Iron-catalyzed activation of endoperoxides for free radical generation and cytotoxicity

This target entry describes a mechanism by which iron catalyzes the cleavage of endoperoxide-containing drugs (e.g., artemisinin), leading to the generation of cytotoxic free radicals. In malaria treatment, intra-parasitic iron activates artemisinin and similar drugs, resulting in the alkylation and damage of parasite proteins. In broader biological systems, iron and iron-oxygen complexes are potent initiators of lipid peroxidation and free radical-mediated oxidative damage. Several nonheme iron enzymes (e.g., FtmOx1) naturally catalyze endoperoxidation, using iron to generate and transfer radicals during biosynthesis. While this process is pivotal for the efficacy of some drugs, it is not a single molecular target but rather a chemical activation mechanism mediated by iron or iron-dependent enzymes, associated with cytotoxicity, oxidative stress, and tissue damage. Its therapeutic relevance is most prominent in the context of antimalarial drug activation, but excessive or off-target activation presents significant safety challenges related to oxidative damage.

Other names

Iron-catalyzed endoperoxidase activationIron-mediated free radical formation via endoperoxidesIron-dependent endoperoxide cleavageIron-driven artemisinin activation (malaria context)FtmOx1 (example of an iron-dependent endoperoxidase)Nonheme iron endoperoxidases

Iron catalyzes cleavage of the endoperoxide bridge, generating cytotoxic free radicals (mainly within parasites or cells with high iron content). Drugs such as artemisinin are activated by iron in the target cell, leading to alkylation and damage of parasite/cellular proteins. Iron-dependent endoperoxidases (e.g., FtmOx1) catalyze the insertion of oxygen and radical generation in biosynthesis or xenobiotic activation.