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Inhibitory effect of ursolic acid derivatives on hydrogen peroxide-and glutathione-mediated degradation of hemin: A possible additional mechanism of action for antimalarial activity

Identifieur interne : 001510 ( Main/Exploration ); précédent : 001509; suivant : 001511

Inhibitory effect of ursolic acid derivatives on hydrogen peroxide-and glutathione-mediated degradation of hemin: A possible additional mechanism of action for antimalarial activity

Auteurs : RBID : Pascal:11-0131277

Descripteurs français

Pascal (Inist)
- Hydrogène, Peroxyde, Glutathion, Marqueur biologique, Mécanisme action, Antipaludique, Activité, Paludisme, Parasite, Plasmodium falciparum.
Wicri :
- topic : Hydrogène.

English descriptors

KwdEn :
- Activity, Antimalarial, Biological marker, Glutathione, Hydrogen, Malaria, Mechanism of action, Parasite, Peroxides, Plasmodium falciparum.

Abstract

Compounds obtained by the condensation of ursolic acid (UA) with 1,4-bis(3-aminopropyl)piperazines have previously been shown as cytocidal to Plasmodium falciparum strains. Preliminary results indicated that the inhibition of β-hematin formation (one of the possible mechanisms of action of antimalarial drugs) was achieved by a few of these molecules with varying efficiencies. To gain further insight in the antimalarial action of UA derivatives, we report here the results of additional pathways that may explain their in vitro cytocidal activity such as inhibition of hemin degradation by H₂O₂ or glutathione (GSH). H₂O₂-mediated hemin degradation was drastically reduced by hydroxybenzyl-substituted UA derivatives while UA and intermediate compounds displayed weaker inhibitory actions. The results of GSH-mediated hemin degradation inhibition did not parallel those of H₂O₂ degradation as hydroxybenzyl-substituted UA only proved to be a weak inhibitor. As H₂O₂ interaction with the iron moiety of hemin is the first step towards its degradation, we assume that the interaction of our products with the ferric ion in the hemin structure is of upmost importance in inhibiting its peroxidative degradation. A two-step mechanism of action implying (1) stacking of the acetylursolic acid structure to hemin and (2) additive protection of hemin ferric iron from H₂O₂ by hydroxyphenyl groups through steric hindrance and/or trapping of oxygen reactive species in the direct neighborhood of ferric iron can be put forward. For GSH degradation pathway, grafting of UA structure with a piperazine structure gave the best inhibition, pleading for the implication of this latter moiety in the inhibitory process.

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Le document en format XML

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<author><name sortKey="Mullie, Catherine" uniqKey="Mullie C">Catherine Mullie</name>
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<author><name sortKey="Dassonville Klimpt, Alexandra" uniqKey="Dassonville Klimpt A">Alexandra Dassonville-Klimpt</name>
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<front><div type="abstract" xml:lang="en">Compounds obtained by the condensation of ursolic acid (UA) with 1,4-bis(3-aminopropyl)piperazines have previously been shown as cytocidal to Plasmodium falciparum strains. Preliminary results indicated that the inhibition of β-hematin formation (one of the possible mechanisms of action of antimalarial drugs) was achieved by a few of these molecules with varying efficiencies. To gain further insight in the antimalarial action of UA derivatives, we report here the results of additional pathways that may explain their in vitro cytocidal activity such as inhibition of hemin degradation by H<sub>2</sub>
O<sub>2</sub>
 or glutathione (GSH). H<sub>2</sub>
O<sub>2</sub>
-mediated hemin degradation was drastically reduced by hydroxybenzyl-substituted UA derivatives while UA and intermediate compounds displayed weaker inhibitory actions. The results of GSH-mediated hemin degradation inhibition did not parallel those of H<sub>2</sub>
O<sub>2</sub>
 degradation as hydroxybenzyl-substituted UA only proved to be a weak inhibitor. As H<sub>2</sub>
O<sub>2</sub>
 interaction with the iron moiety of hemin is the first step towards its degradation, we assume that the interaction of our products with the ferric ion in the hemin structure is of upmost importance in inhibiting its peroxidative degradation. A two-step mechanism of action implying (1) stacking of the acetylursolic acid structure to hemin and (2) additive protection of hemin ferric iron from H<sub>2</sub>
O<sub>2</sub>
 by hydroxyphenyl groups through steric hindrance and/or trapping of oxygen reactive species in the direct neighborhood of ferric iron can be put forward. For GSH degradation pathway, grafting of UA structure with a piperazine structure gave the best inhibition, pleading for the implication of this latter moiety in the inhibitory process.</div>
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O<sub>2</sub>
 or glutathione (GSH). H<sub>2</sub>
O<sub>2</sub>
-mediated hemin degradation was drastically reduced by hydroxybenzyl-substituted UA derivatives while UA and intermediate compounds displayed weaker inhibitory actions. The results of GSH-mediated hemin degradation inhibition did not parallel those of H<sub>2</sub>
O<sub>2</sub>
 degradation as hydroxybenzyl-substituted UA only proved to be a weak inhibitor. As H<sub>2</sub>
O<sub>2</sub>
 interaction with the iron moiety of hemin is the first step towards its degradation, we assume that the interaction of our products with the ferric ion in the hemin structure is of upmost importance in inhibiting its peroxidative degradation. A two-step mechanism of action implying (1) stacking of the acetylursolic acid structure to hemin and (2) additive protection of hemin ferric iron from H<sub>2</sub>
O<sub>2</sub>
 by hydroxyphenyl groups through steric hindrance and/or trapping of oxygen reactive species in the direct neighborhood of ferric iron can be put forward. For GSH degradation pathway, grafting of UA structure with a piperazine structure gave the best inhibition, pleading for the implication of this latter moiety in the inhibitory process.</s0>
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Inhibitory effect of ursolic acid derivatives on hydrogen peroxide-and glutathione-mediated degradation of hemin: A possible additional mechanism of action for antimalarial activity

Inhibitory effect of ursolic acid derivatives on hydrogen peroxide-and glutathione-mediated degradation of hemin: A possible additional mechanism of action for antimalarial activity

Descripteurs français

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri