Evidence for the Importance of High-Valent Fe=O and of a Diketone in the Molecular Mechanism of Action of Antimalarial Trioxane Analogs of Artemisinin

摘要

Ancient Chinese folk medicine has ledfelatively recently to chemical identification of the 1,2,4-trioxane sesquiterpene artemisinin (qinghaosu, 1), representing a new class of fast-acting, clinically useful, antimalarial drugs. This natural endoperoxide and some related synthetic organic endoperoxides, causing oxidative stress to malaria parasites, are reduced by the iron-rich parasites to form cytotoxic radical intermediates. We have designed and synthesized some structurally simplified 1,2,4-trioxanes to determine whether they are reduced by ferrous iron to form the same kinds of radical intermediates as formed upon iron(II) reduction of artemisinin. The simplified triox-anes we report here were formulated such that an intermediate carbon-centered radical would be intercepted before beta-scission of Fe(III)-O [<->Fe(IV)=O] either by a competing beta-scission of a better radical leaving group X from radical intermediate 2a (Scheme 1A) or by a competing subsequent 1,5-hydrogen atom shift in radical intermediate 3a (Scheme 1B); such mechanistically competing reactions were expected to interrupt formation of a high-valent iron—oxo species and thus to diminish or to undermine completely the antimalarial activity of these artemisinin analogs. Also,another analog was designed to have improved and therefore medicinally more desirable antimalarial potency by incorporating a structural feature that would facilitate beta-scission of a high-valent iron—oxo species. We report here in vitro antimalarialactivities that support the intermediacy of such high-valent iron—oxo species via the beta-scission pathway in the antimalarial artemisinin analogs shown in Table 1. We report evidence also of a simple diketone as an unexpectedly antimalarial product formed upon iron(II) reduction of a trioxane.