Elucidation of the natural artemisinin decomposition route upon iron interaction: a fine electronic redistribution promotes reactivity.
The conformational analysis of artemisinin by molecular dynamics and quantum chemistry calculations revealed the existence of seven energy minima with specific interconversion pathways. Among the seven conformers, only , and were able to undergo bond rearrangements upon Fe(2+) interaction. These rearrangements were due to a peculiar puckering of the trioxane ring that brings its three oxygen atoms in an ideal geometrical position for interacting with Fe(2+) ions, promoting an electronic redistribution in the molecule. A rapid molecule rearrangement led to a stable energy minimum structure with an additional ring that is similar to a plant metabolite. Our results suggest an alternative pathway for generating toxic radical chemical species for the malaria parasite, where artemisinin is not toxic by itself but rather is an intermediate for molecular partners that generate radical structures deleterious for the parasite proteins, after electron transfers from the Fe(2+)/artemisinin complex.
Nosoongnoen
Wichit
W
APHP, Hôpital Lariboisière, Service de Biochimie et de Biologie Moléculaire, 2 rue Ambroise Paré, Paris cedex 10, France.
Pratuangdejkul
Jaturong
J
Sathirakul
Korbtham
K
Jacob
Alexandre
A
Conti
Marc
M
Loric
Sylvain
S
Launay
Jean-Marie
JM
Manivet
Philippe
P
D000962:Antimalarials / Q000737:chemistry*; D037621:Artemisinins / Q000737:chemistry*; D002942:Circular Dichroism; D007501:Iron / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D013055:Spectrophotometry, Infrared
D000962:Antimalarials; D037621:Artemisinins; C031327:artemisinin; D007501:Iron