Alkaloids - Lecture 2 Part 1

• Part 1 covers alkaloids in Lecture 2

Medicinally Relevant Alkaloids

• Alkaloids described are medicinally relevant
• They belong to different chemical classes

Alkaloids Recall

• Alkaloids exist as free bases, salts, or N-oxides (N → O)

Free Bases vs. Salts

• Free bases are soluble in organic solvents like chloroform, ether, and ethyl acetate, but insoluble in water
• Salts are insoluble in organic solvents like chloroform, ether, and ethyl acetate, but soluble in water

Types of Alkaloids

• True alkaloids are derived from amino acids and contain a heterocyclic nitrogen
• Protoalkaloids are derived from amino acids and contain a non-heterocyclic nitrogen
• Pseudoalkaloids are derived from non-amino acids and contain a heterocyclic nitrogen

Nitrogenous Ring Structures

• Key nitrogenous ring structures in medicinal alkaloids include pyrrole, pyrrolidine, pyrrolizidine, pyridine, piperidine, tropane, quinoline, isoquinoline, aporphine, nor-lupinane, indole, indolizidine, imidazole, and purine

Alkaloids with Heterocyclic Nitrogen

• This section is about alkaloids possessing heterocyclic nitrogen

Pyridine Group Alkaloids

• The focus is on alkaloids belonging to the pyridine group

Pyridine Alkaloid Types

• Pyridine alkaloids can have a pyridine nucleus only, for example, trigonelline from fenugreek
• Some possess a pyridine nucleus and a nitrogenous ring, for example, nicotine from tobacco
• Other pyridine alkaloids covered include tetrahydropyridine (arecoline), piperidine, and pyridone (ricinine)

Trigonelline Details

• Nicotinic acid + L-tryptophan yields trigonelline
• Trigonelline is very soluble in water and has an antidiabetic effect
• It reacts with HCl
• It is found in fenugreek and coffea beans

Trigonelline Synthesis

• Trigonelline is synthesized from nicotinic acid via N-methylation
• Nicotinic acid is also known as niacin or vitamin B3

Pyridine Nucleus Only - Trigonelline

• Trigonelline is found in foenugreek, cannabis, coffea beans, and strophanthus
• Trigonelline is very soluble in water and soluble in alcohol, but practically insoluble in ether and chloroform
• Trigonelline is a quaternary base.
• Trigonelline is derived from nicotinic acid, which is biosynthesized from L-tryptophan
• Upon heating with HCl, it produces nicotinic acid and methyl chloride

Trigonelline Uses

• It is used as a hypoglycemic drug in diabetic patients
• Galactomannan and 4-OH-isoleucine are related to Trigonelline

Tobacco Alkaloids

• Tobacco alkaloids are derived from nicotinic acid and ornithine
• Tobacco alkaloids can be liquids, solids, or true alkaloids
• They can be volatile or non-volatile

Pyridine Alkaloids with Nitrogenous Ring - Tobacco Alkaloids

• Tobacco is the cured and dried leaves of Nicotiana tabacum (Fam. Solanaceae)
• Volatile liquids include nicotine, nornicotine, and anabasine
• Non-volatile liquid is nicoteine
• Nicotelline is a non-volatile solid
• Nicotine comes from nicotinic acid and ornithine, which is a pyrrolidine precursor
• Tobacco alkaloids are present as salts with citric and maleic acids

Tobacco Alkaloid Classification

• Tobacco alkaloids can be classified as liquids, solids, or insecticides
• Volatile liquids include nicotine, then solid is nicotelline

Additional Tobacco Alkaloid Info

• Nicotine, nornicotine, and anabasine are volatile liquids, while nicoteine is a non-volatile liquid, and nicotelline is a non-volatile solid

Tobacco Alkaloid Extraction and Isolation

• Powdered leaves extraction involves acidifying with H2O/HCl, then extracting
• Next, use alkali NaOH, and steam distillation
• There is a distilled and undistilled fraction
• With distilled fraction, nicotine, nornicotine & anabasine can be seperated using HCl & NaNO2 then Ether, evap
• For the Aqueous layer, add Nicotine HCl.
• With the unditilled fraction, ether increases conc. forming nicoteine (liquid) and nicotelline (crystals)

Tobacco Alkaloid Separation

• Tobacco alkaloids (basic) form salt with mineral acids, but not with NH3
• Nicotine, anabasine, and nornictoine are volatile
• Nicotine is a tertiary amine among volatile alkaloids
• Nicotelline is a solid that is insoluble in ether

Nicotine Properties

• Nicotine is a pale yellow oily liquid
• It is very hygroscopic and non-oxygenated
• Nicotine turns brown in air or light and has an acrid, burning taste
• It is steam volatile and miscible with H2O
• Nicotine has 2 basic N atoms, can unite with 2 molecules of monobasic acids, and has a weaker basicity in the pyridine ring due to unsaturation

Nicotine Identification Tests

• Aqueous nicotine solution + p-dimethylaminobenzaldehyde yields a rose red color changing to violet
• Aqueous nicotine solution + vanillin/HCl yields a red color

Nicotine Pharmacology and Uses

• Nicotine stimulates nicotinic receptors in the brain and muscles, and is classified as a poison, also teratogenic
• Tobacco smoking leads to atherosclerosis and chronic bronchitis
• Nicotine patches and gums help quit smoking
• A 40% nicotine sulfate solution can be used as an insecticide

Tetrahydropyridine Alkaloids - Areca Nut Alkaloids

• These come from the Areca nut (Betel nut), Fam. Arecaceae
• They make up to 0.45% of reduced pyridine alkaloids

Areca Nut Alkaloid Types

• Arecoline (methyl ester) is the most abundant and active
• Other types include Arecaidine (N-methyl guvacine), Guvacine (tetrahydro nicotinic acid), and Guvacoline (guvacine methyl ester)

Arecoline Properties

• Arecoline is a colorless oily liquid and volatile in steam.
• It is a strong base freely miscible with water.
• Reacting Arecoline with HCl yields methyl alcohol + arecaidine (ester hydrolysis)

Arecoline Pharmacology & Uses

• Arecoline works as a CNS stimulant, but high doses can cause depression and paralysis
• It is used as an anthelmintic in veterinary medicine

Hegnauer's Alkaloid Classification

• Classification based on nitrogen type and biochemical origin
• True alkaloids: Amino acids and Heterocyclic, for example, Nicotine, Atropine
• Proto-alkaloids: Amino acids and Non-heterocyclic, for example, Ephedrine
• Pseudoalkaloids: Non-amino acids and Heterocyclic, for example, Coniine

Piperidine Alkaloids

• Examples including Pepper, Lobelia, Pomegranate, and Conium
• Pepper, Lobelia, Pomegranate are True alkaloids
• Conium is a pseudo alkaloid

Piperidine Nucleus Details

• Piperidine is completely saturated pyridine
• True alkaloids derived from lysine amino acid include black pepper, lobelia, and pomegranate alkaloids
• Pseodo-alkaloids include conium alkaloids

Piperidine Alkaloids - Pepper Alkaloids

• These are found in the fruits of Piper nigrum (Fam. Piperaceae)
• Total alkaloids make up 5-9%
• The most abundant alkaloids are piperine & chavicine
• These are neutral to litmus. (nitrogen in amide linkage)
• Does not form stable salts
• Insoluble in water
• Alcoholic KOH yields piperidine and piperic acid

Piperine Identification and Uses

• Piperine + H2SO4 yields a red color
• It is used as a condiment, stimulant, tonic, and rubefacient
• Piperine is used with curcumin to increase its bioavailability by ~1200 times

Lobelia Alkaloids

• Lobelia alkaloids are colorless crystals, with Lobeline HCl that is soluble in chloroform
• They break the tobacco habit
• Lobelia herb is also know as Indian Tobacco

Piperidine Alkaloids - Lobelia Alkaloids

• Lobelia alkaloids are found in the dried leaves and flowering tops of Lobelia inflata L. (Fam. Campanulaceae)
• They contain 0.3 - 0.6% alkaloids, with Lobeline making up ≈ 50%
• Other alkaloids: lobelanine and lobelanidine

Lobelia Alkaloid Structures

• Lobelanine is a Di-ketone
• (-)-Lobeline is a Keto-alcohol
• Lobelanidine is a Di-alcohol

More on Lobelia Alkaloids

• Lobeline is a colorless crystal, and Sparingly soluble in water while Lobeline HCl has a salt is soluble in chloroform. Lobelanine Optically inactive (meso-compound).
• Diketone can form a dioxime.

Lobeline Isolation, Separation, and Uses

• Begin with Powdered Lobelia herb is moistened with water acidified with acetic acid for formation of alk salt.
• The aqueous acidic extract Liberates alk base Extract with Na2CO3 + ether for form oily residue of the total alkaloids Extract using HCI + CHCI3 Then Lobeline HCl is extracted in Chloroform
• Lobeline are respiratory stimulant in low dose, an Expectorant, and assist with breaking the tobacco habit
• Lobeline sulfate in tablets or lozenges has a similar effect as nicotine

Tests to identify Lobeline

Tests for identification of lobeline: With alkalodial color reagents Marqui's reagent red-violet Erdmann's reagent faint green Froehd's reagent rose red blue.

Cloud Identifications for Tests

• Erdmann's uses NIitric acid plus sulphuric acid
• Marquis's uses formaldehyde plus sulphuric acid
• MAye r's uses potassium mercuric iodide
• Dragendorff's uses potassium bismuth iodide

Pomegranate Alkaloids

• reactions of carbonyl compounds And Soluble in water

Pomegranate Alkaloids Classification

• Liquids consist of Pelletierine
• Solid consists of Pseudopelletierine

Piperidine Alkaloids - Pomegranate Alkaloids

• Pomegranate alkaloids are in Fruit rind + root & stem barks
• These alkaloids consist of 0.5-0.9% total alkaloids
• Pelletierine, methyl pelletierine, isopelletierine are all liquids.
• Pseudopelletierine is solid.

Pomegranate Alkaloids Properties

• All are Soluble in water
• All react with carbonyl compounds

Piperidine Alkaloids - Pomegranate Alkaloid Uses

• The active component, Pelletierine tannate is used as anthelmintic drug against tape worms & ascaris
• Its pelletierine tannate (E.P.) has Pomegranate alkaloids and tannates
• Tannate salt is less soluble & less absorbed, reducing toxicity.
• The drug Pelletierine is 10 times more active than pseudopelletierine.

Conium Alkaloid Properties

• PseudoAlkaloid with mice like odour
• Non-oxygenated volatile alkaloid.
• Is colourless oily liquid
• very poisonous alkaloid, used as local analgesic

Piperidine Alkaloids- Conium Alkaloids - Coniine

• Come from hemlock fruit called Conium maculatum, (Fam. Umbelliferae, Apiaceae)
• Coniine & 𝛾-Coniceine exist (0.5 -1.5%).

Coniine Synthesis

• Pseudoalkaloid derived from acetate.
• The nitrogen atom is being inserted through transamination.

Piperidine Alkaloids - Conium Alkaloid Properties

• Coniine & γ-Coniceine have are non-oxygenated and volatile
• Coniine is an oily, colorless liquid that has mice-like odor & burning taste.

Piperidine alkaloids-Coniine Pharmacology & Toxicity

• Coniine has a neuromuscular blocking effect and causes subsequent autonomic ganglia stimulation
• For treatment they are local analgesic For ointment for hemorrhoids & anal fissures.
• Coniine is extremely poisonous Coniine: local analgesic ointment for treatment of hemorrhoids & anal fissures.
• Coniine has 120-300MG Lethal Dose Famous for Socrate's execution

Ricinine Alkaloid

• Ricinine is not compatible in acids
• It sublimates and is soluble in hot water and with no reaction it will start to precipitate

Pyridone alkaloids - Ricinine Facts

• It is derived from, Castor, Ricinus communis L. from (Fam. Euphorbiaceae), 1.1 %
• Sublimes at room temperature
• Soluble in boiling water.
• This compound is neutral or acidic in litmus acid tests
• This drug will form not acid salts
• Wagner will form precipitations of the drug, so if there are no precipitations the drug might not have the intended effect

Toxicity

• Ingestion may cause nausea and vomiting and can result in Hemorrhagic gastroenteritis or liver or renal failure.
• Convolusions from Ingestion may cause a coma and lead to respiratory depression and subsequently death

Alkaloids with Heterocyclic Nitrogen and the Tropane Group

• this is a reference to a tropane alkaloid

Tropane Alkaloid Classification

Tropane alkaloid Optically in/active It contains ester Unstable towards acids & alkalis

Tropane Alkaloids - Major Solanaceous Alkaloids

Hyoscyamine, Atropine, and Hyoscine (scopolamine) Alcohol base tropine tropine scopine Esterifying acid l-tropic acid dl-tropic acid l-tropic acid Optical activity active inactive active

MORE INFO on Tropane

▪ Tropane group: bicyclic, 7-membered group formed by condensation of pyrrolidine + piperidine with 1 N in common ▪ Nitrogen bridge is between C-1 & C-5; two asymmetric carbons, but tropane is optically inactive due to intermolecular compensation (i.e. racemic modification)

MORE General Information on Tropane

• They are unstable in strong acids an alkalis
• They're all termolablie

Further Details on esterfication

Tropane Alkaloid Classifications

Plants of the family Solanaceae Plants of the family Erythroxylaceae Leaves of the coca plant or the family Er throxylacea

Distribution information on where tropane Alkoloids are found

• Solanaceae
• Erythroxylaceae
• Convolvulaceae
• Dioscoreaceae