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J Med Chem ; 49(13): 3790-9, 2006 Jun 29.
Article in English | MEDLINE | ID: mdl-16789736

ABSTRACT

Mixed tetraoxanes 5a and 13 synthesized from cholic acid and 4-oxocyclohexanecarboxylic acid were as active as artemisinin against chloroquine-susceptible, chloroquine-resistant, and multidrug-resistant Plasmodium falciparum strains (IC50, IC90). Most active 13 is metabolically stable in in vitro metabolism studies. In vivo studies on tetraoxanes with a C(4' ') methyl group afforded compound 15, which cured 4/5 mice at 600 and 200 mg.kg-1.day-1, and 2/5 mice at 50 mg.kg-1.day-1, showing no toxic effects. Tetraoxane 19 was an extremely active antiproliferative with LC50 of 17 nM and maximum tolerated dose of 400 mg/kg. In Fe(II)-induced scission of tetraoxane antimalarials only RO* radicals were detected by EPR experiments. This finding and the indication of Fe(IV)=O species led us to propose that RO* radicals are probably capable of inducing the parasite's death. Our results suggest that C radicals are possibly not the only lethal species derived from peroxide prodrug antimalarials, as currently believed.


Subject(s)
Antimalarials/chemical synthesis , Ferrous Compounds/chemistry , Tetraoxanes/chemical synthesis , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Electron Spin Resonance Spectroscopy , Free Radicals/chemistry , Humans , In Vitro Techniques , Mice , Microsomes, Liver/metabolism , Molecular Structure , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Tetraoxanes/chemistry , Tetraoxanes/pharmacology
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