Further Evidence Supporting the Importance of and the Restrictions on a Carbon-Centered Radical for High Antimalarial Activity of 1,2,4-Trioxanes Like Artemisinin

Posner, Gary H.; Wang, Dasong; Cumming, Jared N.; Oh, Chang Ho; French, Andrew N.; Bodley, Annette L.; Shapiro, Theresa A.

doi:10.1021/jm00013a001

Cited by 138 publications

(107 citation statements)

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“…This cleavage results in the formation of oxy‐radicals that rearrange into primary or secondary carbon centered radicals (or electrophilic carbocations through single‐electron transfer oxidation) (Scheme 1). 3 …”

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confidence: 99%

A Click Chemistry‐Based Proteomic Approach Reveals that 1,2,4‐Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile

et al. 2016

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In spite of the recent increase in endoperoxide antimalarials under development, it remains unclear if all these chemotypes share a common mechanism of action. This is important since it will influence cross‐resistance risks between the different classes. Here we investigate this proposition using novel clickable 1,2,4‐trioxolane activity based protein‐profiling probes (ABPPs). ABPPs with potent antimalarial activity were able to alkylate protein target(s) within the asexual erythrocytic stage of Plasmodium falciparum (3D7). Importantly, comparison of the alkylation fingerprint with that generated from an artemisinin ABPP equivalent confirms a highly conserved alkylation profile, with both endoperoxide classes targeting proteins in the glycolytic, hemoglobin degradation, antioxidant defence, protein synthesis and protein stress pathways, essential biological processes for plasmodial survival. The alkylation signatures of the two chemotypes show significant overlap (ca. 90 %) both qualitatively and semi‐quantitatively, suggesting a common mechanism of action that raises concerns about potential cross‐resistance liabilities.

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A Click Chemistry‐Based Proteomic Approach Reveals that 1,2,4‐Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile

et al. 2016

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“…Formation of carbon-centered free radicals has been suggested. 5,[8][9][10][11][12] A recent meta-analysis revealed that ART-containing regimens substantially reduce treatment failure compared to standard antimalarial treatments. 13 ART can significantly prolong the time span of antimalarial treatment efficacy.…”

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confidence: 99%

Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins

et al. 2006

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Artemisinin (ARS) and its derivatives are used for the second-line therapy of malaria infections with Plasmodium falciparum and P. vivax. ARSs also reveal profound antitumor activity in vitro and in vivo. In the present investigation, we correlated the mRNA expression data of 89 angiogenesis-related genes obtained by microarray hybridization from the database of the US National Cancer Institute with the 50% growth inhibition concentration values for eight ARSs (ARS, arteether (ARE), artesunate (ART), artemisetene, arteanuine B, dihydroartemisinylester stereoisomers 1 and 2). The constitutive expression of 30 genes correlated significantly with the cellular response to ARSs. By means of hierarchical cluster analysis and cluster image mapping expression, profiles were identified that determined significantly the cellular response to ART, ARE, artemether and dihydroartemisinylester stereoisomer 1. We have exemplarily validated the microarray data of six out of these 30 genes by realtime RT-PCR in seven cell lines. The fact that sensitivity and resistance of tumor cells could be predicted by the mRNA expression of angiogenesisrelated genes indicate that ARSs reveal their antitumor effects at least in part by inhibition of tumor angiogenesis. As many chemopreventive drugs exert antiangiogenic features, ARSs might also be chemopreventive in addition to their cytotoxic effects.

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“…Active endoperoxide antimalarials are assumed to interact with reduced heme (ferroprotoporphyrin IX) or iron to form free-radical products of both the drug and the heme (27,43,49,52,60). The radicals are thought to react with susceptible groups within parasite enzymes and lipids (10,11,37,44,47,55,56); however, the exact site of action is still a matter of debate.…”

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Artemisinin and a Series of Novel Endoperoxide Antimalarials Exert Early Effects on Digestive Vacuole Morphology

Crespo¹,

Avery

Hanssen

et al. 2008

Antimicrob Agents Chemother

113

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Artermisinin and its derivatives are now the mainstays of antimalarial treatment; however, their mechanism of action is only poorly understood. We report on the synthesis of a novel series of epoxy-endoperoxides that can be prepared in high yields from simple starting materials. Endoperoxides that are disubstituted with alkyl or benzyl side chains show efficient inhibition of the growth of both chloroquine-sensitive and -resistant strains of Plasmodium falciparum. A trans-epoxide with respect to the peroxide linkage increases the activity compared to that of its cis-epoxy counterpart or the parent endoperoxide. The novel endoperoxides do not show a strong interaction with artemisinin. We have compared the mechanism of action of the novel endoperoxides with that of artemisinin. Electron microscopy reveals that the novel endoperoxides cause the early accumulation of endocytic vesicles, while artemisinin causes the disruption of the digestive vacuole membrane. At longer incubation times artemisinin causes extensive loss of organellar structures, while the novel endoperoxides cause myelin body formation as well as the accumulation of endocytic vesicles. An early event following endoperoxide treatment is the redistribution of the pH-sensitive probe LysoSensor Blue from the digestive vacuole to punctate structures. By contrast, neither artemisinin nor the novel endoperoxides caused alterations in the morphology of the endoplasmic reticulum nor showed antagonistic antimalarial activity when they were used with thapsigargin. Analysis of rhodamine 123 uptake by P. falciparum suggests that disruption of the mitochondrial membrane potential occurs as a downstream effect rather than as an initiator of parasite killing. The data suggest that the digestive vacuole is an important initial site of endoperoxide antimalarial activity.Artemisinin is a sesquiterpene lactone antimalarial with a 1,2,4-trioxane heterocyclic core that incorporates a peroxide linkage that is essential for its activity (44). Artemisinin is of major importance as a frontline treatment for malaria, particularly as it is active against chloroquine (CQ)-resistant strains of Plasmodium falciparum (20,23,24,45,66,74). Several groups have reported on pathways for the synthesis of artemisinin, but all require numerous steps and have low yields (5, 35). As a result, artemisinin-based antimalarials are produced semisynthetically from extracts of Artemisia annua. A period of over 1 year is needed for the horticultural, harvesting, extraction, and manufacturing processes (34,41,45), which limits the ease of scale-up of production and makes artemisinin derivatives much more expensive than traditional antimalarials, such as CQ and sulfadoxine-pyrimethamine. Indeed, artemisinin combinations are too costly for many patients, and the supply of counterfeit or inferior drugs is a major problem (4, 45, 71). Another issue is the fact that artemisinin and its derivatives are not suitable for prophylaxis or for use as a monotherapy due to their very short half-lives in vivo. T...

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Further Evidence Supporting the Importance of and the Restrictions on a Carbon-Centered Radical for High Antimalarial Activity of 1,2,4-Trioxanes Like Artemisinin

Cited by 138 publications

References 1 publication

A Click Chemistry‐Based Proteomic Approach Reveals that 1,2,4‐Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile

A Click Chemistry‐Based Proteomic Approach Reveals that 1,2,4‐Trioxolane and Artemisinin Antimalarials Share a Common Protein Alkylation Profile

Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins

Artemisinin and a Series of Novel Endoperoxide Antimalarials Exert Early Effects on Digestive Vacuole Morphology

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