Tetraoxane Antimalarials and Their Reaction with Fe(II)

• Published in: Journal of medicinal chemistry 2006-06, Vol.49 (13), p.3790-3799
• Main Authors: Opsenica, Igor, Terzić, Nataša, Opsenica, Dejan, Angelovski, Goran, Lehnig, Manfred, Eilbracht, Peter, Tinant, Bernard, Juranić, Zorica, Smith, Kirsten S, Yang, Young S, Diaz, Damaris S, Smith, Philip L, Milhous, Wilbur K, Doković, Dejan, Šolaja, Bogdan A
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiparasitic agents; Biological and medical sciences; Cell Line, Tumor; Drug Screening Assays, Antitumor; Electron Spin Resonance Spectroscopy; Ferrous Compounds - chemistry; Free Radicals - chemistry; General aspects; Humans; In Vitro Techniques; Medical sciences; Mice; Microsomes, Liver - metabolism; Molecular Structure; Pharmacology. Drug treatments; Plasmodium falciparum - drug effects; Structure-Activity Relationship; Tetraoxanes - chemical synthesis; Tetraoxanes - chemistry; Tetraoxanes - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050966r

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.