NMR characterization of covalent adducts obtained by alkylation of heme with the antimalarial drug artemisinin

The peroxide function of artemisinin has been activated by iron(II)–heme generated in situ from iron(III)–protoporphyrin–IX or iron(III)–protoporphyrin–IX dimethylester and a reducing agent. In mild conditions, this reaction produced high yield (85%) of heme derivatives alkylated at meso positions by a C4-centered radical derived from artemisinin. The adducts at α-, β-, and δ-meso positions were obtained as major products, and alkylation at γ-meso position was minor (7–13% of the total amount of adducts). These adducts were not separable, but the mixture has been characterized after demetallation by a detailed NMR study.