The Fe2+-mediated decomposition, PfATP6 binding, and antimalarial activities of artemisone and other artemisinins: the unlikelihood of C-centered radicals as bioactive intermediates.
The results of Fe(2+)-induced decomposition of the clinically used artemisinins, artemisone, other aminoartemisinins, 10-deoxoartemisinin, and the 4-fluorophenyl derivative have been compared with their antimalarial activities and their ability to inhibit the parasite SERCA PfATP6. The clinical artemisinins and artemisone decompose under aqueous conditions to give mixtures of C radical marker products, carbonyl compounds, and reduction products. The 4-fluorophenyl derivative and aminoartemisinins tend to be inert to aqueous iron(II) sulfate and anhydrous iron(II) acetate. Anhydrous iron(II) bromide enhances formation of the carbonyl compounds and provides a deoxyglycal from DHA and enamines from the aminoartemisinins. Ascorbic acid (AA) accelerates the aqueous Fe(2+)-mediated decompositions, but does not alter product distribution. 4-Oxo-TEMPO intercepts C radicals from a mixture of an antimalaria-active trioxolane, 10-deoxoartemisinin, and anhydrous iron(II) acetate to give trapped products in 73 % yield from the trioxolane, and 3 % from the artemisinin. Artemisone provides a trapped product in 10 % yield. Thus, in line with its structural rigidity, only the trioxolane provides a C radical eminently suited for intermolecular trapping. In contrast, the structural flexibility of the C radicals from the artemisinins allows facile extrusion of Fe(2+) and collapse to benign isomerization products. The propensity towards the formation of radical marker products and intermolecular radical trapping have no relationship with the in vitro antimalarial activities of the artemisinins and trioxolane. Desferrioxamine (DFO) attenuates inhibition of PfATP6 by, and antagonizes antimalarial activity of, the aqueous Fe(2+)-susceptible artemisinins, but has no overt effect on the aqueous Fe(2+)-inert artemisinins. It is concluded that the C radicals cannot be responsible for antimalarial activity and that the Fe(2+)-susceptible artemisinins may be competitively decomposed in aqueous extra- and intracellular compartments by labile Fe(2+), resulting in some attenuation of their antimalarial activities. Interpretations of the roles of DFO and AA in modulating antimalarial activities of the artemisinins, and a comparison with antimalarial properties of simple hydroperoxides and their behavior towards thapsigargin-sensitive SERCA ATPases are presented. The general basis for the exceptional antimalarial activities of artemisinins in relation to the intrinsic activity of the peroxide within the uniquely stressed environment of the malaria parasite is thereby adumbrated.
Haynes
Richard K
RK
Department of Chemistry, Open Laboratory of Chemical Biology, Institute of Molecular Technology for Drug Discovery and Synthesis, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, PR China. haynes@ust.hk
Chan
Wing Chi
WC
Lung
Chung-Man
CM
Uhlemann
Anne-Catrin
AC
Eckstein
Ursula
U
Taramelli
Donatella
D
Parapini
Silvia
S
Monti
Diego
D
Krishna
Sanjeev
S
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology*; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D003676:Deferoxamine / Q000494:pharmacology; D005296:Ferrous Compounds / Q000378:metabolism*; D007700:Kinetics; D016013:Likelihood Functions; D010963:Plasmodium falciparum / Q000378:metabolism*
C513500:ATP6 protein, Plasmodium falciparum; D000962:Antimalarials; D037621:Artemisinins; D005296:Ferrous Compounds; C514498:artemisone; D000252:Calcium-Transporting ATPases; D003676:Deferoxamine