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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.

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Reaction between plakortin (3 equiv., 2) and hemin-FeIII-Cl (1 equiv., 5) in presence of the reducing agent, 2,3-dimethylhydroquinone (10 equiv., 6) in deuterated chloroform at 25 °C.(a) Chemical structure of the reagents. (b) 1H NMR time-course of the reaction. Proton resonances of 2, decreasing in intensity or broadening upon reaction, are indicated with dotted lines or an asterisk, respectively, and numbered as reported in the structure in (a). Different vertical scales were used in the two sections of the 1H NMR spectra. The peak indicated with # is from tetramethylsilane (TMS). (c) Bar graphs of the percentage of 2 signal intensity, relative to the initial value (t = 0) of 100%.
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f2: Reaction between plakortin (3 equiv., 2) and hemin-FeIII-Cl (1 equiv., 5) in presence of the reducing agent, 2,3-dimethylhydroquinone (10 equiv., 6) in deuterated chloroform at 25 °C.(a) Chemical structure of the reagents. (b) 1H NMR time-course of the reaction. Proton resonances of 2, decreasing in intensity or broadening upon reaction, are indicated with dotted lines or an asterisk, respectively, and numbered as reported in the structure in (a). Different vertical scales were used in the two sections of the 1H NMR spectra. The peak indicated with # is from tetramethylsilane (TMS). (c) Bar graphs of the percentage of 2 signal intensity, relative to the initial value (t = 0) of 100%.

Mentions: NMR was selected as method of choice for the initial characterization of the interaction between 2 and heme. In particular, as shown in Fig. 2, 2 (3 equiv.) was incubated with FeIII protoporphyrin IX dimethyl ester chloride (hemin-FeIII-Cl, 1 equiv., 5) in presence of a large excess of the reducing agent 2,3-dimethylhydroquinone (DMHQ, 10 equiv., 6), according to the procedure described by Meunier and coworkers for 122.


The interaction of heme with plakortin and a synthetic endoperoxide analogue: new insights into the heme-activated antimalarial mechanism
Reaction between plakortin (3 equiv., 2) and hemin-FeIII-Cl (1 equiv., 5) in presence of the reducing agent, 2,3-dimethylhydroquinone (10 equiv., 6) in deuterated chloroform at 25 °C.(a) Chemical structure of the reagents. (b) 1H NMR time-course of the reaction. Proton resonances of 2, decreasing in intensity or broadening upon reaction, are indicated with dotted lines or an asterisk, respectively, and numbered as reported in the structure in (a). Different vertical scales were used in the two sections of the 1H NMR spectra. The peak indicated with # is from tetramethylsilane (TMS). (c) Bar graphs of the percentage of 2 signal intensity, relative to the initial value (t = 0) of 100%.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Reaction between plakortin (3 equiv., 2) and hemin-FeIII-Cl (1 equiv., 5) in presence of the reducing agent, 2,3-dimethylhydroquinone (10 equiv., 6) in deuterated chloroform at 25 °C.(a) Chemical structure of the reagents. (b) 1H NMR time-course of the reaction. Proton resonances of 2, decreasing in intensity or broadening upon reaction, are indicated with dotted lines or an asterisk, respectively, and numbered as reported in the structure in (a). Different vertical scales were used in the two sections of the 1H NMR spectra. The peak indicated with # is from tetramethylsilane (TMS). (c) Bar graphs of the percentage of 2 signal intensity, relative to the initial value (t = 0) of 100%.
Mentions: NMR was selected as method of choice for the initial characterization of the interaction between 2 and heme. In particular, as shown in Fig. 2, 2 (3 equiv.) was incubated with FeIII protoporphyrin IX dimethyl ester chloride (hemin-FeIII-Cl, 1 equiv., 5) in presence of a large excess of the reducing agent 2,3-dimethylhydroquinone (DMHQ, 10 equiv., 6), according to the procedure described by Meunier and coworkers for 122.

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.