Heme alkylation by artesunic acid and trioxaquine DU1301, two antimalarial trioxanes.
The sesquiterpene Artemisinin, an antimalarial drug that is effective against multidrug-resistant Plasmodium falciparum strains, contains a 1,2,4-trioxane, and the endoperoxide function plays a key role in its biological activity. However, its poor solubility means that hemisynthetic derivatives, such as artesunic acid, are preferred for drugs. The reductive activation of the peroxide function of artemisinin by iron(II)-heme produces heme derivatives that are alkylated at meso positions by a C-centered radical derived from artemisinin. We checked if the alkylating ability of trioxane-based drugs toward heme, which might be related to its parasiticidal activity, is a general feature by comparing the chemical reactivity toward heme of the clinically relevant derivative artesunic acid and DU1301, a drug of the trioxaquine family, that is active against P. falciparum. Both artesunic acid and trioxaquine DU1301 efficiently alkylated the heme macrocycle after activation of their peroxide function by the iron(II) of heme itself and thus gave rise to covalently coupled heme-drug products. This heme-drug adduct formation might be related to the high antimalarial activity of DU1301.
Laurent
Sophie A-L
SA
Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France.
Loup
Christophe
C
Mourgues
Sophie
S
Robert
Anne
A
Meunier
Bernard
B
D000478:Alkylation; D000962:Antimalarials / Q000737:chemistry*; D037621:Artemisinins / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D006418:Heme / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D012717:Sesquiterpenes / Q000737:chemistry*; D013386:Succinates / Q000737:chemistry*
D000962:Antimalarials; D037621:Artemisinins; C503606:DU1301; D012717:Sesquiterpenes; D013386:Succinates; D006418:Heme; C111789:artesunic acid