title: Tetraoxane antimalarials and their reaction with Fe(II).
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.
authors.affiliation: Institute of Chemistry, Technology and Metallurgy, Belgrade, Serbia and Montenegro.
authors.forename: Igor
authors.initials: I
authors.lastname: Opsenica
authors.forename: Natasa
authors.initials: N
authors.lastname: Terzić
authors.forename: Dejan
authors.initials: D
authors.lastname: Opsenica
authors.forename: Goran
authors.initials: G
authors.lastname: Angelovski
authors.forename: Manfred
authors.initials: M
authors.lastname: Lehnig
authors.forename: Peter
authors.initials: P
authors.lastname: Eilbracht
authors.forename: Bernard
authors.initials: B
authors.lastname: Tinant
authors.forename: Zorica
authors.initials: Z
authors.lastname: Juranić
authors.forename: Kirsten S
authors.initials: KS
authors.lastname: Smith
authors.forename: Young S
authors.initials: YS
authors.lastname: Yang
authors.forename: Damaris S
authors.initials: DS
authors.lastname: Diaz
authors.forename: Philip L
authors.initials: PL
authors.lastname: Smith
authors.forename: Wilbur K
authors.initials: WK
authors.lastname: Milhous
authors.forename: Dejan
authors.initials: D
authors.lastname: Doković
authors.forename: Bogdan A
authors.initials: BA
authors.lastname: Solaja
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004578:Electron Spin Resonance Spectroscopy; D005296:Ferrous Compounds / Q000737:chemistry*; D005609:Free Radicals / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D045568:Tetraoxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D000970:Antineoplastic Agents; D005296:Ferrous Compounds; D005609:Free Radicals; D045568:Tetraoxanes; C029451:ferrous chloride