antagonizes the mitochondria-dependent cellcidal action. Indeed, when heme synthesis was inhibited, the mitochondria-dependent cellcidal action of ARTs could be dramatically strengthened, and significant yeast growth inhibition at as low as 100 nM ART, an increase of about 25 folds in sensitivity, was observed. We conclude that ARTs are endowed with two major and distinct types of properties: a potent and specific mitochondria-dependent reaction and a more general and less specific heme-mediated reaction. The competitive nature of these two actions could be explained by their shared source of the consumable ARTs, so that inhibition of the heme-mediated degradation pathway would enable more ARTs to be available for the mitochondrial action. These properties of ARTs can be used to interpret the divergent antimalarial and anticancer actions of ARTs.

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“…Intriguingly, despite many years of use clinically meaningful resistance to artemisinin has not yet convincingly been shown. What is more, near forty years since its discovery and with large amount of literatures published regarding its mode of action, how artemisinins inhibit the growth of malarial parasites remains an enigma and in a state of confusion [5], [6].…”

Section: Introductionmentioning

confidence: 99%

“…On the other hand, simple change of molecular hydrophobicity at some unimportant sites can greatly diminish the drug effect [7]. More puzzling is that enantiomers of several of these compounds, including one 1,2,4-trioxanes structurally similar to artemisinin, have been made and tested against their efficacy on malaria parasites: all of them displayed no stereoselective difference in antiparasitic activity between enantiomers [6], [8], [9]. These pieces of structure-efficacy information imply that artemisinins may not achieve their functions through binding specifically to a protein-target site and consequently inhibiting its function.…”

Section: Introductionmentioning

confidence: 99%

Artemisinin Directly Targets Malarial Mitochondria through Its Specific Mitochondrial Activation

et al. 2010

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The biological mode of action of artemisinin, a potent antimalarial, has long been controversial. Previously we established a yeast model addressing its mechanism of action and found mitochondria the key in executing artemisinin's action. Here we present data showing that artemisinin directly acts on mitochondria and it inhibits malaria in a similar way as yeast. Specifically, artemisinin and its homologues exhibit correlated activities against malaria and yeast, with the peroxide bridge playing a key role for their inhibitory action in both organisms. In addition, we showed that artemisinins are distributed to malarial mitochondria and directly impair their functions when isolated mitochondria were tested. In efforts to explore how the action specificity of artemisinin is achieved, we found strikingly rapid and dramatic reactive oxygen species (ROS) production is induced with artemisinin in isolated yeast and malarial but not mammalian mitochondria, and ROS scavengers can ameliorate the effects of artemisinin. Deoxyartemisinin, which lacks an endoperoxide bridge, has no effect on membrane potential or ROS production in malarial mitochondria. OZ209, a distantly related antimalarial endoperoxide, also causes ROS production and depolarization in isolated malarial mitochondria. Finally, interference of mitochondrial electron transport chain (ETC) can alter the sensitivity of the parasite towards artemisinin. Addition of iron chelator desferrioxamine drastically reduces ETC activity as well as mitigates artemisinin-induced ROS production. Taken together, our results indicate that mitochondrion is an important direct target, if not the sole one, in the antimalarial action of artemisinins. We suggest that fundamental differences among mitochondria from different species delineate the action specificity of this class of drugs, and differing from many other drugs, the action specificity of artemisinins originates from their activation mechanism.

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Enantiomeric 1,2,4‐Trioxanes Display Equivalent in vitro Antimalarial Activity Versus Plasmodium falciparum Malaria Parasites: Implications for the Molecular Mechanism of Action of the Artemisinins

Cited by 52 publications

References 35 publications

Five-Membered Ring Peroxide Selectively Initiates Ferroptosis in Cancer Cells

Five-Membered Ring Peroxide Selectively Initiates Ferroptosis in Cancer Cells

Two distinct and competitive pathways confer the cellcidal actions of artemisinins

Artemisinin Directly Targets Malarial Mitochondria through Its Specific Mitochondrial Activation

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