Lecture 11
We started to discuss alkaloids possessing pipyridine ring in their structures, and we verified that
pipyridine ring ring is originated from the amino acid (lysine) ,
But we now that in nature there isn’t black and white , there is always alternative pathways, we can
obtain pipyridine ring not only from lysine but by other alternative pathways
Today we’ll see such alternative pathways before continue to aromatic amino acids as aromatic
precursor .
Coniine : possessing pipyridine nucleus ,isolated as liquid alkaloid from Conium Maculatum ,family :
Apiaceae
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Biogenesis : carbon skeleton of pipyridine nucleus is originated from acetate metabolism .
Last year we discussed acetate- malonate pathway by which we are adding acetyl and malonyl
coA , elongation always by 2 carbons to get poly keto methylene chain (each carbonyl grp
separated by methylene grp),carbon skeleton of ciniine is originated from acetate-malonate
pathway forming poly keto methylene chain using four acetate units
- For Carbonyl and keto grps , it,s easily to start transamination rxn (keto grp vs amino grp),
by donation amino grp from L alanine, we convert our acetate originated chain into
precursor of coniine which is coniceine , coniceine will be reduced to coniine .
- The consistency of the alkaloids , if it is liquid or solid depends on the presence of oxygen ,
oxygenated alkaloids are solids , non oxygenated are liquids
- Coniine is lacking oxygen, so it is liquid.
- U have to read in your reference text book extrarotatory and levo rotator coniine
occurring in the plant ,
- 3 carbon side chain is attached to the alpha carbon to nitrogen , it is not alkylation rxn
required .
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In plant coniine and coniceine are occurring together
Conium maculatum seeds or fruits (because the seeds and fruits are together)are similar in
their appearance to anise seed but it is very difficult to mix between them together because
this substance has very unpleasant smell , so we will immediately recognize even small
quantinty of conium seeds in a cup with anise , this bad smell is due to coniceine(it is not
the major toxic compound)
keep in mind coniine is very toxic
Antiquities was used it for criminals to punish them , they were forced to drink acup of
extracted conium maculatum seeds in order to affect the brain centers
People used it in the past as anti spasmodic agent in very low conc but now it has not
medical utilization
Coniine primary affects peripheral muscles causing paralysis , it is very similar to curare , so
in consciousness cause paralysis starting from peripheral and reaches diaphragm and
causing death .
All parts of the plant are poisonous but the highest percentage in unripe fruits
The doctor said it is not originated from precursor amino acid and she said that the carbon
skeleton and the nitrogen is not originated from an amino acid precursor.
She wants u to say what is the grp of this alkaloid , if u refer to the book u will find coniine
under the grp of alkaloids derived from deamination rxns sub class acetate derived
alkaloids (page no. 401 from medicinal natural products a biosynthetic approach 3rd
eddition )
There is another possibility to synthesize pipyridine ring using nicotinic acid
- The doctor assumed that a 4th year student knows nicotinic acid , pipyridine neucleotide
cycle ,involvement of nicotinic acid in co enzymes , NAD,NADH
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Nicotinic acid can provide us mono unsaturated pipyridine and this another alternative
way
To produce pipyridine starting this time with another precursor . these compounds are
arecoline, Arecaidine , guvacoline, and guvacine
will ba isolated from areca catecha ,family palmae, it is temed as bitternut
Bitternut chewing is a social or religious attitude in south Asia especially India , chewing its
seeds not leaves continuously mixed with other ingredient , they crush bitter nut , mix it
with other aromatic ingredient and chewed in the early morning by Indian .
It is classified as stimulator musticatory , it does not cause any hallucination , it causes
relaxation .
Chewing bitternut is visible when Indian people smile because they have yellowish teeth , it
causes staining of the teeth , people always spitting very dark yellow spots .
Long term use of chewing gum can cause loosing of the teeth, full teething is rarely
recognized in south Asia, it also can cause other inflammation in oral cavity, inflammation in
stomach .. etc , these are common observation but they are not reported .
In medicine it used as anti emetic
Nicotinic acid incorporated in pipyridine nucleus synthesis , the more important to us for
formation of other subclasses of alkaloids which we say alkaloid derived from nicotinic acid .
In fact this sub classification from references is different because nucleus of nicotinic acid
when we use carboxyl grp is pyridine
We have seen pipyridine as derivative or incorporated as into alkaloids, now we’ll see what
are the pyridine incorporated , in some references are referred as pyridine- popyridine
alkaloids
In the past they were studying enolate alkaloids originated from ornithine, lysine, and
aspartic acid (aliphatic a.a), with time this aspartic acid has been excluded from titles , and
the text books included alkaloids originated from nicotinic acid or alkaloids containing
pyridine –pipyridine, but what were studying before reflects the reality more than the
current condition because alkaloids which are based on nicotinic acid or pyridine nucleus
they can be obtained like we have in our mammalian organism using amino acid tryptophan
, it can be via quinolinic acid under hereto pyridine nucleotide cycle and we yield the
nicotinic acid or more common niacin (vit B3)
But what we concern about is how do we obtain nicotinic acid from plant kingdom
We start condensation with aspartic acid with glyceraldehyde-3phosphate
Because of this condensation we can obtain poly substituted pipyridine intermediate
,which well be converted to quinolinic acid
aspartic acid is a derivative of oxalacetic acid , oxalacetic acid is obtained from kreb’s cycle ,
and glyceraldehydes 3 phosphate is obtained from photosynthesis ,u see very basic primary
metabolites yielding glyceraldehyde 3 phoshphate and aspartic acid(secondary metabolites)
, without these essentially steps of photosynthesis and kreb’s cycle u can’t get any of tese
secondary metabolite
quinolinic acid is a di carboxylic acid , the two carboxyl grps are obtained from oxalacetic
acid
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conversion of piyridine to pyridine needs dehydrogenation
sense we have poly substituted pipyridine ring , in addition to dehydrogenase ,we have to
eliminate the hydroxyl grp by simle dehydration (first dehydration step, second dehydration
step and dehydrogenation step),
to convert it to nicotinic acid we need an oxidative moiety , the pyridine nucleotide will be
decarboxylated , and nicotinic acid will be released , now we have a building block .
note that nicotinic acid itself is not the alkaloid , it is the parent of different compound of
different alkaloid
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note that alkaloids derived from nicotinic acid can be termed as derived from aspartic acid
because nicotinic acid originated from aspartic acid
classical examples of nicotinic acid derived alkaloids :
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ricinine : is found in Ricinus communis family Euphorbiaceae (castor beans), but it does
not contaminating in oil which is used as laxative.
More important than castor beans is Tobacco alkaloids :
We have nicotine and nor nicotine
By which carboxylic grp eliminated and attached to ornithine originated pyrollidine ring
Nicotine is possessing a methyl grp , methylation of the methyl grp obtains no nicotine
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Anabasine : we have pyridine we have pyridine and we have pipyridine
The origin of pipyridine in tobacco alkaloids is the amino acid lysine , so we’ll get nicotinic
acid decarboxylated , condensed with pipyridine (lysine originated )
Another alkaloid Anatabine : it is very similar in structure to anabasine , the difference is
anatabine has mono unsaturated pipyridine ring , its heterocyclic ring is originated fron
nicotinic acid while in anabasine originated from nicotinic acid and lysine
Both of anatabine and anabasine occure in the same plant , similarity in the structure but
different biogenetic origin .
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We’ll talk about the plant nictiana tobacum , nicotiana rusticam , nicotiana has 100 diffrenet
species , family solanaceae
- Originally it has been used by indian american(the origin is america) , later by frensh men ,
they took it overseas and cultrated it
- Nicotine is one of the earliest alkaloids isolated (1920), indian amirican smooked it using a
pipe so frensh men smooked it just like them until 1980 they develop new siggirate industry
, in the begening in eurupe they used the pipes to smook
- It didn’t remain in particular area , it has been brought from overseas
- We have in jordan , in Madaba nicotiana tobacum plants
- We don’t have just species of nicotiana , we also have varieties , even in some countries
they said they didn’t culturate it , it is naturalize
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Naturalize means in more than hundred years poeople culturated it , and people didn’t
recognise that people brought it from overseas, the plant is adapted to the soroundings and
it grows alone , so naturalized means the plant has been culturated after many years as it is
endogenus plant.
So tobacco has been cultrated and naturalized in many different countries
Leaves is the site that contains alkaloids although the site of biosynthesis are the roots
Many types of alkaloids have been isolated from nicotiana in the form of volatile liquids,
non volatile liquids, solids, aromatics
According to the species we have the major alkaloid , so nicotine is not always the major
Nicotine and nor nicotine are liquids (don’t have oxygen in their structure)
In cigarette Nicotine is classified as natural compound insecticide and it is available in the
form of its salt because in salt form will be in crystal form , u can prepare easily a solution of
it by solubilizing it by aqueous or semi hydroalkoholic solvent, and splitting the sulphate by
adding often alkaline solution , if there is no alkaline sol we can add simple salt sol , this will
be sufficiently to provide alkaline solution
The insecticidal activity of free alkaloid is more compared to the salt.
In past farmers used to powder the leaves and spread it over other plant, to protect them
from insect attack (in record the dr said insecticidal attack!)
Pure nicotine is used in fumigation of green house, by keeping a small amount of liquid
nicotine in the green house, it will volatilize, and act as insecticide. It also used in stent
Pharmacological activity of Nicotine in stimulation and internalization of peripheral,
autonomic, brain, ganglia ,.. etc it is very well known in activity in pharmacology and
toxicology
The fatal dose of nicotine is : 40 mg ,it is not much diluted , u can find them in just 3
cigarette.
Cigarette must not be opened to children , they may eat some of the tobacco so toxicity
occur , it gives burn sensation , but some children will like thin burning and continue eating
and this will cause a lot of irritation and toxicity , the anti dote is atropine
It is reported in all references to pharmacology that burning sensation of cigarette develops
more than 4000 cmpds , typical smoker apparatus is adjusted and attached to GCMS to
predict theses cmpds
The cmpds can be separated to : 1) gas phase 2) particular phase
Nicotine is part of particular phase because it is found in the suspending on the tar , tar is
more toxic than nicotine
Cigarette producers are forced to write on the boxed the amount of nicotine and the
amount of tar that will be produced during smoking process
Tar contains the most carcinogenic which are polycyclic hydrocarbons ,polycyclic aromatic
hydrocarbons, polycyclic aromatic hydrocarbons, metallic ions ,and radiating ions
The gaseous phase contents: carbon mono oxide, carbon dioxide, volatile sulfur, nitrogen,
compounds, aldehydes, ketons .. etc
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U can separate gaseous phase from particulate phase but u can’t make standard
composition or exact composition because it depends on different factors like: 1) type of
filter used ,
2) quality of paper used in the formation of cigarette, how much this paper is bleached, what
type of cellulose in this paper
3) how dense the cigarette column is , old people used to roll their own cigarette , and now is
industrial produced , there is a big difference how dense the column of the cigarette
.4) the length of the column and its diameter
5) The additional perfumes added
6) the percent of smoked cigarette (very important factor) : what kind of component will be
produced is determined by temp at which these cmpds are burned (temp of pyrolysis )
What affect temp of pyrolysis :the strength of inhalation , if the person inhaled strongly the tem
of pyrolysis will be higher and we get completely different constituent copared to aperson who
is not inhaling very strongly
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Worldwide, it’s not classified as social drug any more , it is classified as non social , a drug to
smoke in closed area in order to protect non smokers
Alkaloids derived from aromatic amino acids :
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We have 3 amino acids : 1) phenyl alanine 2) tyrosine 3)tryptophan
Para hydroxyl phenyl alanine is tyrosine , so phenyl alanine and tyrosine are closely related
The doctor made a little bit deviation from our text book , in the text book they discussed
the alkaloids originated from a.a tyrosine then they discussed alkaloids from phenyl alanine ,
the doctor will put them together , because she consider a more logical attitude in
discussing alkaloids ,to recognize similarities and differences
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‫( الفقرةالسابقة للناس اللي بتدرس من الكتاب‬:P
Alkaloid derived from phenyl alanine and tyrosine have a basic difference in their structure
which is phenyl alanine never contribute nitrogen to the terminal cmpd , so when phenyl
alanine is the precursor it provides carbon skeleton and we need transamination , when
tyrosine is the precursor it will provide carbon skeleton plus nitrogen.
One of the classes to be discussed is phenyl alkyl amines (the name is indicative enough to
know the structure aromatic ring +alkyl chain+nitrogen )
Amaryllidaceae alkaloids for example galanthamine : promising in the treatment of
Parkinson disease and colchicine used in management of acute attacks of gout
Here We have both amino incorporated ,
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We have in this grp isoquinoline alkaloids , opium alkaloid, curare alkaloids..etc
The name phenyl alkyl amine indicates the formation ,we can obtain amine from a.a by
synthetic carboxylase
- Any amino acid can provide it’s biosynthetic amine by synthetic carboxylase , and this
biogenic amine when we modify the structure, then it will never be considered as the true
amine…(min 44:35)
- And this phenyl alkyl amine depending on carbon no. of the side chain we can sub classify as
benzyl amine derivatives , which means we have c6 aromatic and benzyl grp c1 , or we can
elongate the side chain by 2 carbons for example , then we’ll have a phenyl ethyl amine
derivative (so the side chain here is 2 carbons)
- The third grp is very indicative Beta Amino phenyl propane derivatives
u should be able to write down these structures based on this head line
We’ll talk about capciasin alkaloid in the first grp . in the second grp very important adrenaline
catecholamines (we will not discuss this is your homework :/),and we’ll discuss mescaline , in
this grp we’ll talk about ephedrine
Capsacinoids the pungent principle of the capcicums (piper), this the type is not of the black
piper , we talk here about paprikas ( green, red, white sweet piper and ‫شطة‬
- It is very very pungent , these pungent principles are grouped as capsacinoids
- U see aromatic ring originaly , benzyl amine , the amino is esterified within acid grp ang we
obtain amide alkaloid .
- Recognize the cmpd by amide grp, benzene must be benzyl amine and long fatty acid chain
- hydroxy capcaisin are the basic principle of capsicum species especially found in hot chilli
pipers of capsicum frutescens , it is very pungent that u feel the cmpd even if 1 part is in
11million part of water ! Imagine how much u have to dilute if u have 1 gm or 1 kilogram !!
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this pungency is used for its rubefacient effect and skin irritant properties in form of (min
48:43but I think it is roimal ) plasters for treatment of rhumatiod pain of joints and muscles
otherwise in stomach , its irritant activity will cause increase secretion of gastric juices , very
recently they say secretion of gastric juices improve the appetite , dietitians recommend to
take some pungent principle in breakfast , this will increase metabolism and by increasing
the metabolism causing burning of more fat , then weight loss
biogenetically origin capcaisin derived from phenyl alanine so we need to remove of the
nitrogen
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phenyl alanine will continue via cinnamic acid to hydroxyl cinnamic acid then methylation
to get ferulic acid ,beta oxidation of ferulic acid and we’ll obtain vanillic acid , reduction to
get vanillin . vanilline will be converted by changing the methyl to amino grp
corresponding vanillin amine . this react with fatty acid to obtain capciasin
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the strange that we have not pungent taste everywhere because we have the acid moeity
malonyl coA, it is fatty acid with 9 carbons , in nature the majority of fatty acids
biosynthesized are characterized by even numbers , but strange compound posses different
activity ,this is bearing a methyl grp on position 8 and unsaturation between carbons 6and 7
, esterfication get vanillin amide
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this process produces capsaicin , u can oxidize methyl grp to obtain hydroxycapsaicin
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small modification will obtain series of cmpds different in substitution but possessing the
pungent principle
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The end
Done by: shuruq sallam
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