Hydrolysis/decarboxylation would initially remove
one carbon from the iridoid portion and produce
corynantheal.An intermediate of the cinchonamine
type would then result if the tryptamine side-chain
were cleaved adjacent to the nitrogen, and if this
nitrogenwere then bonded to the acetaldehyde function.
Ring opening in the indole heterocyclic ring could generate new amine and keto functions. The
new heterocycle would then be formed by combining
this amine with the aldehyde produced in
the tryptamine side-chain cleavage. Finally, reduction
of the ketone gives
cinchonidine or
cinchonine.
Hydroxylation and methylation at some stage
allows biosynthesis of
quinine and
quinidine. Quinine
and quinidine, or cinchonidine and cinchonine,
are pairs of diastereoisomers, which have opposite
chiralities at two centres (Figure 88). Stereospecific
reduction of the carbonyl in cinchoninone can
control the stereochemistry adjacent to the quinoline
ring (C-9). The stereochemistry at the second
centre (C-8) is also determined during the reduction
step, presumably via the enol form of cinchoninone
(Figure 90).
 |
| Figure 88 |
 |
| Figure 89 |
 |
| Figure 90 |
Cinchona
Cinchona bark is the dried bark from the stem and root of species of
Cinchona (Rubiaceae),
which are large trees indigenous to South America. Trees are cultivated in many parts of
the world, including Bolivia, Guatemala, India, Indonesia, Zaire, Tanzania, and Kenya. About
a dozen different Cinchona species have been used as commercial sources, but the great
variation in alkaloid content, and the range of alkaloids present, has favoured cultivation of
three main species, together with varieties, hybrids, and grafts.
Cinchona succirubra provides
what is called 'red' bark (alkaloid content 5-7%), C.
ledgeriana gives 'brown' bark (alkaloid
content 5-14%), and C.
calisaya 'yellow' bark with an alkaloid content of 4-7%. Selected
hybrids can yield up to 17% total alkaloids. Bark is stripped from trees which are about 8-12
years old, the trees being totally uprooted by tractor for the process.
A considerable number of alkaloids have been characterized in cinchona bark, four of which
account for some 30-60% of the alkaloid content. These are quinine, quinidine, cinchonidine,
and cinchonine, quinoline-containing structures representing two pairs of diastereoisomers
(Figure 88). Quinine and quinidine have opposite configurations at two centres. Cinchonidine
and cinchonine are demethoxy analogues, but unfortunately use of the -id- syllable in the
nomenclature does not reflect a particular stereochemistry. Quinine is usually the major
component (half to two-thirds total alkaloid content) but the proportions of the four alkaloids
vary according to species or hybrid. The alkaloids are often present in the bark in salt
combination with quinic acid or a tannin material called cinchotannic acid.
Cinchotannic acid decomposes due to enzymic oxidation during processing of the bark to
yield a red pigment, which is particularly prominent in the 'red' bark.
Cinchona and its alkaloids, particularly
quinine, have been used for many years in the
treatment of malaria, a disease caused by protozoa, of which the most troublesome is
Plasmodium falciparum. The beneficial effects of cinchona bark were first discovered in South
America in the 1630s, and the bark was then brought to Europe by Jesuit missionaries.
Religious intolerance initially restricted its universal acceptance, despite the widespread
occurrence of malaria in Europe and elsewhere. The name cinchona is a mis-spelling derived
from Chinchon. In an often quoted tale, now historically disproved, the Spanish Countess
of Chinchon, wife of the viceroy of Peru, was reputedly cured of malaria by the bark. For many years, the bark was obtained from South America, but cultivation was eventually
established by the English in India, and by the Dutch in Java, until just before the Second
World War, when almost all the world's supply came from Java. When this source was
cut off by Japan in the Second World War, a range of synthetic antimalarial drugs was
hastily produced as an alternative to quinine. Many of these compounds were based on the
quinine structure. Of the wide range of compounds produced,
chloroquine, primaquine,
and
mefloquine (Figure 91) are important antimalarials. Primaquine is exceptional in
having an 8-aminoquinoline structure, whereas chloroquine and mefloquine retain the 4-
substituted quinoline as in quinine. The acridine derivative
mepacrine (Figure 91), though
not now used for malaria treatment, is of value in other protozoal infections.
Halofantrine(Figure 91) dispenses with the heterocyclic ring system completely, and is based on
phenanthrene. At one time, synthetic antimalarials had almost entirely superseded natural
quinine, but the emergence of
Plasmodium falciparum strains resistant to the synthetic
drugs, especially the widely used prophylactic chloroquine, has resulted in reintroduction
of quinine. Mefloquine is currently active against chloroquine-resistant strains, but, whilst
ten times as active as quinine, does produce gastrointestinal upsets and dizziness, and
can trigger psychological problems such as depression, panic, or psychosis in some
patients. The ability of P.
falciparum to develop resistance to modern drugs means malaria
still remains a huge health problem, and is probably the major single cause of deaths
in the modern world.
Chloroquine and its derivative
hydroxychloroquine (Figure 91),
although antimalarials, are also used to suppress the disease process in rheumatoid
arthritis.
 |
| Figure 91 |
Quinine (Figure 88), administered as free base or salts, continues to be used for treatment
of multidrug-resistantmalaria, though it is not suitable for prophylaxis. The specific mechanism
of action is not thoroughly understood, though it is believed to prevent polymerization of toxic
haemoglobin breakdown products formed by the parasite. Vastly
larger amounts of the alkaloid are consumed in beverages, including vermouth and tonic
water. It is amusing to realize that gin was originally added to quinine to make the bitter
antimalarial more palatable. Typically, the quinine dosage was up to 600 mg three times a day. Quinine in tonic water is now the mixer added to gin, though the amounts of quinine used
(about 80 mg l
−1) are well below that providing antimalarial protection. Quinine also has a
skeletal muscle relaxant effect with a mild curare-like action. It thus finds use in the prevention
and treatment of nocturnal leg cramp, a painful condition affectingmany individuals, especially
the elderly.
 |
| Figure 92 |
 |
| Figure 93 |
Camptothecin* (Figure 93) from
Camptotheca
acuminata (Nyssaceae) is a further example of
a quinoline-containing structure that is actually
derived by modification of an indole system. The
main rearrangement process is that the original β-
carboline 6–5–6 ring system becomes a 6–6–5
pyrroloquinoline by ring expansion of the indole heterocycle (Figure 92). In camptothecin, the
iridoid portion from strictosidine is effectively
still intact, the original ester function being utilized
in forming an amide linkage to the secondary
amine. This occurs relatively early, in
that
strictosamide is an intermediate.
Pumiloside(also isolated from C.
acuminata) and
deoxypumilosideare potential intermediates. Steps
beyond are not yet defined, but involve relatively
straightforward oxidation and reduction processes
(Figure 93).
