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Papaver somniferum 01

The first individual alkaloid, morphine, was isolated in 1804 from poppy (Papaver somniferum).

Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar structure are also attributed to alkaloids. In addition to carbon, hydrogen and nitrogen, alkaloids may also contain oxygen, sulfur and more rarely other elements such as chlorine, bromine, and phosphorus.

Alkaloids are produced by a large variety of organisms, including bacteria, fungi, plants, and animals, and are part of the group of natural products (also called secondary metabolites). Many alkaloids can be purified from crude extracts by acid-base extraction. Many alkaloids are toxic to other organisms. They often have pharmacological effects and are used as medications, as recreational drugs, or in entheogenic rituals. Examples are the local anesthetic and stimulant cocaine; the psychedelic psilocin; the stimulant caffeine; nicotine; the analgesic morphine; the antibacterial berberine; the anticancer compound vincristine; the antihypertension agent reserpine; the cholinomimeric galantamine; the spasmolysis agent atropine; the vasodilator vincamine; the anti-arhythmia compound quinidine; the anti-asthma therapeutic ephedrine; and the antimalarial drug quinine. Although alkaloids act on a diversity of metabolic systems in humans and other animals, they almost uniformly invoke a bitter taste.

The boundary between alkaloids and other nitrogen-containing natural compounds is not clear-cut. Compounds like amino acid peptides, proteins, nucleotides, nucleic acid, amines, and antibiotics are usually not called alkaloids. Natural compounds containing nitrogen in the exocyclic position (mescaline, serotonin, dopamine, etc.) are usually attributed to amines rather than alkaloids. Some authors, however, consider alkaloids a special case of amines.

NamingEdit

Meissner alkalod definition article 1819

The article that introduced the concept of "alkaloid".

The name "alkaloids" was introduced in 1819 by the German chemist Carl Friedrich Wilhelm Meißner, and is derived from late Latin root alkali (which, in turn, comes from the Arabic al-qalwī – "ashes of plants") and the suffix -οειδής – "like". However, the term came into wide use only after the publication of a review article by Oscar Jacobsen in the chemical dictionary of Albert Ladenburg in the 1880s.

There is no unique method of naming alkaloids. Many individual names are formed by adding the suffix "ine" to the species or genus name. For example, atropine is isolated from the plant Atropa belladonna, strychnine is obtained from the seed of Strychnine tree (Strychnos nux-vomica L.). If several alkaloids are extracted from one plant then their names often contain suffixes "idine", "anine", "aline", "inine", etc. There are also at least 86 alkaloids containing the root "vin" (extracted from the Vinca plant).

History Edit

Friedrich Wilhelm Adam Sertuerner

Friedrich Sertürner, the German chemist who first isolated morphine from opium.

Alkaloid-containing plants have been used by humans since ancient times for therapeutic and recreational purposes. For example, medicinal plants have been known in the Mesopotamia at least around 2000 BC. The Odyssey of Homer referred to a gift given to Helen by the Egyptian queen, a drug bringing oblivion. It is believed that the gift was an opium-containing drug. A Chinese book on houseplants written in 1st–3rd centuries BC mentioned a medical use of Ephedra and opium poppies. Also, coca leaves have been used by South American Indians since ancient times.

Extracts from plants containing toxic alkaloids, such as aconitine and tubocurarine, were used since antiquity for poisoning arrows.

Studies of alkaloids began in the 19th century. In 1804, the German chemist Friedrich Sertürner isolated from opium a "soporific principle" (principium somniferum), which he called "morphium" in honor of Morpheus, the Greek god of dreams; in German and some other Central-European languages, this is still the name of the drug. The term "morphine", used in English and French, was given by the French physicist Joseph Louis Gay-Lussac).

A significant contribution to the chemistry of alkaloids in the early years of its development was made by the French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou, who discovered quinine (1820) and strychnine (1818). Several other alkaloids were discovered around that time, including xanthine (1817), atropine (1819), caffeine (1820), coniine (1827), nicotine (1828), colchicine (1833), sparteine (1851), and cocaine (1860).

The first complete synthesis of an alkaloid was achieved in 1886 by the German chemist Albert Ladenburg. He produced coniine by reacting 2-methylpyridine with acetaldehyde and reducing the resulting 2-propenyl pyridine with sodium. The development of the chemistry of alkaloids was accelerated by the emergence of spectroscopic and chromatographic methods in the 20th century, so that by 2008 more than 12,000 alkaloids had been identified.

298px-Bufotenin.svg

Bufotenin

, an alkaloid from some toads, contains an indole core and is produced in living organisms from the amino acid tryptophan.]]

Classification Edit

Nicotine.svg

The nicotine molecule contains both pyridine (left) and pyrrolidine rings (right).

Compared with most other classes of natural compounds, alkaloids are characterized by a great structural diversity and there is no uniform classification of alkaloids.First classification methods have historically combined alkaloids by the common natural source, e.g., a certain type of plants. This classification was justified by the lack of knowledge about the chemical structure of alkaloids and is now considered obsolete.

More recent classifications are based on similarity of the carbon skeleton (e.g., indole-, isoquinoline-, and pyridine-like) or biogenetic precursor (ornithine, lysine, tyrosine, tryptophan, etc.). However, they require compromises in borderline cases; for example, nicotine contains a pyridine fragment from nicotinamide and pyrrolidine part from ornithine and therefore can be assigned to both classes.

Alkaloids are often divided into the following major groups:

  1. "True alkaloids", which contain nitrogen in the heterocycle and originate from amino acids. Their characteristic examples are atropine, nicotine, and morphine. This group also includes some alkaloids that besides nitrogen heterocycle contain terpene (e.g., evonine) or peptide fragments (e.g. ergotamine). This group also includes piperidine alkaloids coniine and coniceine although they do not originate from amino acids.
  2. "Protoalkaloids", which contain nitrogen and also originate from amino acids. Examples include mescaline, adrenaline and ephedrine.
  3. Polyamine alkaloids – derivatives of putrescine, spermidine, and spermine.
  4. Peptide and cyclopeptide alkaloids.
  5. Pseudalkaloids – alkaloid-like compounds that do not originate from amino acids. This group includes, terpene-like and steroid-like alkaloids, as well as purine-like alkaloids such as caffeine, theobromine, theacrine and theophylline. Some authors classify as pseudoalkaloids such compounds such as ephedrine and cathinone. Those originate from the amino acid phenylalanine, but acquire their nitrogen atom not from the amino acid but through transamination.

Some alkaloids do not have the carbon skeleton characteristic of their group. So, galantamine and homoaporphines do not contain isoquinoline fragment, but are, in general, attributed to isoquinoline alkaloids.

Main classes of monomeric alkaloids are listed in the table below:

Class Major groups Main synthesis steps Examples
Alkaloids with nitrogen heterocycles (true alkaloids)
Pyrrolidine derivatives
250px-Pyrrolidine structure.svg
Ornithine or arginine → putrescine → N-methylputrescine → N-methyl-Δ1-pyrroline Cuscohygrine, hygrine, hygroline, stachydrine
Tropane derivatives
96px-Tropane numbered.svg
Atropine group
Substitution in positions 3, 6 or 7
Ornithine or arginine → putrescine → N-methylputrescine → N-methyl-Δ1-pyrroline Atropine, scopolamine, hyoscyamine
Cocaine group
Substitution in positions 2 and 3
Cocaine, ecgonine
Pyrrolizidine derivatives
527px-Pyrrolizidine.svg
Non-esters In plants: ornithine or arginine → putrescine → homospermidine → retronecine Retronecine, heliotridine, laburnine
Complex esters of monocarboxylic acids Indicine, lindelophin, sarracine
Macrocyclic diesters Platyphylline, trichodesmine
1-aminopyrrolizidines (lolines) L-proline + homoserine|L-homoserine → N-(3-amino-3-carboxypropyl)proline → norloline
Piperidine derivatives
70px-Piperidin.svg
Lysine → cadaverine → Δ1-piperideine Sedamine, lobeline, anaferine, piperine
Octanoic acid → coniceine → coniine Coniine, coniceine
Quinolizidine derivatives
87px-Quinolizidine.svg
Lupinine group Lysine → cadaverine → Δ1-piperideine Lupinine, nupharidin
Cytisine group Cytisine
Sparteine group Sparteine, lupanine, anahygrine
Matrine group Matrine, oxymatrine, allomatridine
Ormosanine group Ormosanine, piptantine
Indolizidine derivatives
82px-Indolizidine.svg
Lysine → δ-semialdehyde of α-aminoadipic acid → pipecolic acid → 1 indolizidinone Swainsonine, castanospermine
Pyridine derivatives
440px-Pyridine.svg
Simple derivatives of pyridine Nicotinic acid → dihydronicotinic acid → 1,2-dihydropyridine Trigonelline, ricinine, arecoline
Polycyclic noncondensing pyridine derivatives Nicotine, nornicotine, anabasine, anatabine
Polycyclic condensed pyridine derivatives Actinidine, gentianine, pediculinine
Sesquiterpene pyridine derivatives Nicotinic acid, isoleucine Evonine, hippocrateine, triptonine
Isoquinoline derivatives and related alkaloids
106px-Isoquinoline numbered.svg
Simple derivatives of isoquinoline Tyrosine or phenylalanine → dopamine or tyramine (for alkaloids Amarillis) Salsoline, lophocerine
Derivatives of 1- and 3-isoquinolines N-methylcoridaldine, noroxyhydrastinine
Derivatives of 1- and 4-phenyltetrahydroisoquinolines Cryptostilin
Derivatives of 5-naftil-isoquinoline Ancistrocladine
Derivatives of 1- and 2-benzyl-izoquinolines Papaverine, laudanosine, sendaverine
Cularine group Cularine, yagonine
Pavines and isopavines Argemonine, amurensine
Benzopyrrocolines Cryptaustoline
Protoberberines Berberine, canadine, ophiocarpine, mecambridine, corydaline
Phthalidisoquinolines Hydrastine, narcotine (Noscapine)
Spirobenzylisoquinolines
Ipecacuanha alkaloids Emetine, protoemetine, ipecoside
Benzophenanthridines Sanguinarine, oxynitidine, corynoloxine
Aporphines Glaucine, coridine, liriodenine
Proaporphines Pronuciferine, glaziovine
Homoaporphines Kreysiginine, multifloramine
Homoproaporphines Bulbocodine
Morphines Morphine, codeine, thebaine, sinomenine
Homomorphines Kreysiginine, androcymbine
Tropoloisoquinolines Imerubrine
Azofluoranthenes Rufescine, imeluteine
Amaryllis alkaloids Lycorine, ambelline, tazettine, galantamine, montanine
Erythrina alkaloids Erysodine, erythroidine
Phenanthrene derivatives Atherosperminine
Protopins Protopine, oxomuramine, corycavidine
Aristolactam Doriflavin
Oxazole derivatives
454px-Oxazole structure.svg
Tyrosine → tyramine
Isoxazole derivatives
Isoxazole structure
Ibotenic acid → Muscimol Ibotenic acid, Muscimol
Thiazole derivatives
454px-Thiazole structure.svg
1-Deoxy-D-xylulose 5-phosphate (DOXP), tyrosine, cysteine Nostocyclamide, thiostreptone
Quinazoline derivatives
106px-Quinazoline numbered.svg
3,4-Dihydro-4-quinazolone derivatives Anthranilic acid or phenylalanine or ornithine Febrifugine
1,4-Dihydro-4-quinazolone derivatives Glycorine, arborine, glycosminine
Pyrrolidine and piperidine quinazoline derivatives Vazicine (peganine)
Acridine derivatives
376px-Acridine.svg
Anthranilic acid Rutacridone, acronicine
Quinoline derivatives
106px-Quinoline numbered.svg
Simple derivatives of quinoline derivatives of 2 – quinolones and 4-quinolone Anthranilic acid → 3-carboxyquinoline Cusparine, echinopsine, evocarpine
Tricyclic terpenoids Flindersine
Furanoquinoline derivatives Dictamnine, fagarine, skimmianine
Quinines Tryptophan → tryptamine → strictosidine (with secologanin) → korinanteal → cinhoninon Quinine, quinidine, cinchonine, cinhonidine
Indole derivatives
103px-Indole numbered.svg
See also: indole alkaloids
Non-isoprene indole alkaloids
Simple indole derivatives Tryptophan → tryptamine or 5-hydroxitriptofan Serotonin, psilocybin, dimethyltryptamine (DMT), bufotenin
Simple derivatives of β-carboline Harman, harmine, harmaline, eleagnine
Pyrroloindole alkaloids Physostigmine (eserine), etheramine, physovenine, eptastigmine
Semiterpenoid indole alkaloids
Ergoline Tryptophan → chanoclavine → agroclavine → elimoclavine → paspalic acid → lysergic acid
Monoterpenoid indole alkaloids
Corynanthe type alkaloids Tryptophan → tryptamine → strictosidine (with secologanin) Ajmalicine, sarpagine, vobasine, ajmaline, yohimbine, reserpine, mitragynine, group strychnine and (Strychnine brucine, aquamicine, vomicine)
Iboga-type alkaloids Ibogamine, ibogaine, voacangine
Aspidosperma-type alkaloids Vincamine, vinca alkaloids, vincotine, aspidospermine
Imidazole derivatives
454px-Imidazole structure.svg
Directly from histidine Histamine, pilocarpine, pilosine, stevensine
Purine derivatives
9H-Purine.svg
Xanthosine (formed in purine biosynthesis) → 7 methylxantosine → 7-methyl xanthine → theobrominecaffeine Caffeine, theobromine, theophylline, saxitoxin
Alkaloids with nitrogen in the side chain (protoalkaloids)
β-Phenylethylamine derivatives
147px-Phenylethylamine numbered.svg
Tyrosine or phenylalanine → dioxyphenilalanine → dopamine → adrenaline and mescaline tyrosine → tyramine phenylalanine → 1-phenylpropane-1,2-dione → cathinone → ephedrine and pseudoephedrine Tyramine, ephedrine, pseudoephedrine, mescaline, cathinone, catecholamines (adrenaline, noradrenaline, dopamine)
Colchicine alkaloids Tyrosine or phenylalanine → dopamine → autumnaline → colchicine Colchicine, colchamine
Muscarine
620px-Muscarine.svg
Glutamic acid → 3-ketoglutamic acid → muscarine (with pyruvic acid) Muscarine, allomuscarine, epimuscarine, epiallomuscarine
Benzylamine
114px-Benzylamine.svg
Phenylalanine with valine, leucine or isoleucine Capsaicin, dihydrocapsaicin, nordihydrocapsaicin
Polyamines alkaloids
Putrescine derivatives
Putrescine.svg
ornithine → putrescine → spermidine → spermine Paucine
Spermidine derivatives
420px-Spermidine.svg
Lunarine, codonocarpine
Spermine derivatives
420px-Spermine.svg
Verbascenine, aphelandrine
Peptide (cyclopeptide) alkaloids
Peptide alkaloids with a 13-membered cycle Nummularine C type From different amino acids Nummularine C, Nummularine S
Ziziphine type Ziziphine A, sativanine H
Peptide alkaloids with a 14-membered cycle Frangulanine type Frangulanine, scutianine J
Scutianine A type Scutianine A
Integerrine type Integerrine, discarine D
Amphibine F type Amphibine F, spinanine A
Amfibine B type Amphibine B, lotusine C
Peptide alkaloids with a 15-membered cycle Mucronine A type Mucronine A
Pseudoalkaloids (terpenes and steroids)
Diterpenes
149px-Isoprene.svg
Lycoctonine type Mevalonic acid → izopentenilpyrophosfate → geranyl pyrophosphate Aconitine, delphinine
Steroids
147px-Cyclopentenophenanthrene.svg
Cholesterol, arginine

Properties Edit

Cyclopelamb2

Head of a lamb born by a sheep that ate leaves of the corn lily plant. The cyclopia in the calf is induced by the alkaloid cyclopamine present in the plant.

Most alkaloids contain oxygen in their molecular structure; those compounds are usually colorless crystals at ambient conditions. Oxygen-free alkaloids, such as nicotine or coniine, are typically volatile, colorless, oily liquids. Some alkaloids are colored, like berberine (yellow) and sanguinarine (orange).

Most alkaloids are weak bases, but some, such as theobromine and theophylline, are amphoteric. Many alkaloids dissolve poorly in water but readily dissolve in organic solvents, such as diethyl ether, chloroform or 1,2-dichloroethane. Caffeine, cocaine, codeine and nicotine are water soluble (with a solubility of ≥1g/L), whereas others, including morphine and yohimbine are highly water soluble (0.1–1 g/L). Alkaloids and acids form salts of various strengths. These salts are usually soluble in water and alcohol and poorly soluble in most organic solvents. Exceptions include scopolamine hydrobromide, which is soluble in organic solvents, and the water-soluble quinine sulfate.

Most alkaloids have a bitter taste or are poisonous when ingested. Alkaloid production in plants appeared to have evolved in response to feeding by herbivorous animals; however, some animals have evolved the ability to detoxify alkaloids. Some alkaloids can produce developmental defects in the offspring of animals that consume but cannot detoxify the alkaloids. One example is the alkaloid cyclopamine, produced in the leaves of corn lily. During the 1950s, up to 25% of lambs born by sheep that had grazed on corn lily had serious facial deformations. These ranged from deformed jaws to cyclopia (see picture). After decades of research, in the 1980s, the compound responsible for these deformities was identified as the alkaloid 11-deoxyjervine, later renamed to cyclopamine.

Distribution in natureEdit

Strychnos nux-vomica - Köhler–s Medizinal-Pflanzen-266

Strychnine tree. Its seeds are rich in strychnine and brucine.

Alkaloids are generated by various living organisms, especially by vascular plants – about 10 to 25% of those contain alkaloids. Therefore, in the past the term "alkaloid" was associated with plants.

The alkaloids content in plants is usually within a few percent and is inhomogeneous over the plant tissues. Depending on the type of plants, the maximum concentration is observed in the leaves (black henbane), fruits or seeds (Strychnine tree), root (Rauwolfia serpentina) or bark (cinchona). Furthermore, different tissues of the same plants may contain different alkaloids.

Beside plants, alkaloids are found in certain types of fungi, such as psilocybin in the fungus of the genus Psilocybe, and in animals, such as bufotenin in the skin of some toads. Many marine organisms also contain alkaloids. Some amines, such as adrenaline and serotonin, which play an important role in higher animals, are similar to alkaloids in their structure and biosynthesis and are sometimes called alkaloids.

ExtractionEdit

Piperine crystals

Crystals of piperine extracted from black pepper.

Because of the structural diversity of alkaloids, there is no single method of their extraction from natural raw materials. Most methods exploit the property of most alkaloids to be soluble in organic solvents but not in water, and the opposite tendency of their salts.

Most plants contain several alkaloids. Their mixture is extracted first and then individual alkaloids are separated. Plants are thoroughly ground before extraction. Most alkaloids are present in the raw plants in the form of salts of organic acids. The extracted alkaloids may remain salts or change into bases. Base extraction is achieved by processing the raw material with alkaline solutions and extracting the alkaloid bases with organic solvents, such as 1,2-dichloroethane, chloroform, diethyl ether or benzene. Then, the impurities are dissolved by weak acids; this converts alkaloid bases into salts that are washed away with water. If necessary, an aqueous solution of alkaloid salts is again made alkaline and treated with an organic solvent. The process is repeated until the desired purity is achieved.

In the acidic extraction, the raw plant material is processed by a weak acidic solution (e.g., acetic acid in water, ethanol, or methanol). A base is then added to convert alkaloids to basic forms that are extracted with organic solvent (if the extraction was performed with alcohol, it is removed first, and the remainder is dissolved in water). The solution is purified as described above.

Alkaloids are separated from their mixture using their different solubility in certain solvents and different reactivity with certain reagents or by distillation.

BiosynthesisEdit

Biological precursors of most alkaloids are amino acids, such as ornithine, lysine, phenylalanine, tyrosine, tryptophan, histidine, aspartic acid, and anthranilic acid. Nicotinic acid can be synthesized from tryptophan or aspartic acid. Ways of alkaloid biosynthesis are too numerous and cannot be easily classified. However, there are a few typical reactions involved in the biosynthesis of various classes of alkaloids, including synthesis of Schiff bases and Mannich reaction.

Synthesis of Schiff basesEdit

Schiff bases can be obtained by reacting amines with ketones or aldehydes. These reactions are a common method of producing C=N bonds.

500px-Schiff base formation.svg

In the biosynthesis of alkaloids, such reactions may take place within a molecule, such as in the synthesis of piperidine:

227px-Schiff base formation intramolecular.svg

Mannich reactionEdit

An integral component of the Mannich reaction, in addition to an amine and a carbonyl compound, is a carbanion, which plays the role of the nucleophile in the nucleophilic addition to the ion formed by the reaction of the amine and the carbonyl.

Mannich

The Mannich reaction can proceed both intermolecularly and intramolecularly:

252px-Mannich reaction intramolecular.svg

Dimer alkaloidsEdit

In addition to the described above monomeric alkaloids, there are also dimeric, and even trimeric and tetrameric alkaloids formed upon condensation of two, three, and four monomeric alkaloids. Dimeric alkaloids are usually formed from monomers of the same type through the following mechanisms:

  • Mannich reaction, resulting in, e.g., voacamine
  • Michael reaction (villalstonine)
  • Condensation of aldehydes with amines (toxiferine)
  • Oxidative addition of phenols (dauricine, tubocurarine)
  • Lactonization (carpaine).

The biological roleEdit

The role of alkaloids for living organisms that produce them is still unclear. It was initially assumed that the alkaloids are the final products of nitrogen metabolism in plants, as urea in mammals. It was later shown that alkaloid concentrations varies over time, and this hypothesis was refuted.

Most of the known functions of alkaloids are related to protection. For example, aporphine alkaloid liriodenine produced by the tulip tree protects it from parasitic mushrooms. In addition, presence of alkaloids in the plant prevents insects and chordate animals from eating it. However, some animals adapted to alkaloids and even use them in their own metabolism. Such alkaloid-related substances as serotonin, dopamine and histamine are important neurotransmitters in animals. Alkaloids are also known to regulate plant growth.

Applications Edit

In medicineEdit

Medical use of alkaloid-containing plants has a long history, and, thus, when the first alkaloids were isolated in the 19th century, they immediately found application in clinical practice. Many alkaloids are still used in medicine, usually in the form of salts, including the following:

Alkaloid Action
Ajmaline antiarrhythmic
Atropine, scopolamine, hyoscyamine anticholinergic
Caffeine Stimulant, diuretic, Adenosine receptor antagonist
Codeine cough medicine, analgesic
Colchicine remedy for gout
Emetine antiprotozoal agent
Ergot alkaloids sympathomimetic, vasodilator, antihypertensive
Morphine analgesic
Nicotine Stimulant, Nicotinic acetylcholine receptor agonist
Physostigmine inhibitor of acetylcholinesterase
Quinidine antiarrhythmic
Quinine antipyretics, antimalarial
Reserpine antihypertensive
Tubocurarine Muscle relaxant
Vinblastine, vincristine antitumor
Vincamine vasodilating, antihypertensive
Yohimbine Stimulant, Aphrodisiac

Many synthetic and semisynthetic drugs are structural modifications of the alkaloids, which were designed to enhance or change the primary effect of the drug and reduce unwanted side-effects. For example, naloxone, an opioid receptor antagonist, is a derivative of thebaine that is present in opium.

In agriculture Edit

Prior to the development of a wide range of relatively low-toxic synthetic pesticides, some alkaloids, such as salts of nicotine and anabasine, were used as insecticides. Their use was limited by their high toxicity to humans.

Use as psychoactive drugs Edit

Preparations of plants containing alkaloids and their extracts, and later pure alkaloids, have long been used as psychoactive substances. Cocaine and cathinone are stimulants of the central nervous system. Mescaline and many of indole alkaloids (such as psilocybin, dimethyltryptamine and ibogaine) have hallucinogenic effect.

There are alkaloids that do not have strong psychoactive effect themselves, but are precursors for semi-synthetic psychoactive drugs. For example, ephedrine and pseudoephedrine are used to produce methcathinone and methamphetamine.

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