Alkaloids derived from Tryotophan by addition of C9 or C10
(Terpenoid Indole Alkaloids )
* They are are distributed in three families which are :
- Rubiaceae
- Apocynaceae
- Loganiaceae
* These alkaloids are based on the condesation between tryptamine and
secologanine (which is a large structure that possess 9 carbons ) .
Note : strictosidine is the parent compound resulted from the condensation , secondary
modifications will occur on it to produce the different alkaloids of this class .
* The condensation is identical to that used for the production of compounds
derived from tryptophan + C2 , but here we are using C9 or C10 instead of C2 .
* How secologanine is produced ?
--> By splitting of loganine .
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* Secologanine can occur in the form of Corynanthe group , Aspidosperma
and Iboga groups .
The exact structure of each type of these groups is not to be memorized.
*The typical group is Corynanthe group and the two other groups are resulted
by rearrangement of the Corynanthe skeleton .
* The simplest way to form beta -carboline and Indolenine is by using the
Corynanthe group .
* We have two types of cyclization as we mentioned in the alkaloids derived
from tryptophan + C2 , which are :
- By using the alpha carbon to the (N) atom ( carbon at position 2 ) in tryptamine
, and the compound produced will have Beta -carboline structure .
- By using the beta carbon to (N) atom ( carbon at position 3 ) in tryptamine ,
and the compounds produced will have Indoledine structure .
* These two carbons ( alpha carbon and beta one ) are the important carbons
that are used in the condensation .
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* The aldehyde group in secologanine is the group which is used in the
condensation with the alpha or beta carbons of tryptamine .
We will start discussing the plants that have this type of alkaloids :
Rauwolfia Serpentina ( Apocynaceae ) :
* Its common name is Snakeroot .
* Rauwolfia has been used in Africa for hundreds of years, and in India for at
least 3000 years. It was used as an antidote to snake-bite, it was used to treat
all diseases from snake bite until mental disorders .
* Rauwolfia root ecxtract :
- Clinical tests showed the drug to have excellent antihypertensive and sedative
activity. It was then rapidly and extensively employed in treating high blood
pressure and to help mental conditions, relieving anxiety and restlessness, and
thus initiated the tranquillizer era. The ‘cure for insanity’ was thus partially
justified, and rauwolfia was instrumental in showing that mental disturbance has
a chemical basis and may be helped by the administration of drugs.
- In the past the root extract was used to lower BP and as sedative tranquilizing
agent . Later on the pure compounds ( reserpine , serpentine , rescinnamine )
have been isolated and they started to use pure compounds instead of root
extract , but it has been found that when the patients used pure reserpine the
suffered from sever depression which may end up by suicidal attempt , so they
returned again for the use of root extract rather than the pure compound .
* Rauwolfia contains Indole alkaloids which are obtained from roots .
* These alkaloids are : Reserpine , Rescinnamine , Deserpidine , Serpentine ,
Ajmaline , Ajmalicine .
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* These alkaloids can be subdivided into three groups : Reserpine , Serpentine
, Ajmaline , and they can be separated depending on their basicity , the most
basic one is serpentine , the intermediate one is the ajmaline , and the least
basic are reserpine and rescinnamine .
* Serpentine is a beta-carboline , it is yellow in color because it is conjugated , it
is a crystalline compounds .
* Reserpine has a historical importance because it is the first compound that
was used for treatment of different disorders ( hypertension ) . It has known
utilization from the clinical point of view for its sedative and tranquilizing
activity .
* Reserpine has also been suggested to play a role in the promotion of breast
cancers .
*Ajmaline is the compound which is still used until now as a pure compound
,neither resrpine nor serpentine are of therapeutic use now , ajmaline is used to
control cardiac arrhythmia .
* Ajmalicine = ( Raubasine ) is used as : spasmolytic , anxiolytic and antihypertensive agent .
* These alkaloids are all based on the condensation of tryptamine with
secologanine (C9 ) , they are beta-carboline compounds and a few of them are
Indolenine alkaloids .
Notes about the biosynthesis of these alkaloids :
* The biosynthesis will start from the condensation of tryptamine and
secologanine and the parent compound will be formed , but the biosynthesis
process is not finished by condensation only because you can notice when you
look to the structures of these alkaloids that they are huge in structure , so
there is secondary modifications to the parent compound which is produced
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from this condensation which are : hydroxylation , methylation , esterification
for the free hydroxyl groups with trimethoxy benzoic acid or trimethoxy
cinnamic acid , note that it is not necessary to have all types of modification in
the same compound .
Yohimbe bark (Pausinystalia yohimbe; Rubiaceae) :
* The active ingredient Yohimbine has an importance until now in the treatment
of male impotence specially in diabetic patients , it is not a safe drug because it
has dose dependent hypotensive or hypertensive activity .
* From the recent studies , it has been found that yohimbine has effect on
adipose tissue so it can be useful for the treatment of obesity . These studies
are only trials which are trying to discover that this compound has activity on
adipose tissue but it is not utilized yet .
Nux-vomica :
* Nux-vomica consists of the dried ripe seeds of Strychnos nux-vomica
(Loganiaceae) .
* The active ingredients are Strychnine and Brucine (Indolenine alkaloids ) ,
from medicinal point of view they have low interest . They are toxic and bitter ,
Strychnine is very very bitter and it is more toxic than brucine .
* 100 mg of strychnine is fatal to 70 Kg adult . 60 mg can be fatal depending on
the body weight .
* Its only medicinal use is in very small doses as an appetite stimulant and
general tonic, sometimes with iron salts if the patient is anaemic .
* Strychnine can be used in a very small doses as an appetite stimulant because
it is very bitter and in a very small doses it can stimulate the secretion of the
gastric juices .
* Nowadays its only use is as a poison for the rats (vermin killer ).
* Loss of All body hair is one of its toxicities when it is used bu humans .
*Brucine is less toxic than Strychnine , and its used in some countries for the
denaturation of alcohol .
*Strychnin is very toxic , and it’s a derivative of Brucin , also Strychnin is used
as vermin killer especially for moles .
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*Strychnous toxifira and its constituent Toxifirine are very toxic , but
Toxifirine has the activity similar to D.tuberculin (as muscle relaxant)
*toxicity of Strychnine is similar to tetranol toxicity paralysis, CV events,
noise, headache.
*Toxifirine is dimeric compound of Wieland Gumlich aldehyde.
*there are more than one type of Toxifirin ( Toxifirin 1 , 2 , 3 )
*Aleuronium is semi-synthetic muscle relaxant produced from Toxifirin .
*Toxifirin are ingredients of Loganicaeous curare also .
Venca Alkaloids
*Viniblastine and Vincristine are anti-cancer compounds from Catharanthus
raserus and Venca rosera . they are antimitotic agents , but they cause serious
neurotoxicity .
*other disadvantage of them is their low concentration in nature (we need 5000
Kg of their leaves to produce 1 g of them !!)
*Venicristine has more pharmacological activity than Viniblastine.
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*** NOTE ***
When we say Dimeric alkaloids , this means that the alkaloid composed of two
IDENTICAL units . while when we say Binary alkaloids , this means that its
composed of two NON IDENTICAL units .
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*Vincristine is obtained from oxidation of N-methyl of Vinblastine.
*they and other primary important Venca alkaloids are composed of two
monomeric units (Catharantine and Vendoline) .. notice that these two dimmers
are not identical they’re binary alkaloids.
*Different anhydroderevatives can be formed also , they are biologically active
but they posses a lot of side effects especially cytotoxixity .
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*Vendisine is semi-synthetic derivative of Viniblastine , and used for acute
lymphoid leukemia .
*Venorelbine is a semi-synthetic derivative also , but the most important thing
about it is that its an oral anticancer agent (unlike other anticancer agents
which are IV drugs). The side chain of it is shortened by one carbon unit from
the original amino acid for its synthesis “tryptophan” .. and its used for
childhood leukemia.
*Vinca rosea and Vinca minor , both are close in their shape , they are from same
genus but different species.
Vinka
The Madagascar periwinkle Catharanthus roseus (= Vinca rosea) (Apocynaceae)
is a small herb or shrub originating in Madagascar, but now common in the
tropics and widely cultivated as an ornamental for its shiny dark green leaves
and pleasant five-lobed flowers. Drug material is now cultivated in many parts of
the world.
The plant was originally investigated for potential hypoglycaemic activity
because of folklore usage as a tea for diabetics. Although plant extracts had no
effects on blood sugar levels in rabbits, test animals succumbed to bacterial
infection due to depleted white blood cell levels (leukopenia), though no other
adverse effects were apparent. The selective action suggested anticancer
potential for the plant, and an exhaustive study of the constituents was
initiated. The activity was found in the alkaloid fraction, and more than 150
alkaloids have since been characterized in the plant. These are principally
terpenoid
indole alkaloids, many of which are known in other plants, especially from the
same family. Useful antitumour activity was demonstrated in a number of
dimeric indole alkaloid structures (more correctly, bisindole alkaloids, since the
‘monomers’ are different), including vincaleukoblastine, leurosine, leurosidine,
and leurocristine.
Vinka rosea and Vinka minor are very similar to each other same genius but
different species (Apocynaceae) Independent of vinka minor vinka rosea is
cultivated as an ornamental plant.
Vinca minor is another representative of the strains vinka and main constituent
is vincamine. Vincamine is a monoterpen indole alkaloid (min 35:56) it’s used in
the treatment of the difficult feeding bonds. Because it’s processing astringent
activity. vincamine also improve the cerebral blood flow by increasing the oxygen
and glucose consumption so it’s used primarily in the treatment of samility (min
36:25) it delay not improve the disease. Vincamine is not a safe compound.
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***Vincamine sometimes are used in the treatment of disorders of the vascular
origin ………….
Certain disease having vascular origin processing vasodilator (vincamine is
vasoconstrictor).
They do not produce anticancer agent*** (min 36:41 – 37:27)
Ellipticine (Apocynaceae)
Another anticancer agent is the Ellipticine or orchrosia ellptica it’s a βcarbonate type of compound. Clinical trials with these alkaloids and a number of
synthetic analogues showed them to be potent inhibitors of several cancerous
disorders, but preclinical toxicology indicated a number of side-effects,
including haemolysis and cardiovascular effects. Ellipticines are planar molecules
that intercalate between the base pairs of DNA and cause a partial unwinding of
the helical array. Recent research suggests they also inhibit the enzyme
topoisomerase. Ellipticine is oxidized in vivo mainly to 9-hydroxyellipticine, which
has increased activity, and it is believed that this may in fact be the active
agent. Poor water solubility of ellipticine and derivatives gave problems in
formulation for clinical use, but quaternization of 9-hydroxyellipticine to give
the water-soluble 9-hydroxy-2-N-methylellipticinium acetate (elliptinium
acetate). It’s under clinical investigation.
Cinchona (Rubiaceae)
Very known representor of the amino acid tryptophan are quinine, quinidine,
cinchonidine, and cinchonine. They make up to 60% of the alkaloid among them
quinine is the major compound.
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Quinine: C#8 is S and C#9 is R //// Quinidine C#8 is R and C#9 is S (quinine
and quinidine have opposite stereochemistry)
Quinine and cinchonidine are different in the presence of the methoxy group
with same stereochemistry
Quinidine and cinchonine also have the same stereochemistry and differ in the
presence of methoxy group in quinidine.
Cinchonidine and cinchonine are demethoxy analogues of quinine and quinidine
respectively; 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 two epimers cinchonidinone and cinchoninone equilibrate readily in the plant
through keto–enol tautomerism. Finally, reduction of the ketone group 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, and have opposite chiralities at two
centres, C-8 and C-9 .The stereochemistry at C-8 is easily reversed by
tautomerism in cinchonidinone and cinchoninone as described above. The
stereochemistry adjacent to the quinoline ring (C-9) is controlled by the
reduction step. An enzyme catalysing the reduction of cinchoninone produces an
unequal mixture of cinchonine and cinchonidine, showing that the
stereochemistry of reduction may somehow depend upon the substrate. Cinchona
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and its alkaloids, particularly quinine, have been used for many years in the
treatment of malaria
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%), Cinchona ledgeriana gives ‘brown’ bark (alkaloid content
5–14%), and Cinchona calisaya ‘yellow’ bark with an alkaloid content of 4–7%.
Selected hybrids can yield up to 17% total alkaloids.
Quinine administered as free base or salts, continues to be used for treatment
of multidrug-resistant malaria.
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.
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 cramps, a
painful condition affecting many individuals,
especially the elderly.
Until recently, quinidine was used to treat cardiac arrhymias. It inhibits
fibrillation, the uncoordinated contractionof muscle fibres in the heart.
However, it is rapidly absorbed by the gastrointestinal tract and overdose can
be hazardous, leadingto diastolic arrest. This has effectively curtailed its use.
Quinidine, cinchonine, and cinchonidine also have antimalarial properties, but
these alkaloids are not as effective as quinine. The cardiac effect makes
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quinidine unsuitable as an antimalarial. However, mixtures of total Cinchona
alkaloids, even though low in quinine content, are acceptable antimalarial agents.
This mixture, termed totaquine, has served as a substitute for quinine during
shortages.
Cinchona and its alkaloids, particularly quinine, have been used for many years in
the treatment of malaria, , it was used as safe analgesic up to the 50s or 60s
“for common headache” with the safe drugs now its not used as analgesic
anymore , Until recently, quinidine was used to treat cardiac arrhymias.
Quinine is not a synthetic compound it’s a natural compound , it’s the secondary
metabolite of the cinchona bark , that was first found in south America , it
wascultivated world wide especially in china and the eastern part of asia .
When this source was cut off by Japan in the Second World War, a range of
synthetic antimalarial drugs was hastily produced as alternatives to quinine.
Many of these compounds were based on the quinine structure. They took the
quinline and substituted it with an amino group , a wide range of compounds was
produced, chloroquine, primaquine, and mefloquine.
Primaquine is exceptional in having an 8-aminoquinoline structure, whereas
chloroquine and mefloquine retain the 4-substituted quinoline as in quinine.
The ability of Plasmodium falciparum a” protozoa “ 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. It is estimated that 200–
500 million people are affected by malaria, So it’s a come back to the nature , to
the natural quinine.
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
cramps, a painful condition affecting many individuals, especially the elderly.
Vastly larger amounts of the alkaloid Quinines are consumed in beverages
industry , including vermouth and tonic water.
Long time use of quinines cause hearing impairment, particularly high-frequency
loss. Although some studies suggest that this high-frequency hearing
impairment is reversible, it has not been conclusively established whether such
impairment is temporary or permanent .
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Camptothecin
It’s obtained from Camptothecaacuminata (Nyssaceae) , it is a further example
of a quinoline-containing structure that is derived in nature ,it grows in high
altitudes “Himalayas”, all parts of the tree “ bark ,leaves ,roots” contain
Campatothecin.
Camptothecin derivatives have provided some useful anticancer drug in china , in
many clinical trials its used to treat different kinds of carcinomas.
Camptothecin is a nature compound originated from the Chinese tree
Camptotheca acuminate of the family (Nyssaceae) , all parts of this tree obtain
alkaloids seeds , leaves, barks …
This plant was used in china for the treatment of cancer In limited clinical
trials, camptothecin showed broad-spectrum anticancer activity,
but toxicity and poor solubility were problems
it is s quinoline based alkaloid
Semi-synthetic analogues (9-aminocamptothecin) and the water-soluble
derivatives topotecan and irinotecan showed good responses in a number of
cancers; topotecan and irinotecan are now available for the treatment of ovarian
cancer and colorectal cancer respectively
about the structure we are dealing with the amino acid tryptophan to yield our
b-cabonyl derivative ,, it is a 6-membered ring all carbons are linked together
that includes a pyrrolo[3,4-β]-quinoline moiety (rings A, B and
C), conjugated pyridone moiety (ring D) and one chiral center at position 20
within the alpha-hydroxy lactone ring , it is (6-5-6) b-carbonyl compound when
we have an indole derivative it is changing from (6-5-6) to a (6-6-5) so we are
obtaining a pyrolidine ring (5-membered ring) and the quinoline ring ,, has a very
potent biological activity
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The clinical utilized ones Irinotecan is a carbamate pro-drug by physostigmine ,
when it is administered in the liver it will be converted to the active drug of the
10-hydroxy camptothecin
topotecan is a substituted derivative of camptothecin , and can be used clinically
for the treatment of cancers
something interesting to say that camptothecin and it's derivatives can be
obtained from fungi (endophiles ) not a parasitic type , they cope with the
production of the secondary metabolites that are living in the plant itself not in
sea ,, as Low concentrations of camptothecin have also been detected in cultures
of an unidentified fungus isolated from the inner
bark of Nothapodytes foetida
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If something about the last plant (camptothecin) is not clear you can refer to
the below information from the book .
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GOOD LUCK
Done By :
Deema Mohammed, Rokaya Shroukh Ghoujal, Yasmin Abuali,
Naffin Yanal, Lina Zahran
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