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of the GSH reductase and other enzymes in the parasite. On the other hand, it is
instructive that those C-centered radicals derived from 1 and its derivatives could
attack not only free cysteine and cysteine residue in peptide, but also probably in
cysteine-contained proteins. The formation of the covalent bond adduct between
parasite proteins and 1 and its derivatives mentioned in the literature is mostly pos-
sible. In 2003, Eckstein-Ludwig et al. reported that the malarial calcium-dependent
ATPase (PfATP6) might be the molecular target for qinghaosu.
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PfATP6 is
located in the sarco/endoplasmic reticulum situated outside the food vacuole of
the parasite. This inhibition of PfATP6 was iron-dependent; that is, the free radical
derived from the qinghaosu-iron ion was the active species. However, they did not
have definitive evidence of whether the free radicals from qinghaosu bind to
PfATP6 in several sites. In this respect, our experimental result that an adduct
may be formed between the cysteine residue and the free radicals from qinghaosu
is inspired to understand Eckstein-Ludwig et al.'s discovery.
5.6.5.3 Interaction With Heme
Recently, Robert et al. reviewed their mechanistic study on qinghaosu deriva-
tives.
14,287
They identified some adducts of heme and the primary C-centered
free radical 162 through the meso-position from the reaction of qinghaosu with
Fe(III)-heme and 2,3-dimethylhydroquinone in methylene chloride
302
or Fe(III)-
heme and GSH in dimethyl sulfoxide.
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Structure 5-27 shows the major
qinghaosu-heme adduct after demetallation. However, they did not clearly point
how these adducts were related with the action mode of the antimalarial or the inhi-
bition of the hemozoin formation. Also, in 2002, a heme-qinghaosu named hemart
was reported and showed that hemart stalls all mechanisms of heme polymeriza-
tion, which results in the death of the malarial parasite.
304
However, their hemart
was synthesized just by mixing equivalent heme and qinghaosu in dimethyl aceta-
mide (DMA) at 37
C for 24 hours. It is not clear that hermart is a complex or a
covalent adduct. The primary C-centered free radical 162 is only formed by reac-
tion of qinghaosu and heme in the presence of reducing agents, but not in the
absence of the reductants. In 2003, Haynes et al. pointed out that qinghaosu
antimalarials do not inhibit hemozoin formation and hence ruled out the role of
the qinghaosu-heme adduct as an inhibitor.
305
H
NH
N
HO
AcO
HN
N
O
O
H
3
COOC
COOCH
3
Structure 5-27
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