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Ferryl–oxo heme intermediate in the antimalarial mode of action of artemisinin
Author(s) -
Kapetanaki Sofia,
Varotsis Constantinos
Publication year - 2000
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(00)01592-1
Subject(s) - hemin , chemistry , trioxane , heme , artemisinin , dimer , porphyrin , hemozoin , stereochemistry , photochemistry , organic chemistry , plasmodium falciparum , malaria , immunology , copolymer , biology , enzyme , polymer
Fourier transform infrared (FTIR) and resonance Raman (RR) spectroscopies have been employed to investigate the reductive cleavage of the O–O bond of the endoperoxide moiety of the antimalarial drug artemisinin and its analog trioxane alcohol by hemin dimer. We have recorded FTIR spectra in the ν(O–O) and ν as (Fe–O–Fe) regions of artemisinin and of the hemin dimer that show the cleavage of the endoperoxide and that of the hemin dimer, respectively. We observed similar results in the trioxane alcohol/hemin dimer reaction. The RR spectrum of the artemisinin/hemin dimer reaction displays a vibrational mode at 850 cm −1 that shifts to 818 cm −1 when the experiment is repeated with 18 O–O 18 endoperoxide enriched trioxane alcohol. The frequency of this vibration and the magnitude of the 18 O–O 18 isotopic shift led us to assign the 850 cm −1 mode to the Fe IV =O stretching vibration of a ferryl–xoxo heme intermediate that occurs in the artemisinin/hemin dimer and trioxane alcohol/hemin reactions. These results provide the first direct characterization of the antimalarial mode of action of artemisinin and its trioxane analog, and suggest that artemisinin appears to react with heme molecules that have been incorporated into hemozoin and subsequently the heme performs cytochrome P450‐type chemistry.