Tetraoxane Antimalarials and Their Reaction with Fe(II)

Opsenica, I; Terzic, N; Opsenica, D; Angelovski, G; Lehnig , M; Eilbracht, P; Tinant, B; Juranic, Z; Smith, KS; Yang, YS; Diaz, DS; Smith, PL; Milhous , WK; Djokovic, D; Solaja, BA

doi:10.1021/jm050966r

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Tetraoxane Antimalarials and Their Reaction with Fe(II)

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https://pubs.acs.org/doi/pdf/10.1021/jm050966r?rand=tgrpx9pl
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引用

Opsenica, I., Terzic, N., Opsenica, D., Angelovski, G., Lehnig, M., Eilbracht, P., Tinant, B., Juranic, Z., Smith, K., Yang, Y., Diaz, D., Smith, P., Milhous, W., Djokovic, D., & Solaja, B. (2006). Tetraoxane Antimalarials and Their Reaction with Fe(II). Journal of Medicinal Chemistry, 49(13), 3790-3799. doi:10.1021/jm050966r.

引用: https://hdl.handle.net/11858/00-001M-0000-0013-D12D-D

要旨

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.