Lecture # 10
Pyrrolizidine , Indolizidine and Quinolizidine Alkaloids
* Some of them are derived from lyscine amino acid and the other from
ornithine amino acid.
* These alkaloids have limited distribution in the nature, they are common
constituents of some animals and plants.
* They are toxic alkaloids.
* pyrrolizidine , indolizidine and quinolizidine alkaloids are similar in their
structure.
* Pyrrolizidine is composed of two pyrrolidine rings , Quinolizidine is composed
of two piperidine rings , Indolizidine is composed of piperidine and pyrrolidine
rings , so they are closely related compounds .
* These alkaloids contain a common nitrogen atom between the their 2 rings,
this nitrogen is at the ring junction and it belongs to the two rings of these
alkaloids .
* Numbering of the atoms in the structure of these alkaloids is not starts
from the heterocyclic atom ( nitrogen ) , the numbering is in a clockwise
manner , by this type of numbering the nitrogen will take the number four
or five according to the type of the alkaloid .
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# We will start with:
pyrrolizidine alkaloids :
* They are characterized by the presence of two fused pyrrolidine rings .
* There is a common nitrogen between these two rings .
* They are based on the presence of two five membered nitrogenous rings ,
we said before that the five membered heterocyclic ring is derived from
the amino acid ornithine . So we will expect theoretically that two molecules
of ornithine should be incorporated into the structure of the pyrrolizidine
alkaloids .
* We don't know exactly if the incorporated ornithin is as its biogenic amine
putrescine or a derivative of the putrescine .
* We are starting with two molecules of the amino acid ornithine , one of
the ornithine molecules will go to the formation of putrescine ( or its
derivative as we said ) , the other ornithine molecule will go to the
formation of a poly-amine which is the spermidine .
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* Then a condensation between parts of the spermidine and putrescine will
yield an obligatory intermediate which is the homospermidine ( Acyclic opened
chain compound ) .
* Homospermidine then via several intermediates will be cyclized to form the
basic alcohols of the phyrrolizidine alkaloids .
* One of the well-known alcohol moieties is the " retronecine" .
* Pyrrolizidine alkaloids have an alcohol moiety (like the tropane alkaloids) ,
so we can add some acids and convert them to their ester alkaloids , the
alcohols are very rarely occurring in a free form in the nature , usually they
are esterified with acids to form the ester alkaloids .
* The basic alcohols in the pyrrolizidine alkaloids carries a suffix " necine " like
the retronecine , so when we see in an alcohol a suffix necine we have to
think that this must be the alcoholic base of the pyrrolizidine alkaloids .
* The characteristics of these necine alcohols :
- All of them are bearing an obligatory hydroxymethyl group to form the
esters and it is on carbon # 1 .
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- Many of them are bearing a second , third or forth hydroxyl groups , the
second alcoholic hydroxyl group are found on carbon number seven , the other
hydroxyl groups are on C3 or C6 .
Note --> The hydroxyl groups on the second , third or forth carbons are not
obligatory BUT the hydroxymethyl group on carbon #1 is obligatory to all
necine alcohols .
*this obligatory –OH in retronecine (alcohole moiety) of all pyroloizidine
alkaloids is involved in the formation of the corresponding esters.
Note all pyrolozidine alkaloids are sharing the same alcohol moiety
(retronecine) but they are differing in the carboxylic acid that has
incorporated in the ester formation.
*Now, let us take a look on the acidic part of the pyrolozidine etser:
Until now a few acids have been encountered in the formation of pyrolozidine
esters, and these acids are:
Rare, C5, C7, C8 or C10 aliphatic acids, mono or dibasic, saturated or
unsaturated and they are headline as –necic acids.
One of these acids is the senecic acid.
Senecic acid
*It is a 10Cs dibasic carboxylic acid, experimental evidence has demonstrated
that it is in fact obtained by the incorporation of two molecules of the
amino acid l-isoleucin
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*senecionine :
The 2 isoleucine units
*it is obtained from Senecio species is a cyclic diester (lacton) of retronecine
(alcohol) with senecic acid.
*1,7 dihydroxy retronecine +
dicarboxylic senecic acid  diester senecionine
(one of the most toxic representative pyrolozidine alkaloids).
*it has been
found that the toxicity of this compound and other related
pyrolozidine alkaloids depends on the presence of the macro lacton ring and
the occurrence of more and more esterified –OHs within the structure.
for example : toxicity will increase in case of having dicarboxlyic acid rather
than mono ,additional –OHs on C2 and C6 on the alcohol moiety and these –
OHs are also esterified.
Note : if we have tiglic acid rather than senecic acid the resulted ester will
be more toxic.
* Pyrrolizidine
alkaloids have a somewhat restricted distribution, but are
characteristic of many genera of the Boraginaceae (e.g. Heliotropium,
Cynoglossum, and Symphytum), the Compositae/Asteraceae (e.g. Senecio and
Eupatorium), and certain genera of the Leguminosae/ Fabaceae (e.g.
Crotalaria), and Orchidaceae.
*
Many pyrrolizidine alkaloids are known to produce pronounced hepatic
toxicity, hepatic tumors and jaundice.
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Note grassing animals feeding with plants containing these toxic materials
can transfer its toxicity to humans.
*Very recently WHO has made a list of plant species containing pyrolozidine
alkaloids and so far they reached the number of about 280 species (it
considers a big number regarding certain areas), 60 of them are medicinal
species used in the traditional medicine of different civilizations as a remedy
for inflammatory, rheumatic, and gastrointestinal disorders but they are
unsafe especially if they are not standardized.
*we will jump to the next subclass,
*Quinolizidine
Alkaloids:
* The lupin alkaloids, found in species of Lupinus (Leguminosae/Fabaceae) and
responsible for the toxic properties associated with lupins, are characterized
by a quinolizidine skeleton (figure below, fused piperideine rings ) ,This
bicyclic ring system is closely related to the ornithine-derived pyrrolizidine
system, but is formed from two molecules of lysine.
*using these two molecules of lysine will end up by the formation of the
basic compound of quinolizidine alkaloids which is Lupinine.
*Quinolizidine
alkaloids are not required to occur as an ester.
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*lupinine
can act as a terminal compound and as an intermediate at the same
time to be used for the addition of a third cadaverine unit.
so 2 molecules of biogenic amine cadaverines yield lubinine and the addition
of a third cadaverine unit give us the more common compound which is
sparteine.
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A third
cadaverine
unit
Now again let’s look at Sparteine, it is also a toxic compound, in the past
it’s used due to it’s medicinal properties now let’s analyse the structure.
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*It’s not water soluble, it’s a tetracyclic molecule, it’s a dymeric Quinolizidine
alkaloids because it has two Quinolizidine nucleus formed by the incorporation
of a third Lysine molecule with definitely two N, and this compound can be
modified by oxidation and eliminating of terminal link and converted from
tetracyclic into tricyclic (Cytisine) in which we have an additional OH group.
*They are very toxic compounds and have a bitter taste, their occurrence in
the nature is restricted to some plants families and subfamilies, we have the
big plant family Leguminose which have subfamilies, one of the subfamilies is
baciunaceae and Fabaceae so these Quinolizidine alkaloids are most commonly
distributed in these subfamilies.
)‫(الترمس‬Lupinus lutens:
*We have sweet variety and bitter variety, sweet variety is what we eat, it’s
rich in protein. Toxic Quinolizidine alkaloids like Sparteine neutralized because it
has a very potent oxytocic activity therefore it’s used in late stages of
pregnancy to enhance the contraction of the uterus( has similar activity to
oxytocin), it’s used in cardiovascular system in the treatment of tachycardia
and in this case it will decrease contractility and excitability of the
myocardial. Nowadays we don’t consider Sparteine in the treatment of
cardiovascular disorders and has no clinical use, in the past it induce head
impotence (side effect), again now from a chemical point of view because of
their toxicity they are not interest.
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*The third subgroup of our chapter is:
3- Indolidizine
*We can consider them as hybrid substances between Pyrrolizidine and
Quinolizidine because it’s five and six member nitrogenous rings with a common
N, here amino acid Lysine is incorporated which means that Piperideine ring
will be formed and the carbons of five member ring must be originated from
whenever else as we have many carbon donors in the biological system
(Acetoacetyl CoA, Malonyl CoA) they are donors of other 2 or 3 or 4
carbons. Malonyl CoA condensation with carboxylic acid derivative of Piperideine
(pipecolic acid) to get intermediate used to end up with five and six member
structure Indolidizine alkaloids.
*From the beginning we said that none of these alkaloids are widely spread, in
fact the Indolidizine alkaloids are least common in the plant kingdom rather
they are primarily isolated from animal kingdom (frogs, toads), but two
Indolidizine alkaloids where isolated from the plant kingdom and tested for
their biological activity (Castanospermine , Swainsonine),
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they are interested for the scientists because of their ant-viral activity as
well as anti- proliferative activity.
In Castanospermine when we look to the structure, in addition to the
presence of Indolidizine nucleus we recognize the presence of many OH groups
(polyhydroxylated, which is responsible about the biological activity).
Castanospermine anti-viral activity is by inhibiting Glycosidase Enzyme which is
involved in the formation of the envelope of HIV, (MOA: inhibition of this
enzyme will prevent the formation of glycoprotein so inhibiting the
proliferation of HIV), it’s a promising agent and there’s several analogues, one
of them resulted from the esterification of OH on carbon # 6 to get
Celgosivir which is experimented as a drug widely used in the treatment of
AIDs, But unfortunately, the terminal studies with regard to the clinical
experiments can't give answer to the expected results and they stopped the
experiments of celgosivir for the treatment of AIDS, but in the same time
they found that it can be used for the management of hepatitis C . currently
celgosivir is at investigation as possible agent in the treatment of hepatitis C
but not of AIDS. Other derivatives of castanospermine are in preparation to
be considered as anti-AIDS preparations.
Swainsonine :
*Possessing anti-proliferative and anti-metastatic activity. So it is preventing
dissemination of tumors or formation of metastasis as an anti-cancer agent,
isolated from plants as well as from animals.
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So the sub-chapter of indolizidine, pyrrolidine and quinolizidine alkaloids
linking both lysine and ornithine in the formation of structures with basic
characteristic of two ring system either two 5-membered or two 6-membered
or 5 & 6 membered rings system.
*Alkaloids derived from L-lysine :
A-piperidine alkaloids
*Although the vast majority of piperidine alkaloids are derived from L-lysine,
there are other sources we will discuss them after discussing the lysine derived
ones.
-Pomegranatae( Punicagranatum, Punicaceae)
The bark of the stem or roots contains pelletierine, it is very widely used in
the past for anthelmintic activity but nowadays when it is used ,for
treatment of tapeworm for example, it is not used for human medicine but
for veterinary medicine.
The name of pelletierine is related to the French scientist Joseph Pelletier
who isolate it and determine its structure and give it his name, and
presumably closely related structures are also bearing his name like norpelletierine, iso-pelletierine&pseudo-pelletierine. So, many pelletierines have
been isolated from the bark of the Punicagranatumand when we look to the
structure we will recognize that it is actually two parts; one part is
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piperidine derived from the amino acid lysine and the other part is a simple
acetyl group.
Then pelletierine can be converted to pseudo-pelletierine, iso-pelletierine,norpelletierine or anaferine.
There is a similar structure to anaferine we have preiously seen it which is
cuscohygrine; a derivative of ornithine. So anaferine is an analog of
cuscohygrine.
*Anaferine is detected in many Solanaceae species, although it is a derivative
of lysine. solanaceae contains ornithine derived alkaloids but anaferine as a
small compound has been detected also in Solanaceae.
Lobelia Inflata ( Indian Tobacco ) :
* The family is ( Lobeliaceae or Campanulaceae).
* Originated from North America.
* Favored by the original inhabitants of North America and Indians .
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* It is used as an alternative of smoking alone or together with (Nicotiana
Tobacco ) by North Americans and Indians .
* In lobelia Inflata we can find piperidine alkaloids which are lobeline and
related compounds, but when this plant is smoked then thousands of
compounds are produced which are products of pyrolysis .
* Extract of the plant contain Lobeline , possessing anti-asthmatic properties
, it is used in the treatment of bronchitis and in the smoking cessation and
it has a dose dependent activity .
* More recently Lobeline suggested to treat methamphetamine abuse but not
yet clinically utilized .
Structure Of Lobeline :
*In the center we have piperidine ring which is derived from lysine , and on
the both sides of the ring we have a C6C2 unit attached to the alpha
carbon of the ring ( beside N ) .
The biosynthesis of Lobeline :
* The C6C2 units on both sides are originating from benzolyacetyl-CoA .
* Benzolyacetyl-CoA is an intermediate in the β-oxidation of cinnamic or
"shikimic" acid ( by elimination of one carbon of cinnamic acid ) .
* Then by condensation using different reactions we will obtain lobeline and
related compounds .
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Note : In the above figure the Dr mentioned only the highlighted compounds
(piperidinium cation , benzolyacetyl-CoA , Cinnamic acid , Lobeline ).
Piper Nigrum :
* In the past it was used for simple infections , rheumatoid arthritis and
gonorrhea .
* Nowadays it is used as a spice.
* We use piper nigrum to achieve pungency and aromatic flavor in our food.
*We have different secondary metabolites in piper :
-The compounds those are responsible for aromatic flavor which are volatile
oils.
-The compound that is responsible for pungency which is piperine .
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Piperine structure :
 From the structure of piperine we can notice that :
* It is a colored compound because of the conjugated double bonds .
* It is a tertiary amine .
* It has an amide group (Nitrogen is linked to a carboxyl group by an
amide linkage ) .
 There is isomerization because of the double bonds , and the cis isomer of the
piperine is the Chaviscine .
Chaviscine :
*The biosynthesis of piperine :
 From the Piperine structure we can notice that it has a piperidine ring , and an
acid moiety ; the piperidine ring is originated from lysine , and the acid moiety is
from piperic acid .
 Piperic acid :
* It is an aromatic acid which has a side chain composed of five carbons at carbon
number one and a 3,4 methelene dioxy group .
* As being an aromatic acid then it is derived from shikimic acid pathway .
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* 3,4 methelene dioxy cinnamic acid is the starter compound (see the figure below)
* Piperic acid side chain is composed of 5 carbons as we said and the side chain of
cinnamic acid is composed of three carbons , so we need an elongation process .
* In the nature we have 3 possibilities for elongation using ( acetoacetyl-CoA ,
Malonyl-CoA and Acetyl-CoA ) , In our case the elongation will be using the Malonyl
CoA (by the addition of two carbons to the side chain ) .
 The last step in the biosynthesis is the condensation between the piperidine ring
and the piperic acid .
Good Luck 
Done By :
Deema Mohammed , Hadeel Damra , Heba Jabr , Haya Odeh
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