Download L23-24-25 Alkaloids Medicinal Plants

We talked previously about alkaloids, we have mentioned the Isoquinoline and
Tetrahydroisoquinoline, these are common in plant Papaver somniferum, Quinolone
and its structural isomer, Iso quinolone, in addition to tetrahydroisoquiniloine, these
alkaloids are wildly spread in different plants, also we have benzyl isoquinoline and
benzyl tetrahydroisoquinoline, which are common constituents in the opium.
Their biosynthesis starts with two molecules of tyrosine which is an aromatic
amino acid, one of these tyrosine moieties will be decarboxylated to give Tyramine,
and subsequent hydroxylation step will convert Tyramine to dopamine, the second
tyrosine molecule will go Transamination reaction and will be converted to its
corresponding keto-acid ( 4-OH phenyl pyruvic acid) , keep in mind that always the
a.a that goes under transamination reaction, it will donate the amino group and be
converted to the corresponding keto-acid, after the formation of the keto-acid, there
will be a decarboxylation followed by a reduction reaction, we will obtain (4-OH
phenyl acetaldehyde) , the final step is the condensation of Dopamine with 4-OH
phenyl acetaldehyde, and intermediate will be formed which is very important for the
formation of benzyl tetrahydroisiquinoline, ( S-norococlaurine) , notice that we are
forming the benzyl tetrahydroisoquinoline and then it will be converted to
isoquinoline,
by simple dehydrogenation reaction,
so the formation of Snorococlaurine is very important for the formation of benzyl tetrahydroisoquinoline
and benzyl isoquinoline alkaloids, the process of synthesizing alkaloids involves
many complex reactions, to end up by the formation of morphinan alkaloids, this
requires the conversion from the S to the R compounds, actually the conversion of
the S-norococlaurine to the benzyl isoquonilne is some what more simple , and the
resulting compomd in its simplest form will be papverine (it is also an opium
alkaloid), again papaverine synthesis is simpler than morphinan alkaloid synthesis.
Morphinan alkaloids, (thebaine, morphine, codeine), positions three and six are
important, also there is an ether linkage between carbons 4 and 5, now positions
three and six are important as they determine the substitution pattern that enables
us to distinguish between the three types of the morphinan alkaloids, You Have To
Memorize The Substitution pattern Of These Three Morphinan Alkaloids , the
conversions between these molecules are not simple as you think, you should keep
in your mind that the conversion involves many intermediates. Why is this
important? For example, codeine, which is the most utilized morphinan alkaloids,
when it is needed in large proportions, we can rely on such conversion reactions to
convert morphine (by methylation) and thebaine (by demethylation) to codeine.
These substitutions are important as we can invest them in the isolation
process, morphine for example is characteristic by having an alcoholic and phenolic
hydroxyls , these free hydroxyl groups are important in the molecule metabolism as
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they can be attached with glucouronic acid moieties, which are eliminated in form of
glucouronates.
The morphinan alkaloids were named in old literature as “phenanthrene
derivates”, which indicates the presence of 3cyclic rings in the structure; they were
studied as phenanthrene derivates of opium.
Opium refers to the air-dried, extracted milky juice obtained from the unripe
fruits of Papaver somniferum L.Papaveraceae , in Jordan we have Papaver rajus “ ‫شقائق‬
‫”النعمان‬, their capsules are smaller and longitudinal rather than round shaped capsules
as that of the papaver somniferum, so there are some morphological differences
between these 2 plants, but P. rhoeas does not produce opium, now to extract the
opium from P.somniferum , we have to detect the color changes of the capsule to the
yellowish color, then the cuts are made vertically or horizontally according to method
that is followed in the cultivating country , then the milky juice usually exudates
without pressing the capsule, the milky exudate will harden to a brownish material,
this brown material will be scraped so as not to clog the cuts, and accordingly the
capsule will undergo rounds of scrapping to get the full exudate, this takes around 23 days, the collected brownish gummy material is called crude opium. It will be
shaped to different arrangements (i.e cake-shaped) then segmented to different
segments with different weights, the crude opium is processed and standardized and
used to form opium tinctures or utilized for the extraction of different principles,
you have to keep in mind that there are regulation and control about the cultivation
and the utilization of opium.
The process of cutting is a skilled process, when you make deep cuts in the
capsule, the milky tubes are usually connected, but by deep cutting , instead of
getting the juice getting outward, it will go inward, and there will be a very low yield
of opium.
The extraction of opium is exclusively confined to P.somniferum, but by the
continuous research, it was found that in Papaver bracteatum , the biosynthesis of
the opium alkaloids stops at the formation of thebaine, when this plant is harvested
and submitted to extraction, there will be a high yield of thebaine, and also its
growth is not restricted climatically to hot areas, note this plant (its cultivation is
governed also ) is utilized for its high yield of thebaine alongside its wide cultivation
among different climates, and the chemically extracted thebaine is converted to other
semisynthetic derivatives.
Thebaine by itself does not have analgesic activity, and it is considered as raw
material for the semi synthesis of different derivatives, (semisynthetic codeine and
semisynthetic morphine)
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The seeds of P.somniferum and P.bracteatum lack alkaloids, so they are used
for the expression of fixed oils used in cooking, the oils are free of alkaloids and used
for the preparation of margarine.
The opium is extracted from the roots of P.somniferim and the aerial parts of P.
bracteatum
Opium is the richest-alkaloid drug, Phenolic alkaloids are usually occurring in
their free form or in form of their salts, we have organic acids that form esters with
alkaloids, just in P.sominefrum , there is meconic acid that binds with alkaloids found
in this plant to form esters, it is a dicarboxylic acid, it is used for the analytical
method of identification of P.somniferum alkaloids, it reacts with ferric chloride to give
a very intense red color, the extracted opium contains different principles in addition
to alkaloids.
There are different classes of alkaloids , written in your sheet, study them .
The opium alkaloids are utilized for their medicinal values, used to synthesize
different semisynthetic derivatives, we have actually synthetic analogues of opium
alkaloids, called “opioids”, that possess analgesic activity, the point of producing the
semisynthetic and synthetic analogues is that morphine is a standard analgesic,
usually other analgesics are compared for their potencies with morphine, but it is
also a strong narcotic, so usually the semisynthetic and synthetic analogues are
prepared so as to get the same level of analgesia but with less CNC effects (addiction,
tolerance).
Morphinan alkaloids derivatives:
 Etorphine : 10X more potent that morphine, it is a derivative of thebaine.
 Buprenorphine : derivative of thebaine
 Naloxone :
symptoms
semisynthetic
compound
that
antagonizes
the
withdrawal
 Ethyl morphine : obtained by treatment of morphine with ethyl iodide , it is
analgesic and less addictive than morphine,
 Hydromorphone : analgesic but less than morphine
 Diacetyl morphine(heroin) : stronger analgesic than morphine, as the 2 OH at C
3+6 are converted to acetyl groups so the whole compound is lipophilic and
able to penetrate the CNS, it was used as cough suppressant , but addiction
developed after 3 weeks of parenteral administration, the patient suffered from
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physical withdrawal symptoms, so heroin is not therapeutically utilized , but it
is used to terminate the pain suffered by AIDS patients,
 Apomorphine ; dehydrated morphine, strong emetic drug, given IV so as emesis
will be observed immediately after administration,
Papaverine is known for its addictive properties, narcotic, anti-spasmodic agent,
smooth muscle relaxant with vasodilatory activity, in the last few years it was used
for the treatment of male impotence, given topically for this indication.
It is a bnzyl isoquinoline derivative …
 Narcotine : was previously named for its narcotic properties, and later on, they
discovered that it did not possess any narcotic activity and its name was
changed to noscapine, also noscapine lost its pharmacological activity as cough
suppressant as it is teratogenic.
 Morphine is the most important alkaloid, it affects almost all body systems, it
affects the CNS resulting in euphoria and drowsiness, it constricts the pupil
(meiosis), it has depressant activity on the respiration, it increases the
production of GIT juices so this results in GIT disturbances (nausea, emesis,
constipation),
Opium tinctures are used in hemorrhoid preparation,
first.
but they are standardized
 Codeine is widely used as cough suppressant.
 Thebaine is the least utilized morphinan drug, it is used mainly as raw
material.
Tetrahydroisoquiniloine
alkaloids
are
derived
from
the
roots
of
Cephalis ipecacuanha L.Rubiaceae, it is a south American plant, and the most two
important constituents are: emetine and cephaline, the difference between them is
that emetine is the methylated cephaline, the use of emetine is not confined to its
characteristic emetic properties, but it is used also in the treatment of amoebic
dysentery, and at low concentrations it is used as expectorant, the crude extracts in
form of syrups are used as emetics, these active principles have 2 molecules of
tetrahydroisoquinoline, what links these 2 tetrahydroisoquinoline is 9 carbons , the
origin of them is secologanin, we have psychotrine and O-methyl psychotrine, they
are the common dehydrogenation products of cephaline and emetine respectively,
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Curare refers to collectively water extracted arrow poisons, but curarine is a
pure isolated alkaloids, usually it is used by Indian for hunting purposes, curare are
prepared from Chondrodendron tomentosum ( an example on plants contain
tetrahydrquinoline alkaloids) , or other plants ( Strychnos spp
), and these
Strychnos spp yield strychnine as the toxic principle, again notice that these
tetrahydrquinoline alkaloids could be found in form of their dimers.
These principles are well known for their muscle relaxing activity, actually their
potencies were determined by doing in vivo experiments on monkeys “ monkey tests”,
as the monkey climbs less number of trees, this indicates the greater potency of the
injected arrow poison.LOL!.
So they were counting the trees the monkey could jump after injecting the
arrow poison.
Tubocurarine is used as a short muscle relaxant especially in abdominal
surgery, it competes with Ach at the muscarinic receptors,
its actions are
antagonized by the use of Ach esterase inhibitors i.e. pyridostigmine, also it is used
in the treatment of myasthenia gravis, tetanus.
Tubocurarine : is a benzyl tetrahydrquinoline alkaloids, by phenolic oxidation,
an ether linkage will be formed between the 2 monomers, notice there could be 2
identical (R+R), (S+S) or (R+S) norcoclaurine molecules involved in the structure.
Notice the presence of the mono quaternary (positively charged )amine, its
presence renders the structure water soluble, actually for long time, they were
thinking as this compound possessed Di quaternary amine parts, and accordingly
the first synthetic analogue “Decamethonium” was synthesized based on this idea (
the structure had possessed Di quaternary amine), in addition to that the distance
between these Di quaternary amines is 10 carbons.(Deca; 10 C)
 In suxamethonium : there were 2 acetyl choline units , joined together to from the
structure.
 Atracurium is close to papaverine. Used as muscle relaxant
Indole alkaloids
Based on tryptophan a.a, Decarboxylation to get the biogenic amine, we will obtain
the indole alkyl amine, so they are the decarboxylated derivatives of l-tryptophan,
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then the resulting structure will undergo different modifications to get : 5hydroxylated derivative (serotonin), N-methylated derivative (Psilcon), etc…
Notice the 2 cyclic nitrogens in the structure of eserine
 PlZ go back and check your slides,,,, the structures are IMPORTANT
AND read every single detail written in your slides about : serotonin, melatonin,
Psilocybe spp and serine :]
 Ordeal poison : =D..Interestingly, in the past the calabar beans (containg the
physiosygmine) were used as method of judgement, if there was a person who was
suspected of doing an offence, he was given a drink of calabar beans, if he
regurgitated the drink ,it was assumed that he is innocent , but if he died, he
would be then the Guilty and he deserved such a fate..+_+
Now the amino acid tryptophan, combined with 5C part originated from terpenoid
chemistry, gives Lysergic acid, the stereochemistry of C8 is important, we may have
D-Lysergic acid (active form) (erometrine or ergobasine) , or when the COOH group is
in the alpha position , we will obtain the D-isolysergic acid (inactive).
Ergot alkaloids can be structurally divided to simple amides(simplees amides are
formed by adding ammonia), such as ergine.
Ergine : D-lysergic acid amide
 Water soluble and water insoluble derivatives : read your sheet
 Peptide insoluble derivatives are formed by linking 3 A.A to lysergic or isolysergic
acid , to have tricyclic structure.
when we refer to ergot alkalodis, we talk about the parasitic activity of Fungus
Secalum coruntum on Rye(type of cereal) from family Triticeae., the ergot Rye can
affect any grass, but its preferable host is the Rye, it usually affects the ovary, and
the resulting alkaloids are found in the resting body of the fungus, there was a
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problem of ergot poising, the symptoms of such case are : stomach pain and there
was circulatory poising, poising the circulation of the lower extremities, and
palpitation of the extremities. These all are collectively termed as “Ergotism” which
arise upon the prolonged contact with the ergot alkaloids.
 Ergotamine (ergobasine=ergonovine) possesses the oxytocic activity, used to
induce the labor and to control the postpartum hemorrhage, they are based on DLysergic acid
 Methyl ergonovine is the semisynthetic derivative.
 lysergic acid diethylamide it is (LSD)
Read all the notes written in this slide about different alkaloid derivatives.
Last chapter : Quinine and Quinidine derivatives
Quinine and quinidine, cinchonine and cinchonidine, these pairs are differing in
each other in that (cinchonine and cinchonidine) lack the COH3 at C6`.
Quinine and quinidine are stereoisomeric at positions 8 and 9
Quinidine and cinchonine have the same stereochemistry [8R, 9S]
Quinine and cinchonidine have the same stereochemistry [8S, 9R]
Read the slide and memorize their uses.
Notice: quinine synthetic analogues, resistance has emerged against them but not
against the natural compound, also artemicinin (sesquiterpene) is another natural
drug, used as antimalarial.
Quinine in the past was used as analgesic, and its prolonged use resulted in
“Cinchonism”, which is characterized by transient loss of hearing, and blindness.
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