3. ALKALOIDS

Introduction

These compounds are renown for their potent pharmacological activities.  Whilst tiny amounts of some can immobilise an elephant or a rhinoceros, others have important clinical use such as analgesics, antimalerial, antispasmotics, for pupil dilation, and treatment of hypertension, mental disorders and tumours.
They are all nitrogen heterocycles which occur mainly in plants as their salts of common carboxylic acids such as citric, lactic, oxalic, acetic, malic and tartaric acids as well as fumaric, benzoic, aconitic and veratric acids.  Their amine character produce an alkaline solution in water and hence the origin of their name - alkaloids.
The alkaloids are extracted from plants by extraction with organic solvent.  For example seeds which are rich in oils can be extracted with petroleum ether.  Methanol is also used to extract the alkaloids and after filtration and evaporation the extract is diluted with water acidified and steam distilled to remove the last traces of methanol.  After several days at 0 - 5oC the aqueous residue usually clears and it is then possible to separate the organic layer.  The organic material is extracted with ether or chloroform, the extracts evaporated and steam distilled again.  Volatile alkaloids are separated.  The aqueous residue is made alkaline and extracted yet again.  The extracts are evaporated and then begins the task of trying to separate the constituents in crystalline form either as the free base or if not as acid salts.
There is a wide variety of structural types of alkaloid e.g. monocyclic, dicyclic, tricyclic, tetracyclic etc. as well as cage structures.

1. Monocyclic alkaloids.

Coniine (1), whose structure is based on piperidine, is highly toxic.  It may be extracted from hemlock and it was used by the ancient Greeks for state executions, Socrates being the most famous victim.
On the other hand, nicotine (2), the main alkaloid constituent of tobacco, is based on the five membered pyrrolidine and six membered pyridine structures. It is without doubt the most well known alkaloid, and its calming effect together with its addictiveness has probably caused the death of more people in the world than any other compound.
 

 
The Biosynthesis of Coniine. - Lysine was thought to be the most likely precursor and indeed feeding the hemlock plant with 14C labelled lysine produced radioactive coniine.  However it is possible that lysine is degraded to a simpler compound which is the real precursor.  Indeed feeding the hemlock plant with diamino pentane and also with labelled acetate also led to incorporation of the label.   The feeding of labelled acetate produces coniine with alternating carbon atoms (2, 4, 6, and 2’) labelled.  The high level of label incorporation indicates that the actual biosynthesis of coniine originates from a polyketide.
2. Bicyclic alkaloids.
The tropane alkaloids are based on a 1,4 nitrogen bridged cycloheptane structure.
Atropine is isolated from Belladonna plants, commonly known as "Deadly Nightshade".
 

Atropine is widely used in medicine in doses of about 0.1 mg for its muscle relaxant properties.  Thus it is used as an antispasmotic including the dilation of the pupil by relaxing the eye muscles and so assist eye treatment, and it is available for the treatment of organophosphate/nerve gas poisoning.
Not surprisingly cocaine, which comes from the coca plant,  has similar properties to atropine and at one time it was used as a local anaesthetic but is rarely used medically nowadays due to its toxic and addictive effects.
There are a number of alkaloids which are derivatives of quinoline, isoquinoline and their hydrogenated analogues.

 
 
 

Papaverine, an opium constituent, has antispasmotic properties and has also been used as an analgesic. Today it is used as a minor constituent with morphine usually to enhance the analgesic properties of a weaker drug such as aspirin.
Emetine is a derivative of tetrahydro isoquinoline which is isolated from the root of a S. African creeper.  It has been used as an expectorant, but now replaced by codeine and other non alkaloid drugs such as ephedrine and diphenylhydramine.
The most widely used of the quinoline alkaloids is quinine which is isolated from the bark of the cinchona tree.  It is used as an antimalarial drug in 0.6 g doses, as a skeletal muscle relaxant it is used in .2 g doses to relieve nocturnal cramps and at trace levels as a bitter flavouring in tonic water.
3. Polycyclic alkaloids
The indole structure is also a common feature of alkaloid structures and can be identified as part of polycyclic alkaloids such as reserpine, vinblastine, strychnine and lysergic acid.

 

Of these reserpine has the most important clinical use i.e. for the treatment of high blood pressure and as a tranquilliser.
Vinoblastine and its analogues are used to treat acute leukaemia, lymphomas and some solid breast and lung tumours.
Strychnine is very poisonous and was once used to control rodents, but it has been replaced by poisons which are less toxic to man.
The active ingredient of the ergot fungus which grows on cereal grasses such as rye, is a lysergic acid amide.  LSD is the diethylamide derivative (X = NEt2) of lysergic acid has hallucinogenic properties.  It has no medical applications, but ergotamine tartrate (a tripeptide derivative) is used to treat acute migraine. Its dihydro derivative is even more powerful.
Note that Cannabis (marijuana/Indian hemp), which is a mild hallucinogen, is a pyrone dreivative and not an alkaloid.  It is also said to be "habit forming"

Morphine, which constitutes ca 10% of the extract from opium poppies, is one of the most potent alkaloids.  It is a very effective pain killer and is used in medicine when pain is absolutely intolerable.
On the other hand,  its acetyl derivative, heroin,  is widely abused because of its short-term production of an overwhelming relaxing well-being feeling. Both are highly addictive and with prolonged use produce very harmful physiological effects on the body.
 
 
 


 

The most commonly used of this class of opioids in medicine is codeine.  It is a minor constituent of opium but is made by the methylation of morphine.  It is a fairly good analgesic but causes constipation.  Thus about 8 mg is often added to either .4 or .5 g. tablets of aspirin or paracetamol.  It is also used as a cough suppressant and as an antidiarrhoeal drug.  It must be used with care since it is still addictive although to a lesser extent than morphine.
 

ALKALOIDS
Labelling work on a number of alkaloids has indicated that diaminocarboxylic acids are the main biochemical precursors of alkaloids.
Biosynthesis. - 1) Atropine.  Feeding the Belladonna plant with the aminoacid ornithine which was 14C labelled at the C-2 position produced atropine labelled at the C-1 position as shown.
 

 
 
2) Nicotine.  Feeding the tobacco plant with 14C-1 labelled aminoacid ornithine gave nicotine equally labelled at C-2’ and C-5’ sites as shown.
 

 

This indicated an intermediate in the biosynthetic pathway which had a symmetrical distribution of the label such as 1,4-diaminobutane, which could arise from decarboxylation of onithine.  Feeding with 14C-2 15N-5 labelled ornithine gave nicotine with 50% loss on the 15N label whereas feeding with 14C-2 15N-2 labelled ornithine gave nicotine with 100% loss on the 15N label.   These observations were attributed to the presence of an equilibrium with the a-keto acid .
 

 
 

3) Coniine. - Lysine was thought to be the most likely precursor and indeed feeding the hemlock plant with 14C labelled lysine produced radiolabelled coniine but the site of the label was not investigated.  However it was realised that lysine might be degraded to a simpler compound which is the real precursor.  Indeed feeding the hemlock plant with diamino pentane and also with labelled acetate also led to incorporation of the label.   In addition feeding of labelled acetate produces coniine with alternating carbon atoms (2, 4, 6, and 2’). labelled.  It was concluded at this point that the high level of label incorporation indicates that the actual biosynthesis of coniine originates from a polyketide. Further work has indicated that lysine is an intermediate but that it has the polyketide origin.
4) Lycopodine.  Extensive studies of this alkaloid using 14C and 3H labelling has provided evidence that lysine is the starting material.   This time 1,5-diaminopentane is the symmetrical intermediate.  After oxidation it cyclises to form an imine which after addition of 2-propanone gives iso-pelletierine.  Aldol condensation of iso-pelletierine followed by several more steps produces lycopodine with 25% of the  14C label spread amongst the carbonyl group and the 3 carbons bound.
 


 
 
 
 


The next section is: 4. POLYKETIDES