Determination of the structures of radicals formed in the reaction of antimalarial drug artemisinin with ferrous ions.
While artemisinin 1 has been widely used to treat malaria in traditional Chinese medicine, its exact antimalarial mechanism remains unclear. To elucidate the mechanisms of the antimalarial action by artemisinin, the reactions of artemisinin, artemether 2 and artesunate 3 with Fe2+were analyzed using an electron spin resonance (ESR), high performance liquid chromatography-electron spin resonance (HPLC-ESR) and high performance liquid chromatography-electron spin resonance-mass spectrometer (HPLC-ESR-MS). α-(4-Pyridyl-1-oxide)-N-tert-butylnitrone (4-POBN) was used as a spin trap reagent in the reactions. Radicals were detected by ESR and structures of the radicals were determined by HPLC-ESR-MS. Based on the ions, m/z 478, m/z 418 and m/z 238 which were determined by HPLC-ESR-MS, we identified following radicals: artemisinin-derived primary and secondary radicals, 6 and 7; acetyl radical, 8; a radical formed through elimination of acetyl group from 6, 10 in the reaction of artemisinin with Fe2+. Radicals, 7 and 8 were also detected in the reaction of artemether and artesunate.
Department of Chemistry, Wakayama Medical University, 580 Mikazura, Wakayama 641-0011, Japan.
Marie
M
Asano
Department of Chemistry, Wakayama Medical University, 580 Mikazura, Wakayama 641-0011, Japan. Electronic address: chem1@wakayama-med.ac.jp.
Hideo
H
Iwahashi
D000962:Antimalarials / Q000737:chemistry*; D000077549:Artemether; D037621:Artemisinins / Q000737:chemistry*; D000077332:Artesunate; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000737:chemistry; D007501:Iron / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry; D012997:Solvents / Q000737:chemistry
D000962:Antimalarials; D037621:Artemisinins; D005609:Free Radicals; D011725:Pyridines; D012997:Solvents; C043438:alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone; D000077332:Artesunate; D000077549:Artemether; D007501:Iron
Antimalarial action by radical; Artemether; Artemisinin; Artesunate; HPLC-ESR-MS