Iron(II)-induced degradation of antimalarial beta-sulfonyl endoperoxides: evidence for the generation of potentially cytotoxic carbocations.
Reactions of antimalarial beta-sulfonyl endoperoxides 9 and 10, which, like yingzhaosu A (2), derive from the 2,3-dioxabicyclo[3.3.1]nonane system 3, with iron(II) salts were studied. Product analysis of the iron(II)-induced degradations provided evidence for the intermediacy of carbon-centered cyclohexyl radicals 20 and 31 and their possible oxidation to the corresponding carbocations 21 and 32. It is conceivable that the antimalarial activity of beta-sulfonyl endoperoxides of type 5 may derive from alkylation of vital intraparasitic biomolecules by free radicals and/or carbocations, generated within the malaria parasite through a similar iron(II)-induced degradation process.
Szpilman
A M
AM
Department of Organic Chemistry, The Weizmann Institute of Science, 76100 Rehovot, Israel.
Korshin
E E
EE
Hoos
R
R
Posner
G H
GH
Bachi
M D
MD
D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism*; D005609:Free Radicals / Q000737:chemistry / Q000378:metabolism; D007501:Iron / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010545:Peroxides / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism; D013441:Sulfinic Acids / Q000737:chemistry
D000962:Antimalarials; D005609:Free Radicals; D010545:Peroxides; D011355:Prodrugs; D013441:Sulfinic Acids; D007501:Iron