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parasite DNA damage: (Qinghaosu could permeate the membrane, reach the
nucleus of parasite, and react with Fe(II)) could be fulfilled, but it is possible
that the DNA damage may be responsible for the toxicity of qinghaosu and its deri-
vatives on the tumor cell line, just as in the case of some other antitumor com-
pounds, such as enediyne compounds. The positions of DNA attacked by the
qinghaosu free radical are being studied, and it was observed that deoxygunosine
(dG), perhaps deoxyadenosine (dA), in some cases, was attacked.
5.6.5.2 Interaction With Amino Acid, Peptide, and Protein
As early as the 1980s, it was indicated that some proteins such as cytochrome oxi-
dase in the membranes and mitochondria were a target for the action of qin-
ghaosu.
291
Meshnick et al. have performed a series of experiments about the
interaction between qinghaosu and proteins in the presence of heme and have con-
cluded that the binding between qinghaosu and albumin probably involves thiol and
amino groups via both iron-dependent and -independent reactions. However, they
have not isolated and confirmed such covalent adducts and have presented the ques-
tion, ''how does protein alkylation lead to parasite death?''
8,292-294
Recent studies on the chemistry of a digestive vacuole (pH 5.0-5.4) within P.
falciparum have revealed a defined metabolic pathway for the degradation of hemo-
globin. Plasmodium has a limited capacity for de novo amino acid synthesis, so
hemoglobin proteolysis may be essential for its survival. However, hemoglobin
degradation alone seems insufficient for the parasite's metabolic needs because it
is a poor source of methionine, cysteine, glutamine, and glutamate and contains
no isoleucine. On the other hand, as pointed out by Fracis et al., several experiments
show that cysteine protease has a key role in the hemoglobin degradation pathway;
it has even been hypothesized that the plasmepsins generate hemoglobin fragments
that cannot be further catabolized without cysteine protease action.
295
On the other hand, malaria parasite-infected red blood cells have a high concen-
tration of the reduced GSH, the main reducing agent in physiological systems.
296
It
was also reported that excess GSH in a parasite may be responsible for protecting
the parasite from the toxicity of heme.
297,298
In general, GSH takes part in many
biological functions, including the detoxification of cytosolic hydrogen peroxide
and organic peroxides and then protects cells from being damaged by oxidative
stress. Therefore, depletion of GSH or inhibiting GSH reductase in a parasite cell
will induce oxidative stress and then kill these cells.
299
Accordingly, as the first step, the interaction of qinghaosu and cysteine in the
presence of a catalytic amount of Fe(II/III) was studied. From the reaction mixture,
a water-soluble compound was isolated. This compound could be visualized with
ninhydrin on TLC, and it showed a formula of C
16
H
27
NO
6
S
H
2
O. Treatment of this
compound with acetic anhydride yielded a cyclic thioether 165, which in turn
undoubtedly showed the formation of adduct 166 of 1 and cysteine through a s
bond between C-3 and sulfur.
281
A stable adduct 167 of cysteine and 170 was
then isolated in 33% yield with the same reaction protocol.
185
As mentioned,
both adducts of cysteine with primary and secondary free radical derived from arte-
mether were also identified recently, albeit in low yield (Structure 5-25).
282
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