Evidence for Fe(Ⅳ)=O in the Molecular Mechanism of Action of the Trioxane Antimalarial Artemisinin

摘要

Among the 300-500 million people worldwide who are currently infected with malaria, about 2 million deaths, many of them children, occur each year. As malaria parasites develop ever-increasing multidrug resistance to traditional alkaloidal antimalarial drugs, artemisinin (quinghaosu, 1), a non-alkaloidal endoperoxide natural product discovered in China, and related 1,2,4-trioxanes are increasingly being used for effective chemotherapy of malaria. These organic peroxides, causing oxidative stress to malaria parasites, apparently are reduced by the iron-rich parasites to form cytotoxic radical intermediates. Using an oxygen-18-labeled trioxane and some mechanism-based synthetic analogs, we have shown that a carbon-centered radical, formed from an oxy radical via an intramolecular 1,5-hydrogen atom shift, is important for antimalarial activity. We now report several kinds of evidence supporting the intermediacy of a high-valent, non-heme, iron-oxo species resembling mat characteristic of monoxygenase metalloenzymes and known to cause oxidative damage to biological macromol-ecules.