Chemistry Reference
In-Depth Information
Qinghaosu can be used by physicians for the treatment for chloroquine-resistant
malaria; it must have a different mode of action from that of chloroquine. Early study
by Chinese scientists demonstrated that artemisinin drugs had a direct parasiticidal
action against P. falciparum in the erythrocytic stage both in vitro and in vivo.
274
Also, the morphologic changes were observed under the electron microscope.
274
Qinghaosu drugs were added to the media, and samples were taken at definite inter-
vals for electromicroscopic examination. The injuries of membrane structures of the
parasite included swelling of the limiting membrane and the nuclear membrane, and,
formation of the autophagic vacuole. It was also found that some free radical scaven-
gers, such as vitamin E, would reduce the efficiency of qinghaosu. However, the
inherent reason for these observed phenomena have not been acknowledged.
5.6.3 The Free Radical Reaction of Qinghaosu and Its
Derivatives With Fe(II)
Qinghaosu is a sesquiterpene molecule containing carbon, hydrogen, oxygen, and
no nitrogen atoms and can used by physicians for the treatment of multidrug-
resistant strains of P. falciparum. It is obvious that its antimalarial mechanism is
different from previous alkaloidal antimalarial drugs such as quinine and chloro-
quine. Since the discovery of 1, what will be its action mode on the molecular
level is a widely interesting question, although it is a difficult task. Actually until
now, the action mode of quinine and other synthetic alkaloidal antimalarial drugs
has not been so clearly understood.
275
Qinghaosu acts parasite at its intra-erythrocytic asexual stage. At this stage, the
parasite takes hemoglobin as its nutritional resource, digests hemoglobin, and
leaves free heme, which is then polymerized to parasite safety poly-heme (hemo-
zoin). Two other points should be mentioned: Over 95% iron in the human body
exists as heme in the red blood cell, and the peroxide segment of 1 and its deriva-
tives is essentially responsible for its activity.
Being aware of the DNA cleavage with the Fenton reagent
276,277
and the above-
mentioned situation of qinghaosu-parasite-red blood cell, this laboratory has
studied the reaction of qinghaosu and its derivatives with ferrous ion in aqueous
acetonitrile since the early 1990s. At first, the reaction of 1 and ferrous sulfate
(1:1 in mole) was run in H
2
O-CH
3
CN (1:1 in volume, pH 4) at room temperature.
It was interesting to find that the two major products were tetrahydrofuran com-
pound 28 and 3-hydroxy deoxyqinghaosu 15, which have been identified as the
natural products of qinghao, pyrolysis products, and the metabolites of qinghaosu
in vivo mentioned above. After careful chromatography, a miner product epoxide
157 was identified. In addition, acetylation of the remaining high-polarity products
yielded the acetyl tetrahydrofuran compound 158. Based on the analysis of these
products, a reaction mechanism of an oxygen-centered free radical followed by
single- electron rearrangement was suggested in 1995-1996 (Scheme 5-25).
278
Since then, several qinghaosu derivatives have been treated with ferrous sulfate
in the same reaction condition. Except for some hydrolysis products, similar deri-
vatives of tetrahydrofuran compound 28 and 3-hydroxy deoxyqinghaosu 15 were
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