Abstract
A Diels-Alder/thiol-olefin co-oxygenation approach to the synthesis of novel bicyclic endoperoxides 17a-22b is reported. Some of these endoperoxides (e.g., 17b, 19b, 22a and 22b) have potent nanomolar in vitro antimalarial activity equivalent to that of the synthetic antimalarial agent arteflene. Iron(II)-mediated degradation of sulfone-endoperoxide 19b and spin-trapping with TEMPO provide a spin-trapped adduct 25 indicative of the formation of a secondary carbon centered radical species 24. Reactive C-radical intermediates of this type may be involved in the expression of the antimalarial effect of these bicyclic endoperoxides.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkanes / chemical synthesis
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Alkanes / chemistry*
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Alkanes / pharmacology*
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Alkenes / chemical synthesis
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Alkenes / chemistry*
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Alkenes / pharmacology*
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Animals
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Antimalarials / chemical synthesis*
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Antimalarials / chemistry
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Antimalarials / pharmacology*
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Cyclization
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Cyclohexenes
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Epoxy Compounds / chemistry
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Limonene
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Molecular Structure
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Oxygen / chemistry*
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Peroxides / chemistry
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Plasmodium berghei / drug effects
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Structure-Activity Relationship
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Sulfhydryl Compounds / chemistry*
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Terpenes / chemistry
Substances
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Alkanes
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Alkenes
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Antimalarials
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Cyclohexenes
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Epoxy Compounds
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Peroxides
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Sulfhydryl Compounds
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Terpenes
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Limonene
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Oxygen
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nonane