Alkaloid Biosynthesis and Classification

Biosynthesis of Alkaloids

  • The biosynthesis of many alkaloidal structures can be rationalized through simple chemical reactions involving amino acids.
  • Common alkaloidal precursors (amino acids):
    • Phenylalanine
    • Tyrosine
    • Tryptophan
    • Histidine
    • Anthranilic acid
    • Lysine
    • Ornithine
  • General reactions:
    • Decarboxylation: Removal of a carboxyl group or carbon dioxide.
    • Transamination: Transfer of an amino group from one molecule to another without forming ammonia.
  • The resulting amines or aldehydes can react to form a Schiff base.
  • The Schiff base can further react with a carbanion in a Mannich-type condensation.

Classification of Alkaloids

  • Alkaloids are typically classified based on the basic chemical structures from which they are derived.

Pyridine-Piperidine Alkaloids

  • Pyridine (tertiary base) is converted to piperidine (secondary base) upon reduction.
  • These nuclei (pyridine and piperidine) form the foundation of this group.
  • Subgroups:
    • Derivatives of piperidine (e.g., lobeline from lobelia).
    • Derivatives of nicotinic acid (precursor of pyridine) (e.g., arecoline from areca).
    • Derivatives of both pyridine and pyrrolidine (e.g., nicotine from tobacco).

Plants Containing Pyridine-Piperidine Alkaloids

1. Lobelia (Indian Tobacco)
  • Consists of dried leaves and tops of Lobelia inflata (Fam. Lobeliaceae).
  • Contains 14 alkaloids, with (-)-lobeline being the major and most important one.
  • Lobeline produces similar, but weaker, pharmacological effects to nicotine on:
    • Peripheral circulation
    • Neuromuscular junction
    • CNS
  • It is incorporated into tablets or lozenges to aid in breaking the tobacco habit.
  • Most controlled studies suggest lobeline has only a placebo effect on decreasing physical craving for cigarettes.
  • Lobeline is a derivative of piperidine.
2. Areca (Areca Nut or Betel Nut)
  • Consists of dried, ripe seeds of Areca catechu (Fam. Palmae).
  • Contains several alkaloids that are reduced pyridine derivatives:
    • Arecoline (arecaidine methyl ester)
    • Arecaidine (N-methyl guvacine)
    • Guvacine (tetrahydronicotinic acid)
    • Guvacoline (guvacine methyl ester)
  • Arecoline is the most active and abundant alkaloid in areca.
  • Also contains tannin, lipids, volatile oil, and gum.
  • Use: Anthelmintic (anti-worm).
3. Tobacco
  • Dried leaf of Nicotiana tabacum (Fam. Solanaceae).
  • Cultivated for smoking.
  • Contains about 0.6−0.90.6-0.9% of nicotine, with a lesser amount of nornicotine.
  • Nicotiana glauca contains anabasine in addition to nicotine.
  • Nicotine is an oily liquid alkaloid, colorless when pure but turns yellow upon oxidation.
Nicotine
  • Nicotine is a ganglionic (nicotinic) cholinergic receptor agonist.
  • Complex pharmacologic actions include effects mediated by binding to receptors in:
    • Autonomic ganglia
    • Adrenal medulla
    • Neuromuscular junction
    • Brain
  • The free base is more toxic than its salt.
  • Nicotine is toxic to humans due to its effects on the nervous system.
  • Low doses (e.g., from cigarette smoke, 1−21-2 mg) stimulate ganglionic neurotransmission, leading to:
    • Tachycardia (increased heart rate)
    • Rise in blood pressure
    • Increased gastrointestinal peristalsis
  • Small doses can act as a respiratory stimulant.
  • Initial doses may cause nausea, vomiting, and related effects of hypercholinergic activation.
  • In the brain, nicotine is a stimulant at low doses, improving:
    • Attention
    • Alzheimer learning
    • Memory functions
    • Decreases anxiety
  • Rapid development of tolerance to unwanted effects is a key characteristic.
  • High doses of nicotine rapidly produce a ganglionic blockade (inhibition of transmission) after initial stimulation, leading to:
    • Bradycardia (decreased heart rate)
    • Hypotension (low blood pressure)
    • Impairment of adrenaline release
  • In the CNS, large doses induce:
    • Generalized mental depression
    • Tremors
    • Nausea
    • Convulsions
  • Large doses cause respiratory depression.
  • Chronic use can result in psychological and physical dependence.
  • Medicinal use: Relieving symptoms during smoking cessation programs.
  • Transdermal nicotine system (patch): Releases 5−75-7 to 15−2115-21 mg/24h of nicotine.
    • Nicotine is absorbed from the patch into the bloodstream.
    • Replaces nicotine from smoking, reducing withdrawal effects.
    • The amount of nicotine is decreased over time until use is stopped.
  • Available as a chewing gum base (2-4 mg nicotine).
  • Alternative sources of nicotine help reduce withdrawal symptoms.
  • Biosynthesis of nicotine: From ornithine, aspartic acid, and glyceraldehyde.
4. Pomegranate
  • Fruit, fruit rind, or stem bark of Punica granatum (Fam. Punicaceae).
  • Contains alkaloids: Pelletierine and pseudo-Pelletierine.
  • Used as an anthelmintic.
  • Biosynthesized from lysine & acetate.

Tropane Alkaloids

  • Dicyclic compounds formed by condensation of a pyrrolidine precursor (ornithine) with three acetate-derived carbon atoms.
  • Both pyrrolidine and piperidine are involved in the tropane molecule's structure.
  • Tropane alkaloids consist of two parts:
    • Alcohol part
    • Acidic part

Examples of Tropane Alkaloids:

1. Hyoscyamine Alkaloid
  • Alcohol part: 3-hydroxy derivative of tropane (tropine or pseudotropine, depending on the –OH group's orientation).
  • 3−α3-\alpha-isomer is more active and common than the 3−β3-\beta-isomer.
  • Acidic part: (-)-tropic acid, which undergoes esterification with the alcoholic part to form the final alkaloid.
    • The (-)-isomer is hyoscyamine.
    • The (+)-isomer of hyoscyamine is not found in the plant.
    • The (±)-isomer of hyoscyamine is atropine.
    • Hyoscyamine is more active than atropine.
2. Scopolamine or Hyoscine Alkaloid
  • Alcohol part: Scopine, which is esterified with (-)-tropic acid to give the final alkaloid.
    • Hyoscine (scopolamine) is an epoxide of atropine & it is the (-)-isomer
    • The (±)-isomer of scopolamine is atrosine
    • Semi-synthetic derivatives, e.g., Hyoscine N-butyl bromide (Buscopan) are of medicinal importance
3. Cocaine Alkaloids
  • Alcohol part: Ecgonine, which is esterified with cinnamic acid, benzoic acid, or truxillic acid to give three types of alkaloids.
  • When ecgonine methyl ester reacts with truxilic acid (formed from the condensation of two molecules of cinnamic acid), it yields truxilline alkaloid.