Heme-artemisinin adducts

In addition, these artemisinin-heme adducts appear to be generated in artemisinin-treated parasites (/4). 

Artemisinin (qinghaosu) antimalarial activity, 1309, 1313 biological targets, 1311-13 ESR spin-trapping agents, 1291 Feai) degradation, 1283, 1293, 1295-6 heme adducts, 1298, 1311-12 heterolyhc cleavage of peroxide bond, 1301-2, 1309... 

Loup C, Lelievre J, Benoit-Vical F, Meunier B. (2007) Trioxaquines and heme-artemisinin adducts inhibit the in vitro formation of hemozoin better than chloroquine. Antimicrob Agents Chemother 51 3768-3770. 

Robert and Meunier have isolated and characterized covalent adducts of metallopor-phyrins with artemisinin. Initial attempts using an iron(II) heme model were inconclusive, since the strong paramagnetism of the iron did not allow detailed characterization of the adduct and attempts at demetallation resulted in its degradation. Therefore, manganese(II) tetraphenylporphyrin (TPP) was used since it required milder demetallation conditions and the adduct 50a was formed. The suggested mechanism for the alkylation involves a pendent ethyl radical 50 (Scheme 13). 

As mentioned earlier, alkylation of heme by artemisinin was first reported by Meshnick and coworkers after identification of heme-drug adducts by mass spectrometry, but no... 

Full nuclear magnetic resonance (NMR) assignments for artemisitene 27 were reported for the first time <2001J(P1)2421> and the NMR characterization of covalent adducts obtained by the alkylation of heme with artemisinin 9a and its derivatives has been described <2002ICA488, 2005AGE2060>. 

Kannan, R. Sahal, D. Chauhan, V. S. Heme-artemisinin adducts are crucial mediators of the ability of artemisisnin to inhibit heme polymerization. Chem. Biol, 2002, 9(3) 321-332. 

Artemisinin (9) is reported to form an adduct with heme and hemin <9iMi 620-03, 94Mi 620-0i>. Solutions of ferrous ammonium sulfate and (9) generate in the presence of a spin trap an unspecified free radical <93AAC1108>. Hemin, and particularly intraerythrocytic heme, is thought to activate (9) and engender radicals that kill the parasite by alkylating specific membrane-associated proteins. 

This hypothesis was based on the evidence that, in several experimental models, artemisinin reacts with iron ions and in particular it interacts strongly with hemin (ferriprotoporphyrin IX) and its ferrous form (ferroprotoporphyrin IX) to give covalent adducts [68]. However, two different recent evidences have weakened this postulated mode of action i) it has been recently demonstrated that, once in the parasite cell, artemisinin only scarcely accumulates within the food vacuole and, thus, a key role of its interaction with heme is unlikely [69] ii) some artemisinin derivatives that are extremely active as antimalarials show very low tendency in vitro to form carbon radicals [70]. 

How can the alkylation of heme by artemisinin kill the parasite Plasmodium falciparum s histidine-rich protein (PfHRP-II) promotes the formation of hemozoin. Ibis protein contains repeats of the sequence His-His-Ala, together histidine and alanine making up 76% of the mature protein (27). HRP is able to bind approximately SO molecules of heme at pH 7 (28), and 17 at pH 4.8, thus acting as a scaffold for heme, important in the initiation of hemozoin chains (29). Recent studies suggest that the heme-artemisinin adducts (Figure 1) are able to bind to PfHRP-II widi a higher afBnify than heme itself, splace heme from PfHRP-II, and diat either low pH or chloroquine dissociates heme but not heme-artemisinin adducts from PfHRP-II (3Cf). 

The binding of heme-artemisinin adducts to H -n with high affinity constants may result in the inhibition of hemozoin fonnation leading to the building-up of the concentration of free heme within the parasite. 

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