Chemistry Reference
In-Depth Information
concluded that allylic hydroperoxide (49) are the key intermediate in the conversion
of 23 to 1 and its other congeners, and this conversion may not need to invoke the
participation of enzymes.
154
This biogenetic synthesis has been employed to pre-
pare isotopic-labeled qinghaosu.
155
Since the 1990s, several attempts have been
made to enhance qinghaosu production in the cell and tissue culture by omittance
or addition of medium components, precursor feedings, and modulating the bio-
synthesis route,
149,156
but at this time, the biosynthesis approach is still an academic
method to provide this antimalarial drug.
On the other hand, the progress in the production of qinghaosu is also made from
the selection and breeding of high-yielding cultivars.
157,158
In this respect, hybrid
lines containing up to 1.4% qinghaosu on a dry leaves basis have been obtained by
selection and crossing, in wild populations, of genotypes with high qinghaosu
concentration.
The genetic engineering of qinghao (A. annua) has also been paid great attention
recently; some preliminary results about the early stage of qinghaosu biosynthesis
have been reported. For example, amorpha-4,11-diene synthase, an enzyme respon-
sible for the cyclization of farnesyl diphosphate into ring sesquiterpene, has been
expressed in Escherichia coli and production of amorpha-4,11-diene (122) was
identified.
159,160
5.5
DERIVATIVES AND ANTIMALARIAL ACTIVITY
Early pharmacological and clinical studies showed that qinghaosu possessed fast
action, low toxicity, and high activity on both drug-resistant and drug-sensitive
malaria, even if the severe patients suffering from cerebral malaria could rapidly
recover after nasal feeding of qinghaosu. However, the high rate of parasite recru-
descence was observed. There was great need for improvement on the inconvenient
administration and the high recrudescence rate.
It has been noted that qinghaosu has a special structure bearing peroxy group
and rare -O-C-O-C-O-C-O segment, which is different from that of all known
antimalarial drugs. In the primary chemical structure-activity study,
96,97
the func-
tion of the peroxy group for antimalarial activity was first examined. The negative
result of deoxyartemisinin for the antimalarial activity against Plasmodium berghei
in mice showed that the peroxy group was essential. Soon afterward, it was found
that some other simple peroxides including monoterpene ascaridol had no activity.
These facts demonstrated that the peroxy group was an essential, but not a suffi-
cient, factor.
When dihydroartemisinin was found to be more active than qinghaosu and the
introduction of the hydroxy group into the molecular nucleus could not improve its
solubility in water, three types of dihydroartemisinin derivatives were synthesized
and evaluated in China (Scheme 5-9).
96,97,161
The first 25 compounds (in oil solution) were tested in the mice-infected
chloroquine-resistant P. berghei by administration of intramuscular injection.
162
Most
of these derivatives showed more activity than qinghaosu and dihydroartemisinin.
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