Introduction to Alkaloids

General Information about Alkaloids

• They are difficult to define due to their non-homogeneous chemical, biochemical, and physiological properties.
• All alkaloids are organic nitrogenous compounds.
• Primarily sourced from plants, alkaloids are also found in animals, fungi, and bacteria.
• Most alkaloids possess basic properties as a result of the presence of amino nitrogen.
• Many alkaloids display marked physiological activity.

Occurrence in Plants

• Alkaloids can be found in various parts of plants like seeds (nux vomica, areca).
• Also in fruits (black pepper, conium).
• Leaves (belladonna leaf, hyoscyamus).
• Underground stems (sanguinaria, corydalis).
• Roots (aconite, belladonna root).
• Rhizomes and roots (ipecac, hydrastis).
• Barks (cinchona, pomegranate).
• They can also be found in fungi, such as ergot.

Nomenclature

• Names are derived from the genus of the source plant (hydrastine, atropine).
• Names are derived from the species name of the source plant (cocaine, belladonnine).
• Names are derived from the common name of the drug (ergotamine).
• Names are derived from the physiological activity (emetine, morphine).
• Names are derived from the discoverer (pelletierine).
• Chemical nomenclature dictates that alkaloid names end in "-ine."

Toxicity

• Animal intoxication is often due to ingestion of food contaminated with alkaloid-containing plants.
• Factors influencing toxicity include the amount ingested and the sensitivity of the animal.
• Certain alkaloids, including the steroidal alkaloid cyclopamine found in Veratrum californicum (Liliaceae), are harmful to mammals.
• Teratogen effects can be caused by the compound in Veratrum californicum(Liliaceae) known as cyclopamine.

Function in Plants

• They act as poisonous agents protecting against insects and herbivores.
• They are end products of detoxification reactions, which lock up compounds harmful to the plant.
• They act as regulatory growth factors.
• They serve as reserve substances providing nitrogen or other essential elements.

Pharmacological Action

• Some alkaloids such as morphine and codeine act as analgesics and narcotics.
• Some alkaloids such as strychnine and brucine act as central stimulants.
• Some alkaloids such as atropine and homatropine act as mydriatics.
• Some alkaloids such as physostigmine and pilocarpine act as myotics.
• Some alkaloids such as ephedrine can increase blood pressure.
• Some alkaloids such as reserpine can decrease blood pressure in hypertensive individuals.

Properties

• Most alkaloids are well-defined crystalline substances that form salts with acids.
• They may exist freely, as salts, or as N-oxides (amine oxides) in plants.
• Amine oxides contain the functional group N⁺-O⁻, and are weak bases with high polarity.
• Small amine oxides are hydrophilic and possess excellent water solubility.
• Alkaloids contain carbon, hydrogen, and nitrogen.
• Most alkaloids also contain oxygen, while some (coniine, nicotine, and sparteine) do not and are liquids.
• Colored alkaloids are rare; berberine is yellow, and sanguinarine salts are copper-red.
• Alkaloids typically contain one nitrogen atom, though some (like ergotamine) can have up to five.
• The nitrogen atom can be a primary (RNH₂), secondary (R₂NH), or tertiary amine (R₃N).
• The nitrogen atom's unshared electron pair causes alkaloids to be basic, resembling ammonia chemically.
• Alkaloid basicity varies with molecular structure and functional group location.
• Alkaloids form salts with aqueous mineral acids, like ammonia.
• Treating an alkaloid salt with hydroxide ions releases the free amine.
• Quaternary ammonium compounds (like tubocurarine chloride) have four organic groups covalently bonded to nitrogen.
• The quaternary ammonium ion's positive charge is balanced by a negative ion.
• Quaternary ammonium ions are unaffected by hydroxide ions, therefore there chemical properties differ from amines.
• Alkaloids are generally insoluble or sparingly soluble in water.
• Salts formed by reaction with acids are usually freely water-soluble.
• Free alkaloids are typically soluble in ether, chloroform, or nonpolar, immiscible solvents.
• Alkaloidal salts are insoluble in these solvents.

Tests for Alkaloids

• Most alkaloids precipitate from neutral or slightly acidic solutions with Mayer's reagent (potassium mercuric iodide solution).
• Wagner's reagent (iodine in potassium iodide solution) causes precipitation.
• Solution of tannic acid causes precipitation.
• Hager's reagent (saturated picric acid solution) causes precipitation.
• Dragendorff's reagent (potassium bismuth iodide solution) causes precipitation.
• Precipitates can be amorphous or crystalline with various colors: cream (Mayer’s), yellow (Hager’s), or reddish-brown (Wagner’s and Dragendorff’s).
• Certain reagents give precipitates with proteins, requiring careful application of tests.
• Caffeine and other purine derivatives may not precipitate like most alkaloids.
• To detect caffeine, mix with potassium chlorate and hydrochloric acid, evaporate, and expose the residue to ammonia vapor, a purple color indicates a positive result (murexide test).

Biosynthesis

• Biosynthesis of alkaloids can be rationalized through chemical reactions involving amino acids.
• Decarboxylation and transamination of amino acids yield corresponding amines or aldehydes.
• These participate in a Mannich-type condensation.
• These can react to form a Schiff base, which in turn can react with a carbanion in a Mannich type of condensation.

Major Amino Acids Involved in Biosynthesis:

• Ornithine
• Lysine
• Phenylalanine
• Tyrosine
• Anthranilic acid: known for having the COOH & NH₂ groups not on the same carbon atom.
• Tryptophan

Classification Due to Hegnauer:

• True (Typical) alkaloids derive from amino acids and have nitrogen in a heterocyclic ring (e.g., Atropine).
• Protoalkaloids derive from amino acids but do not have nitrogen in a heterocyclic ring (e.g., Ephedrine).
• Pseudo alkaloids do not derive from amino acids but have nitrogen in a heterocyclic ring (e.g., Caffeine).
• False alkaloids are not alkaloids but give false positive reaction with alkaloidal reagents (e.g. homatropine).

Classification by Ring Structure:

• Pyridine-piperidine combined
• Tropane
• Quinoline
• Isoquinoline
• Indole
• Imidazole
• Steroid
• Lupinane
• Alkaloidal amine
• Purine

Alkaloid Classification by basic chemical structures

• Derivatives of pyridine and piperidine, like arecoline, pelletierine, lobeline, coniine, and nicotine
• Atropine, hyoscyamine, and hyoscine are derivatives of tropane, a condensation product of pyrrolidine and piperidine.
• Cinchona alkaloids (quinine, quinidine, cinchonine, cinchonidine) contain quinoline.
• Hydrastine, d-tubocurarine, emetine, and certain Opium alkaloids have an isoquinoline nucleus.
• Ergonovine, reserpine, and strychnine derive from the indole ring.
• Pilocarpine has the imidazole ring.
• Caffeine and theobromine are purine bases.
• Morphine and codeine have the phenanthrene ring.
• Aconitine and protoveratrine contain a steroidal structure.

Extraction by Fractional Extraction

• Defatting with non-polar solvents (Petroleum Ether, benzene, alkane) removes chlorophyll, wax, volatile oils, and fixed oils.
• Use filtration and methanol or 95% ethanol to extract.
• Concentrate by rotary evaporation.
• Add 2% tartaric acid and ethyl acetate separates layers to extract desired parts.
• (For week or neutral alkaloids) use the organic layer.
• *(acidic layer, Tartaric acid) which have alkaloidal salts use the Aqueous layer.
• To break the salt, add NH3 or Sodium bicarbonate. Then add ethyl acetate again so will it separate into two layes again:
• Aqueous layer (Quaternary alkaloids 4º)
• Organic layer (For basic alkaloid 1º,2º,3º)

Purification of Extracts

• Direct Crystallization is the simplest; the crude extract is evaporated to dryness, and the residue is dissolved in a crystallizing solvent (single organic solvent or a mixture).
• Increasing order of alkaloids solubility: Hexane, benzene, ether, ethylacetate, methanol, acetone, chloroform &dioxane.

Other Purification Methods

• Steam distillation : Used for liquid alkaloids (coniine, nicotine, sparteine) in rare cases.
• Crystallization of sparingly soluble salts with choice of acid unlimited (HCl, HBr, oxalic, picric, perchloric, sulfuric, maleic, tartaric acids widely used).
• Procedure: dissolve crude base in methanol or acetone, add ethereal solution of the acid.
• Oxalates, picrates & perchlorates are usually formed by mixing ,anolic solutions of the base & the acid.
• Distribution between immiscible solvents: Alkaloids taken up in dilute acid, recovered by adding ammonium hydroxide and extracting with water-immiscible organic solvent (benzene, chloroform, ether is usually the choice).

Pyridine-Piperidine-Pyrolidine Alkaloids

• Tertiary base pyridine converts into the secondary base piperidine upon reduction.
• This group is divided sometimes into three: piperidine derivatives (lobeline from lobelia).
• Nicotinic acid derivatives (arecoline from areca).
• Derivatives of both pyridine-pyrolidine (nicotine from tobacco).
• Nicotine: Biosynthetic pathway leads where ornithine is incorporated into nicotine by tobacco plants to have a symmetric labeling pattern.
• The N-methylpyrrolinium ion is key for electrophilic aromatic substitution attached to C-3 in the pyridine ring of nicotinic acid.

Drugs Containing Pyridine-Piperidine Alkaloids

• Tobacco are dried leaves of Nicotiana tobacco F: Solanaceae.
• Smoking tobacco contains 0.6-0.9% alkaloids (main one is nicotine that is, when oxidized, turns yellow).
• Nicotine is a ganglionic (nicotinic) cholinergic receptor agonist that has complex pharmacologic actions including effects mediated by binding to receptors in autonomic ganglia, the adrenal medulla, the neuromuscular junction & the brain leading psychologic and physical dependence.
• Smoking tobacco correlates to cardio vascular including peripheral vasoconstriction and tachycardia with an increase in systolic & diastolic blood pressure.
• 50% of smokers die of heart disease with 20% of smokers dieing from lung cancer.
• Carcinogenicity of tobacco correlates to N-nitroso nor nicotine.
• It is found in cigarettes, cigars & chewing tobacco at levels in the range of 2-90pp (parts per billion N-nitrosamines considered hazardous).
• Lobelia or Indian tobacco are dried leaves & tops of Lobelia inflate F: Lobeliaceae (Campanulaceae).
• The drug contains 14 alkaloids with many piperidine and N-methylpiperidine derivatives (lobeline, lobelanine, and lobelanidine with lobeline most important).
• Lobeline as colorless crystals slightly soluble in water but soluble in hog alcohol, its form as tablets/lozenges are formerly used for expectoration.
• In 0.5 to 1.5 mg of dosage, lobeline sulfate in intended tablets are geared toward treating tobacco, amphetamines, cocaine or alcohol addictions.
• Areca is the dried, ripe seed of Areca catechu (Fam. Palmae) that contains several alkaloids which are reduced pyridine derivatives.
• Among them are arecoline (arecaidine methyl ester), arecaidine (N- methyl guvacine), guvacine (tetrahydronicotinic acid) and guvacoline (guvacine methyl ester).
• Total alkaloids can range up to 0.45%
• Arecoline Hydrobromide is used in veterinary medicine as an anthelmintic drug against parasitic worms.Arecoline is a parasympathomimetic (agonist) which acts on the muscarinic and nicotinic receptors.

Pharmacological Effects of Arecoline

• Vasodilation
• Hypotension, and reflex of tachycardia at low doses
• Stimulation of intestinal tone and peristalsis
• Increase in secretions (hypersalivation and sweating)
• Myosis
• Bladder contraction

Pomegranate

• Pomegranate Root and Stem Bark or Granatum is derived from Punica granatum (Fam. Punicaceae).
• They contain about 0.5–0.9% volatile liquid alkaloids
• The chief being pelletierine and pseudopelletierine, together with about 22% of tannin.
• Pelletierine tannate is a mixture of the tannates of the alkaloids, was included in the BP 1948 and was used as an anthelmintic with a specific action on tapeworms.
• Conium or hemlock are the poisonois but unripe fruit of Conium maculatum F: Umbellifareae, rich in coniide, acting as anti spasmodic
• Accidental ingestion of Conium may lead to central nervous system depression, respiratory failure, acute rhabdomyolysis, acute renal failure and even death by non-depolarizing blockers
• Piper are dried but unripe fruits of Piper nigrum F: Piperaceae, rich in 4.5-8% of piperine.
• Piper is used as as a condiment with stimulant with febrifuge properties, black pepper is prepared from the unripe fruits of Piper nigrum, and white pepper is prepared from the ripe fruits .
• Piperine possesses a piperidine moiety combined with piperic acid for an amide function
• On hydrolysis of piperine you'll get another alkaloid piperidine with liquid properties!

Tropane Alkaloids

• It consists of (-)-hyoscyamine for medicinal purposes with atropine (stabile racemate) and hyoscine (scopolamine) as the principal alkaloids. The compounds are esters that, when esterifies, may hydrolyze by heating at 60°C with baryta water. Atropine yields tropic acid and tropine whereas hyoscine yields tropic acid and oscine because they are extremely poisonous.
• Tropane is a bicyclic amine of a pyrrolidine and piperidine ring with 2 carbon atoms and a nitrogen atom that can be formed from condensation of pyrrolidine precursor (ornithine) with three carbon atoms from acetate but can form through tropane as well.

Biosynthesis Of Tropane Alkaloids

• Labeled ornithine have revealed its stereo incorporation to make pyrrolidine ring as the main precursor but may use tropic acid after esterificafion with hyocyamine and methylated tropine for hyoscyamine yield
• THe 3-hydroxy version if tropine is known as Tropane; Tropane formation of tropic acid can be from an intro molecular arrangement of phenyllactate for the biosynthesis.

Forms

• 1. Salanaceous Toprine Alkaloids with -isomer to hyoscyamine and +=isomer lost and atropine as racemic but most active and used in medicinal forms because is easily found
• 2. erythoxylon (coco) compounds with high semi synthetics
• It is dried leaf/root of Atropa belladonna F: Solanaceae that includes (hyoscymine, apoatropine, belladonnine, scopolamine(hyoscine) found in lethal amounts due to the deadly nightshade form
• It possesses anticholinergic properties and is used to control excess motor activity of the gastrointestinal tract and spasm of the urinary tract. it decreases intestinal tone, paralyzes the ureters but may show vasodilatation as a side property to those doses of toxic properties

Henbane

• Hyoscyamus or Henbane has flowering tops of Hyoscyamus niger F: Solanaceae but 0.04% is used or hyscyamine for Egyptian variation.
• Stramonium includes 0.4% top that is derived from the hyocymine.