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The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism

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ABSTRACT

4a: In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue with heme. Obtained results indicate that the studied compounds produce reactive carbon radical species after being reductively activated by heme. In particular, similarly to artemisinin, the formation of radicals prone to inter-molecular reactions should represent the key event responsible for Plasmodium death. To our knowledge this is the first experimental investigation on the reductive activation of simple antimalarial endoperoxides (1,2-dioxanes) by heme and results were compared to the ones previously obtained from the reaction with FeCl2. The obtained experimental data and the calculated molecular interaction models represent crucial tools for the rational optimization of our promising class of low-cost synthetic antimalarial endoperoxides.

No MeSH data available.


Proposed reaction mechanism of the synthetic analog 4a with heme-FeII-Cl.
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f7: Proposed reaction mechanism of the synthetic analog 4a with heme-FeII-Cl.

Mentions: The formation of the products reported in Fig. 6 can be rationalized by assuming the reductive activation of 4a by heme-FeII, generated in situ by the reducing agent 6, the homolytic cleavage of the peroxide bond and the formation of the two different alkoxy radicals, either on O1 (pathway a) or on O2 (pathway b) (Fig. 7). The subsequent homolytic cleavage of an adjacent C-C bond (beta scission) can give rise to two different alkyl carbon centered radicals, namely 18 from pathway a, and 19 from pathway b. At this step of the reaction, products 12 and 10 can be formed in the pathway a and b, respectively. In pathway a, the primary C5 centered radical 18 undergoes a classic carbon-carbon bond cleavage with oxidation of O2 and reduction of FeIII to FeII. These intra-molecular rearrangements can lead to the formation of the products 10 and 11. In pathway b, the α-carbonyl radical 19 can provide the covalent adduct 14 with heme. NMR assignment of 14 signals revealed the presence of the enol form of the carbonyl group (Supplementary Figure S7) as a consequence of its participation in heme conjugation.


The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism
Proposed reaction mechanism of the synthetic analog 4a with heme-FeII-Cl.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382535&req=5

f7: Proposed reaction mechanism of the synthetic analog 4a with heme-FeII-Cl.
Mentions: The formation of the products reported in Fig. 6 can be rationalized by assuming the reductive activation of 4a by heme-FeII, generated in situ by the reducing agent 6, the homolytic cleavage of the peroxide bond and the formation of the two different alkoxy radicals, either on O1 (pathway a) or on O2 (pathway b) (Fig. 7). The subsequent homolytic cleavage of an adjacent C-C bond (beta scission) can give rise to two different alkyl carbon centered radicals, namely 18 from pathway a, and 19 from pathway b. At this step of the reaction, products 12 and 10 can be formed in the pathway a and b, respectively. In pathway a, the primary C5 centered radical 18 undergoes a classic carbon-carbon bond cleavage with oxidation of O2 and reduction of FeIII to FeII. These intra-molecular rearrangements can lead to the formation of the products 10 and 11. In pathway b, the α-carbonyl radical 19 can provide the covalent adduct 14 with heme. NMR assignment of 14 signals revealed the presence of the enol form of the carbonyl group (Supplementary Figure S7) as a consequence of its participation in heme conjugation.

View Article: PubMed Central - PubMed

ABSTRACT

4a: In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue with heme. Obtained results indicate that the studied compounds produce reactive carbon radical species after being reductively activated by heme. In particular, similarly to artemisinin, the formation of radicals prone to inter-molecular reactions should represent the key event responsible for Plasmodium death. To our knowledge this is the first experimental investigation on the reductive activation of simple antimalarial endoperoxides (1,2-dioxanes) by heme and results were compared to the ones previously obtained from the reaction with FeCl2. The obtained experimental data and the calculated molecular interaction models represent crucial tools for the rational optimization of our promising class of low-cost synthetic antimalarial endoperoxides.

No MeSH data available.