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The first individual alkaloid, morphine, was isolated in 1804 from the opium poppy (Papaver somniferum).[1]

Alkaloids are a broad class of naturally occurring organic compounds that contain at least one nitrogen atom. Some synthetic compounds of similar structure may also be termed alkaloids.[2]

Alkaloids are produced by a large variety of organisms including bacteria, fungi, plants, and animals.[3] They can be purified from crude extracts of these organisms by acid-base extraction, or solvent extractions followed by silica-gel column chromatography.[4] Alkaloids have a wide range of pharmacological activities including antimalarial (e.g. quinine), antiasthma (e.g. ephedrine), anticancer (e.g. homoharringtonine),[5] cholinomimetic (e.g. galantamine),[6] vasodilatory (e.g. vincamine), antiarrhythmic (e.g. quinidine), analgesic (e.g. morphine),[7] antibacterial (e.g. chelerythrine),[8] and antihyperglycemic activities (e.g. berberine).[9][10] Many have found use in traditional or modern medicine, or as starting points for drug discovery. Other alkaloids possess psychotropic (e.g. psilocin) and stimulant activities (e.g. cocaine, caffeine, nicotine, theobromine),[11] and have been used in entheogenic rituals or as recreational drugs. Alkaloids can be toxic (e.g. atropine, tubocurarine).[12] Although alkaloids act on a diversity of metabolic systems in humans and other animals, they almost uniformly evoke a bitter taste.[13]

The boundary between alkaloids and other nitrogen-containing natural compounds is not clear-cut.[14] Most alkaloids are basic, although some have neutral[15] and even weakly acidic properties.[16] In addition to carbon, hydrogen and nitrogen, alkaloids may also contain oxygen or sulfur. Rarer still, they may contain elements such as phosphorus, chlorine, and bromine.[17] Compounds like amino acid peptides, proteins, nucleotides, nucleic acid, amines, and antibiotics are usually not called alkaloids.[15] Natural compounds containing nitrogen in the exocyclic position (mescaline, serotonin, dopamine, etc.) are usually classified as amines rather than as alkaloids.[18] Some authors, however, consider alkaloids a special case of amines.[19][20][21]

Naming

[edit]
The article that introduced the concept of "alkaloid".

The name "alkaloids" (German: Alkaloide) was introduced in 1819 by German chemist Carl Friedrich Wilhelm Meissner, and is derived from late Latin root alkali and the Greek-language suffix -οειδής -('like').[nb 1] 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.[22][23]

There is no unique method for naming alkaloids.[24] Many individual names are formed by adding the suffix "ine" to the species or genus name.[25] For example, atropine is isolated from the plant Atropa belladonna; strychnine is obtained from the seed of the Strychnine tree (Strychnos nux-vomica L.).[17] Where several alkaloids are extracted from one plant their names are often distinguished by variations in the suffix: "idine", "anine", "aline", "inine" etc. There are also at least 86 alkaloids whose names contain the root "vin" because they are extracted from vinca plants such as Vinca rosea (Catharanthus roseus);[26] these are called vinca alkaloids.[27][28][29]

History

[edit]
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 Mesopotamia from about 2000 BC.[30] 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.[31] A Chinese book on houseplants written in 1st–3rd centuries BC mentioned a medical use of ephedra and opium poppies.[32] Also, coca leaves have been used by Indigenous South Americans since ancient times.[33]

Extracts from plants containing toxic alkaloids, such as aconitine and tubocurarine, were used since antiquity for poisoning arrows.[30]

Studies of alkaloids began in the 19th century. In 1804, the German chemist Friedrich Sertürner isolated from opium a "soporific principle" (Latin: principium somniferum), which he called "morphium", referring to 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).[34] 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.[35]

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.[36][37]

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

Classifications

[edit]
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. There is no uniform classification.[38] Initially, when knowledge of chemical structures was lacking, botanical classification of the source plants was relied on. This classification is now considered obsolete.[17][39]

More recent classifications are based on similarity of the carbon skeleton (e.g., indole-, isoquinoline-, and pyridine-like) or biochemical precursor (ornithine, lysine, tyrosine, tryptophan, etc.).[17] However, they require compromises in borderline cases;[38] for example, nicotine contains a pyridine fragment from nicotinamide and a pyrrolidine part from ornithine[40] and therefore can be assigned to both classes.[41]

Alkaloids are often divided into the following major groups:[42]

  1. "True alkaloids" contain nitrogen in the heterocycle and originate from amino acids.[43] Their characteristic examples are atropine, nicotine, and morphine. This group also includes some alkaloids that besides the nitrogen heterocycle contain terpene (e.g., evonine[44]) or peptide fragments (e.g. ergotamine[45]). The piperidine alkaloids coniine and coniceine may be regarded as true alkaloids (rather than pseudoalkaloids: see below)[46] although they do not originate from amino acids.[47]
  2. "Protoalkaloids", which contain nitrogen (but not the nitrogen heterocycle) and also originate from amino acids.[43] Examples include mescaline, adrenaline and ephedrine.
  3. Polyamine alkaloids – derivatives of putrescine, spermidine, and spermine.
  4. Peptide and cyclopeptide alkaloids.[48]
  5. Pseudoalkaloids – alkaloid-like compounds that do not originate from amino acids.[49] This group includes terpene-like and steroid-like alkaloids,[50] as well as purine-like alkaloids such as caffeine, theobromine, theacrine and theophylline.[51] Some authors classify ephedrine and cathinone as pseudoalkaloids. Those originate from the amino acid phenylalanine, but acquire their nitrogen atom not from the amino acid but through transamination.[51][52]

Some alkaloids do not have the carbon skeleton characteristic of their group. So, galanthamine and homoaporphines do not contain isoquinoline fragment, but are, in general, attributed to isoquinoline alkaloids.[53]

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[54]
Ornithine or arginine → putrescine → N-methylputrescine → N-methyl-Δ1-pyrroline[55] Cuscohygrine, hygrine, hygroline, stachydrine[54][56]
Tropane derivatives[57]
Atropine group
Substitution in positions 3, 6 or 7 		Ornithine or arginine → putrescine → N-methylputrescine → N-methyl-Δ1-pyrroline[55] Atropine, scopolamine, hyoscyamine[54][57][58]
Cocaine group
Substitution in positions 2 and 3 		Cocaine, ecgonine[57][59]
Pyrrolizidine derivatives[60]
Non-esters In plants: ornithine or arginine → putrescine → homospermidine → retronecine[55] Retronecine, heliotridine, laburnine[60][61]
Complex esters of monocarboxylic acids Indicine, lindelophin, sarracine[60]
Macrocyclic diesters Platyphylline, trichodesmine[60]
1-aminopyrrolizidines (lolines) In fungi: L-proline + L-homoserine → N-(3-amino-3-carboxypropyl)proline → norloline[62][63] Loline, N-formylloline, N-acetylloline[64]
Piperidine derivatives[65]
Lysine → cadaverine → Δ1-piperideine[66] Sedamine, lobeline, anaferine, piperine[46][67]
Octanoic acid → coniceine → coniine[47] Coniine, coniceine[47]
Quinolizidine derivatives[68][69]
Lupinine group Lysine → cadaverine → Δ1-piperideine[70] Lupinine, nupharidin[68]
Cytisine group Cytisine[68]
Sparteine group Sparteine, lupanine, anahygrine[68]
Matrine group. Matrine, oxymatrine, allomatridine[68][71][72]
Ormosanine group Ormosanine, piptantine[68][73]
Indolizidine derivatives[74]
Lysine → δ-semialdehyde of α-aminoadipic acid → pipecolic acid → 1 indolizidinone[75] Swainsonine, castanospermine[76]
Pyridine derivatives[77][78]
Simple derivatives of pyridine Nicotinic acid → dihydronicotinic acid → 1,2-dihydropyridine[79] Trigonelline, ricinine, arecoline[77][80]
Polycyclic noncondensing pyridine derivatives Nicotine, nornicotine, anabasine, anatabine[77][80]
Polycyclic condensed pyridine derivatives Actinidine, gentianine, pediculinine[81]
Sesquiterpene pyridine derivatives Nicotinic acid, isoleucine[21] Evonine, hippocrateine, triptonine[78][79]
Isoquinoline derivatives and related alkaloids[82]
Simple derivatives of isoquinoline[83] Tyrosine or phenylalanine → dopamine or tyramine (for alkaloids Amarillis)[84][85] Salsoline, lophocerine[82][83]
Derivatives of 1- and 3-isoquinolines[86] N-methylcoridaldine, noroxyhydrastinine[86]
Derivatives of 1- and 4-phenyltetrahydroisoquinolines[83] Cryptostilin[83][87]
Derivatives of 5-naftil-isoquinoline[88] Ancistrocladine[88]
Derivatives of 1- and 2-benzyl-izoquinolines[89] Papaverine, laudanosine, sendaverine
Cularine group[90] Cularine, yagonine[90]
Pavines and isopavines[91] Argemonine, amurensine[91]
Benzopyrrocolines[92] Cryptaustoline[83]
Protoberberines[83] Berberine, canadine, ophiocarpine, mecambridine, corydaline[93]
Phthalidisoquinolines[83] Hydrastine, narcotine (Noscapine)[94]
Spirobenzylisoquinolines[83] Fumaricine[91]
Ipecacuanha alkaloids[95] Emetine, protoemetine, ipecoside[95]
Benzophenanthridines[83] Sanguinarine, oxynitidine, corynoloxine[96]
Aporphines[83] Glaucine, coridine, liriodenine[97]
Proaporphines[83] Pronuciferine, glaziovine[83][92]
Homoaporphines[98] Kreysiginine, multifloramine[98]
Homoproaporphines[98] Bulbocodine[90]
Morphines[99] Morphine, codeine, thebaine, sinomenine,[100] heroin
Homomorphines[101] Kreysiginine, androcymbine[99]
Tropoloisoquinolines[83] Imerubrine[83]
Azofluoranthenes[83] Rufescine, imeluteine[102]
Amaryllis alkaloids[103] Lycorine, ambelline, tazettine, galantamine, montanine[104]
Erythrina alkaloids[87] Erysodine, erythroidine[87]
Phenanthrene derivatives[83] Atherosperminine[83][93]
Protopines[83] Protopine, oxomuramine, corycavidine[96]
Aristolactam[83] Doriflavin[83]
Oxazole derivatives[105]
Tyrosine → tyramine[106] Annuloline, halfordinol, texaline, texamine[107]
Isoxazole derivatives
Ibotenic acid → Muscimol Ibotenic acid, Muscimol
Thiazole derivatives[108]
1-Deoxy-D-xylulose 5-phosphate (DOXP), tyrosine, cysteine[109] Nostocyclamide, thiostreptone[108][110]
Quinazoline derivatives[111]
3,4-Dihydro-4-quinazolone derivatives Anthranilic acid or phenylalanine or ornithine[112] Febrifugine[113]
1,4-Dihydro-4-quinazolone derivatives Glycorine, arborine, glycosminine[113]
Pyrrolidine and piperidine quinazoline derivatives Vazicine (peganine)[105]
Acridine derivatives[105]
Anthranilic acid[114] Rutacridone, acronicine[115][116]
Quinoline derivatives[117][118]
Simple derivatives of quinoline derivatives of 2–quinolones and 4-quinolone Anthranilic acid → 3-carboxyquinoline[119] Cusparine, echinopsine, evocarpine[118][120][121]
Tricyclic terpenoids Flindersine[118][122]
Furanoquinoline derivatives Dictamnine, fagarine, skimmianine[118][123][124]
Quinines Tryptophan → tryptamine → strictosidine (with secologanin) → korinanteal → cinhoninon[85][119] Quinine, quinidine, cinchonine, cinhonidine[122]
Indole derivatives[100]
See also: indole alkaloids
 Non-isoprene indole alkaloids
Simple indole derivatives[125] Tryptophan → tryptamine or 5-Hydroxytryptophan[126] Serotonin, psilocybin, dimethyltryptamine (DMT), bufotenin[127][128]
Simple derivatives of β-carboline[129] Harman, harmine, harmaline, eleagnine[125]
Pyrroloindole alkaloids[130] Physostigmine (eserine), etheramine, physovenine, eptastigmine[130]
Semiterpenoid indole alkaloids
Ergot alkaloids[100] Tryptophan → chanoclavine → agroclavine → elimoclavine → paspalic acid → lysergic acid[130] Ergotamine, ergobasine, ergosine[131]
Monoterpenoid indole alkaloids
Corynanthe type alkaloids[126] Tryptophan → tryptamine → strictosidine (with secologanin)[126] Ajmalicine, sarpagine, vobasine, ajmaline, yohimbine, reserpine, mitragynine,[132][133] group strychnine and (Strychnine brucine, aquamicine, vomicine[134])
Iboga-type alkaloids[126] Ibogamine, ibogaine, voacangine[126]
Aspidosperma-type alkaloids[126] Vincamine, vinca alkaloids,[27][135] vincotine, aspidospermine[136][137]
Imidazole derivatives[105]
Directly from histidine[138] Histamine, pilocarpine, pilosine, stevensine[105][138]
Purine derivatives[139]
Xanthosine (formed in purine biosynthesis) → 7 methylxantosine → 7-methylxanthine → theobromine → caffeine[85] Caffeine, theobromine, theophylline, saxitoxin[140][141]
Alkaloids with nitrogen in the side chain (protoalkaloids)
β-Phenylethylamine derivatives[92]
Tyrosine or phenylalanine → dioxyphenilalanine → dopamine → adrenaline and mescaline tyrosine → tyramine phenylalanine → 1-phenylpropane-1,2-dione → cathinone → ephedrine and pseudoephedrine[21][52][142] Tyramine, ephedrine, pseudoephedrine, mescaline, cathinone, catecholamines (adrenaline, noradrenaline, dopamine)[21][143]
Colchicine alkaloids[144]
Tyrosine or phenylalanine → dopamine → autumnaline → colchicine[145] Colchicine, colchamine[144]
Muscarine[146]
Glutamic acid → 3-ketoglutamic acid → muscarine (with pyruvic acid)[147] Muscarine, allomuscarine, epimuscarine, epiallomuscarine[146]
Benzylamine[148]
Phenylalanine with valine, leucine or isoleucine[149] Capsaicin, dihydrocapsaicin, nordihydrocapsaicin, vanillylamine[148][150]
Polyamines alkaloids
Putrescine derivatives[151]
ornithine → putrescine → spermidine → spermine[152] Paucine[151]
Spermidine derivatives[151]
Lunarine, codonocarpine[151]
Spermine derivatives[151]
Verbascenine, aphelandrine[151]
Peptide (cyclopeptide) alkaloids
Peptide alkaloids with a 13-membered cycle[48][153] Nummularine C type From different amino acids[48] Nummularine C, Nummularine S[48]
Ziziphine type Ziziphine A, sativanine H[48]
Peptide alkaloids with a 14-membered cycle[48][153] Frangulanine type Frangulanine, scutianine J[153]
Scutianine A type Scutianine A[48]
Integerrine type Integerrine, discarine D[153]
Amphibine F type Amphibine F, spinanine A[48]
Amfibine B type Amphibine B, lotusine C[48]
Peptide alkaloids with a 15-membered cycle[153] Mucronine A type Mucronine A[45][153]
Pseudoalkaloids (terpenes and steroids)
Diterpenes[45]
Lycoctonine type Mevalonic acid → Isopentenyl pyrophosphate → geranyl pyrophosphate[154][155] Aconitine, delphinine[45][156]
Steroidal alkaloids[157]
Cholesterol, arginine[158] Solanidine, cyclopamine, batrachotoxin[159]

Properties

[edit]

Most alkaloids contain oxygen in their molecular structure; those compounds are usually colorless crystals at ambient conditions. Oxygen-free alkaloids, such as nicotine[160] or coniine,[36] are typically volatile, colorless, oily liquids.[161] Some alkaloids are colored, like berberine (yellow) and sanguinarine (orange).[161]

Most alkaloids are weak bases, but some, such as theobromine and theophylline, are amphoteric.[162] Many alkaloids dissolve poorly in water but readily dissolve in organic solvents, such as diethyl ether, chloroform or 1,2-dichloroethane. Caffeine,[163] cocaine,[164] codeine[165] and nicotine[166] are slightly soluble in water (with a solubility of ≥1g/L), whereas others, including morphine[167] and yohimbine[168] are very slightly water-soluble (0.1–1 g/L). Alkaloids and acids form salts of various strengths. These salts are usually freely soluble in water and ethanol and poorly soluble in most organic solvents. Exceptions include scopolamine hydrobromide, which is soluble in organic solvents, and the water-soluble quinine sulfate.[161]

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.[169] 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. After decades of research, in the 1980s, the compound responsible for these deformities was identified as the alkaloid 11-deoxyjervine, later renamed to cyclopamine.[170]

Distribution in nature

[edit]
Strychnine tree. Its seeds are rich in strychnine and brucine.

Alkaloids are generated by various living organisms, especially by higher plants – about 10 to 25% of those contain alkaloids.[171][172] Therefore, in the past the term "alkaloid" was associated with plants.[173]

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 (for example, black henbane), fruits or seeds (Strychnine tree), root (Rauvolfia serpentina) or bark (cinchona).[174] Furthermore, different tissues of the same plants may contain different alkaloids.[175]

Beside plants, alkaloids are found in certain types of fungus, such as psilocybin in the fruiting bodies of the genus Psilocybe, and in animals, such as bufotenin in the skin of some toads[24] and a number of insects, markedly ants.[176] Many marine organisms also contain alkaloids.[177] 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.[178]

Extraction

[edit]
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.[179] Most methods exploit the property of most alkaloids to be soluble in organic solvents[4] 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.[180] Plants are thoroughly ground before extraction.[179][181] Most alkaloids are present in the raw plants in the form of salts of organic acids.[179] The extracted alkaloids may remain salts or change into bases.[180] 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.[179][182]

Alkaloids are separated from their mixture using their different solubility in certain solvents and different reactivity with certain reagents or by distillation.[183]

A number of alkaloids are identified from insects, among which the fire ant venom alkaloids known as solenopsins have received greater attention from researchers.[184] These insect alkaloids can be efficiently extracted by solvent immersion of live fire ants[4] or by centrifugation of live ants[185] followed by silica-gel chromatography purification.[186] Tracking and dosing the extracted solenopsin ant alkaloids has been described as possible based on their absorbance peak around 232 nanometers.[187]

Biosynthesis

[edit]

Biological precursors of most alkaloids are amino acids, such as ornithine, lysine, phenylalanine, tyrosine, tryptophan, histidine, aspartic acid, and anthranilic acid.[188] Nicotinic acid can be synthesized from tryptophan or aspartic acid. Ways of alkaloid biosynthesis are too numerous and cannot be easily classified.[85] However, there are a few typical reactions involved in the biosynthesis of various classes of alkaloids, including synthesis of Schiff bases and Mannich reaction.[188]

Synthesis of Schiff bases

[edit]
Main article: Schiff base

Schiff bases can be obtained by reacting amines with ketones or aldehydes.[189] These reactions are a common method of producing C=N bonds.[190]

In the biosynthesis of alkaloids, such reactions may take place within a molecule,[188] such as in the synthesis of piperidine:[41]

Mannich reaction

[edit]
Main article: Mannich reaction

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.[190]

The Mannich reaction can proceed both intermolecularly and intramolecularly:[191][192]

Dimer alkaloids

[edit]

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:[193]

There are also dimeric alkaloids formed from two distinct monomers, such as the vinca alkaloids vinblastine and vincristine,[27][135] which are formed from the coupling of catharanthine and vindoline.[194][195] The newer semi-synthetic chemotherapeutic agent vinorelbine is used in the treatment of non-small-cell lung cancer.[135][196] It is another derivative dimer of vindoline and catharanthine and is synthesised from anhydrovinblastine,[197] starting either from leurosine[198][199] or the monomers themselves.[135][195]

Biological role

[edit]

Alkaloids are among the most important and best-known secondary metabolites, i.e. biogenic substances not directly involved in the normal growth, development, or reproduction of the organism. Instead, they generally mediate ecological interactions, which may produce a selective advantage for the organism by increasing its survivability or fecundity. In some cases their function, if any, remains unclear.[200] An early hypothesis, that alkaloids are the final products of nitrogen metabolism in plants, as urea and uric acid are in mammals, was refuted by the finding that their concentration fluctuates rather than steadily increasing.[14]

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, the presence of alkaloids in the plant prevents insects and chordate animals from eating it. However, some animals are adapted to alkaloids and even use them in their own metabolism.[201] Such alkaloid-related substances as serotonin, dopamine and histamine are important neurotransmitters in animals. Alkaloids are also known to regulate plant growth.[202] One example of an organism that uses alkaloids for protection is the Utetheisa ornatrix, more commonly known as the ornate moth. Pyrrolizidine alkaloids render these larvae and adult moths unpalatable to many of their natural enemies like coccinelid beetles, green lacewings, insectivorous hemiptera and insectivorous bats.[203] Another example of alkaloids being utilized occurs in the poison hemlock moth (Agonopterix alstroemeriana). This moth feeds on its highly toxic and alkaloid-rich host plant poison hemlock (Conium maculatum) during its larval stage. A. alstroemeriana may benefit twofold from the toxicity of the naturally occurring alkaloids, both through the unpalatability of the species to predators and through the ability of A. alstroemeriana to recognize Conium maculatum as the correct location for oviposition.[204] A fire ant venom alkaloid known as solenopsin has been demonstrated to protect queens of invasive fire ants during the foundation of new nests, thus playing a central role in the spread of this pest ant species around the world.[205]

Applications

[edit]

In medicine

[edit]

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.[206] Many alkaloids are still used in medicine, usually in the form of salts widely used including the following:[14][207]

Alkaloid Action
Ajmaline Antiarrhythmic
Emetine Antiprotozoal agent, emesis
Ergot alkaloids Vasoconstriction, hallucinogenic, Uterotonic
Glaucine Antitussive
Morphine Analgesic
Nicotine Stimulant, nicotinic acetylcholine receptor agonist
Physostigmine Inhibitor of acetylcholinesterase
Quinidine Antiarrhythmic
Quinine Antipyretic, antimalarial
Reserpine Antihypertensive
Tubocurarine Muscle relaxant
Vinblastine, vincristine Antitumor
Vincamine Vasodilating, antihypertensive
Yohimbine Stimulant, aphrodisiac
Berberine Antihyperglycaemic[10]

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.[208] For example, naloxone, an opioid receptor antagonist, is a derivative of thebaine that is present in opium.[209]

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.[210]

Use as psychoactive drugs

[edit]

Preparations of plants and fungi containing alkaloids and their extracts, and later pure alkaloids, have long been used as psychoactive substances. Cocaine, caffeine, and cathinone are stimulants of the central nervous system.[211][212] Mescaline and many indole alkaloids (such as psilocybin, dimethyltryptamine and ibogaine) have hallucinogenic effect.[213][214] Morphine and codeine are strong narcotic pain killers.[215]

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.[216] Thebaine is used in the synthesis of many painkillers such as oxycodone.

See also

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Explanatory notes

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Citations

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  1. ^ Luch, Andreas (2009). Molecular, Clinical and Environmental Toxicology, Volume 1: Molecular Toxicology. Vol. 1. Springer. p. 20. ISBN 9783764383367. OCLC 1056390214.
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Alkaloid

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Alkaloids are a diverse class of naturally occurring organic compounds, with over 12,000 known structures, characterized by the presence of at least one atom within a heterocyclic ring structure, typically exhibiting basic properties due to the nitrogen's . These compounds are primarily secondary metabolites biosynthesized from such as , , or , and they often display potent physiological activities in biological systems. Found predominantly in but also in fungi, , marine organisms, and some animals, alkaloids serve ecological roles including defense against herbivores and pathogens through their bitterness and toxicity. The term "alkaloid" was coined in 1819 by German chemist Carl F. Wilhelm Meissner to describe these nitrogenous bases, following the isolation of from the opium poppy () in 1805 by , marking the first recognized plant alkaloid. This discovery initiated systematic studies into their chemistry, with subsequent isolations including in 1818 and in 1820, highlighting their complex structures and pharmacological potential. of alkaloids involves enzymatic pathways that incorporate from precursors, leading to a vast array of structural variations; for instance, alkaloids derive from , while alkaloids stem from . Alkaloids are broadly classified into three main types based on their biosynthetic origins: true alkaloids, which are heterocyclic derived directly from ; protoalkaloids, which arise from but lack a heterocyclic ring; and pseudoalkaloids, which are not derived from but incorporate nitrogen through other pathways, such as from or terpenoids. They can also be categorized by chemical skeleton, including prominent groups like (e.g., ), (e.g., ), (e.g., serotonin), and (e.g., ) alkaloids. Notable examples include from and , from , and from bark, each demonstrating unique bioactivities. In pharmacology, alkaloids hold significant therapeutic value, serving as analgesics (e.g., morphine), antimalarials (e.g., quinine), stimulants (e.g., caffeine), and anticancer agents, with many modern drugs derived from or inspired by these natural products. Their biological activities extend to antimicrobial, anti-inflammatory, and neuroprotective effects, underscoring their role in drug discovery, though toxicity concerns necessitate careful study. Ongoing research explores their ecological functions and potential in addressing antimicrobial resistance and neurological disorders.

Naming and Definition

Etymology and Historical Naming

The term "alkaloid" was coined in 1819 by the German chemist and pharmacist Carl Friedrich Wilhelm Meissner to describe a class of naturally occurring organic compounds with basic properties, derived primarily from plants. The word originates from "alkali," itself from the Arabic "al-qali," referring to the calcined ashes of saltwort plants (Salsola kali) rich in sodium carbonate and used historically for soap and glass production, combined with the Greek suffix "-oid" from "eidos," meaning form or resemblance, thus denoting substances resembling alkalis in their reaction with acids to form salts. In the early 19th century, following the isolation of in 1805 by , naming practices for alkaloids were largely descriptive, drawing from their botanical origins, discoverers, or pharmacological effects to facilitate identification amid rapid discoveries. For example, was named after , the Greek god of dreams, reflecting its potent and properties from the opium poppy (). Similarly, atropine, isolated in 1833 from Atropa belladonna (deadly nightshade), derives its name from —one of the three Fates in who severed the thread of life—symbolizing the plant's toxic, potentially fatal effects that cause and . These conventions often appended the suffix "-ine" to Latinized plant genera or effect-related terms, as seen in names like (from ) or (from ), emphasizing empirical observation over structural insight. As alkaloid chemistry matured in the late 19th and 20th centuries, naming evolved from ad hoc descriptors to more standardized systems, culminating in guidelines from the International Union of Pure and Applied Chemistry (IUPAC). Under IUPAC recommendations in the Nomenclature of Organic Chemistry (Blue Book, Chapter P-10), alkaloids as nitrogenous bases are named using retained trivial names for well-known parent structures (e.g., for derivatives, for alkaloids) where historically entrenched, or systematic substitutive for novel compounds, treating them as von Baeyer polycyclic systems, fused heterocycles, or derivatives with prefixes like "nor-" for demethylation. This framework ensures unambiguous identification while preserving legacy names in and studies, balancing tradition with precision for the diverse class exceeding 20,000 known members.

Chemical Criteria and Scope

Alkaloids are defined as naturally occurring organic compounds that contain at least one atom and exhibit basic properties, typically arising from the of electrons on the , which allows them to form salts with acids. These compounds are secondary metabolites predominantly found in plants, but also in fungi, , and some animals, and they often display physiological activity in biological systems. The term "alkaloid" derives from their alkaline nature, reflecting the basic character imparted by the atom. Structurally, alkaloids require the presence of at least one atom, usually incorporated into a heterocyclic ring system, with the majority biosynthesized from such as , , , or through and further modifications. The basicity stems specifically from the availability of the nitrogen's , which can accept a proton, though this property varies based on the electronic environment around the nitrogen—such as in cases where the lone pair is delocalized into an aromatic system, reducing basic strength. Non-basic nitrogen-containing compounds, like peptides, proteins, or simple amines without the characteristic complexity, are excluded from this class, as they lack the alkaline reactivity and structural sophistication typical of alkaloids. The scope of alkaloids is delineated into three main types based on their biosynthetic origins: true alkaloids, which are heterocyclic derived directly from ; protoalkaloids, which arise from but lack a heterocyclic ring; and pseudoalkaloids, which are not derived from but incorporate through other pathways, such as from or terpenoids. True alkaloids feature fully integrated into a heterocyclic ring and are directly derived from , exemplified by alkaloids like or alkaloids like atropine. In contrast, protoalkaloids contain from precursors but lack a heterocyclic ring, resulting in acyclic or simpler structures, such as ephedrine from . Boundary cases include betaines, which are zwitterionic like derived from ; they are sometimes broadly included due to their natural occurrence and content but often excluded from strict alkaloid classifications because their quaternary lacks a free , rendering them non-basic and neutral rather than alkaline. oxides, such as N-oxides of pyrrolizidine alkaloids, are generally included within the scope as they represent oxidized derivatives of basic alkaloids, retaining physiological relevance despite altered basicity, and are often isolated in this form from plants.

History

Early Isolation and Discoveries

The isolation of the first alkaloid, morphine, marked a pivotal moment in natural product chemistry. In 1804, German pharmacist Friedrich Sertürner successfully extracted morphine from opium derived from the Papaver somniferum poppy plant by dissolving the raw opium in acid, followed by neutralization with ammonia to precipitate the crystalline substance. This acid-base extraction technique represented an early application of solvent-based methods to purify bioactive compounds from plant material, enabling Sertürner to identify morphine as the primary active agent responsible for opium's analgesic properties. Sertürner's work, published in 1817 after further refinement, laid the groundwork for systematic alkaloid research by demonstrating that complex plant extracts could yield pure, pharmacologically potent isolates. Building on this foundation, pharmacists and chemists advanced isolation techniques through solvent extraction, targeting alkaloids in various plant sources. In 1819, German chemist isolated from beans using alcohol and water-based extractions, recognizing its stimulating effects and contributing to early understandings of alkaloid in organic solvents. Similarly, in 1820, French pharmacists Pierre-Joseph Pelletier and Joseph-Bienaimé Caventou extracted from bark via alcohol dissolution followed by acid treatment and crystallization, a method that improved yield and purity over traditional decoctions. These innovations by Runge and Pelletier popularized solvent extraction as a reliable tool for alkaloid purification, facilitating the identification of pharmacologically active principles in diverse botanicals. Subsequent discoveries further expanded the repertoire of isolated alkaloids and their applications in . In 1818, Pelletier and Caventou also isolated from the seeds of , revealing its extreme toxicity. In 1828, German chemists Wilhelm Posselt and Karl Ludwig Reimann isolated from tobacco leaves using solvent extraction with alcohol and acids, highlighting its potent physiological effects and toxicity. Four years later, in 1832, French chemist Pierre Robiquet obtained from through a similar extraction process involving acid solubilization and precipitation, revealing it as a milder relative to . These early isolations profoundly influenced by providing standardized compounds for therapeutic use; notably, quinine's purification revolutionized treatment, replacing unreliable bark infusions with a targeted antimalarial agent that reduced mortality during 19th-century epidemics and colonial expeditions. Collectively, such breakthroughs spurred the pharmaceutical industry's growth, shifting medicine from empirical herbal remedies to evidence-based alkaloid-derived drugs.

Development of Alkaloid Chemistry

The development of alkaloid chemistry accelerated in the late 19th and early 20th centuries as researchers shifted from isolation to structural elucidation, employing degradative techniques to dismantle complex molecules into identifiable fragments. Methods such as Hofmann exhaustive methylation, pioneered in 1851, involved quaternization of followed by to yield alkenes and reveal carbon skeletons, while Emde degradation used metal reductions to cleave benzyl-nitrogen bonds in alkaloids. These approaches were essential for mapping ring systems in compounds like and , though progress was slow due to the intricate polycyclic architectures typical of alkaloids. A pivotal milestone came in 1925 when Robert Robinson elucidated the structure of through systematic degradation and synthetic correlations, confirming its core fused with a ring. Robinson's work built on earlier degradations by researchers like Knorr and , integrating empirical formulas with partial syntheses to resolve longstanding ambiguities in alkaloids. His contributions extended to biosynthetic theory; in 1917, Robinson proposed the first hypotheses for alkaloid formation, positing that simple and aldehydes condense via Mannich-like reactions to form and other skeletons, influencing subsequent biogenetic studies. The mid-20th century marked a transformative shift with the introduction of spectroscopic tools, particularly after the 1950s. (NMR) , advanced by the development of high-resolution instruments in the 1960s, allowed precise determination of proton environments and in alkaloids without destructive , as seen in the structural of complex indole types like ajmaline. (MS), evolving from electron impact to tandem MS by the 1970s, provided molecular weights and fragmentation patterns that pinpointed nitrogen positions and side chains, accelerating elucidations of over 10,000 known alkaloids. These techniques supplanted degradative methods for routine use, enabling rapid advances in fields like chemistry. In the late 20th and early 21st centuries, alkaloid chemistry integrated approaches to uncover genetic underpinnings. efforts in the 2010s identified biosynthetic gene clusters in plants like , revealing tandem duplications and co-localized enzymes for monoterpenoid alkaloids such as vinblastine precursors; for example, transcriptomic analysis mapped over 30 genes in strictosidine synthase clusters across chromosomes. complemented this by correlating metabolite profiles with , facilitating pathway reconstructions through isotope labeling and high-throughput LC-MS. These developments have illuminated non-canonical enzymes, like cytochrome P450s in late-stage modifications. Global contributions have enriched the field, with European chemists like Robinson laying foundational synthetic frameworks, while Asian researchers, particularly from India and China, advanced extractions from regional flora such as Rauwolfia species using chromatography innovations in the 1970s–1980s. Latin American scientists, drawing on Amazonian biodiversity, contributed isolation strategies for tropane alkaloids from Solanaceae in the 1990s, emphasizing ethnobotanical integrations. In the 2020s, research has increasingly addressed sustainable sourcing amid biodiversity loss, with supercritical fluid extractions and synthetic biology proposed to reduce pressure on endangered species like those yielding paclitaxel precursors.

Classifications

Structural Types

Alkaloids are classified structurally based on their core chemical skeletons, particularly the heterocyclic ring systems containing atoms, which form the basis of their and diversity. This classification emphasizes the arrangement of rings and functional groups, reflecting the vast structural variability among these compounds. True alkaloids, the predominant group, incorporate within a heterocyclic framework derived typically from precursors, while exceptions exist outside this norm. The major structural classes include several key heterocyclic types. Pyrrolidine alkaloids feature a five-membered ring with one nitrogen atom, as seen in , a compound isolated from plants that combines a ring with a pyridine moiety. Piperidine alkaloids possess a six-membered ring containing , exemplified by piperine from black pepper, which includes a piperidine linked to a phenyl ring via a peptide bond. Pyridine alkaloids are characterized by a six-membered ring with nitrogen, such as trigonelline found in fenugreek seeds, notable for its betaine structure. Tropane alkaloids consist of a bridged bicyclic system derived from pyrrolidine, represented by cocaine from coca leaves, which bears ester functionalities enhancing its pharmacological profile. Quinoline alkaloids involve a fused benzene and pyridine ring, with quinine from cinchona bark serving as a classic antimalarial example featuring a quinuclidine side chain. Isoquinoline alkaloids display a fused benzene and partially saturated pyridine ring, as in morphine from opium poppy, which includes phenolic and alcoholic groups critical to its opioid activity. Indole alkaloids are built around a fused benzene and pyrrole ring, including strychnine from Strychnos nux-vomica, a toxic compound affecting neurotransmission. Imidazole alkaloids contain a five-membered ring with two nitrogen atoms, like pilocarpine from Pilocarpus jaborandi, used in glaucoma treatment. Purine alkaloids feature a fused imidazole and pyrimidine system, such as caffeine from coffee beans, a xanthine derivative with methyl groups at specific . These heterocyclic structures often exhibit complex , with multiple chiral centers influencing ; for instance, vinca alkaloids like possess several asymmetric carbons in their intricate polycyclic frameworks, contributing to their microtubule-binding properties. Non-heterocyclic exceptions, known as protoalkaloids, contain nitrogen from but lack incorporation into a , such as from Ephedra plants, which features a backbone. This structural diversity underscores the adaptability of alkaloids in natural systems, though all classes share the defining basic nitrogen characteristic.

Biosynthetic Origins

Alkaloids are primarily classified by their biosynthetic origins, which trace back to specific precursor molecules and metabolic pathways that dictate their core structures. This classification highlights the diversity of alkaloid formation in nature, predominantly from amino acids but also from other biogenic units, emphasizing the role of plants, fungi, and microbes in secondary metabolism. The majority of alkaloids derive from amino acid precursors through pathways involving decarboxylation, transamination, and condensation reactions that form characteristic heterocyclic rings. Ornithine and arginine serve as precursors for pyrrolidine alkaloids, such as nicotine and hygrine, where ornithine undergoes decarboxylation to putrescine, followed by condensation to build the pyrrolidine ring. Lysine acts as the starting point for piperidine alkaloids, like piperine and lobeline, via decarboxylation to cadaverine and subsequent cyclization. Tyrosine is the key precursor for isoquinoline alkaloids, including the benzylisoquinoline subclass in opium poppies; here, two molecules of tyrosine are converted to dopamine and 4-hydroxyphenylacetaldehyde through decarboxylation and oxidation, which then condense to form (S)-norcoclaurine, the foundational unit for compounds like morphine and codeine. Tryptophan provides the indole nucleus for indole alkaloids, such as strychnine and vinblastine, beginning with decarboxylation to tryptamine and further modifications via condensation and prenylation. Histidine contributes to imidazole alkaloids, exemplified by pilocarpine, through decarboxylation to histamine and ring closure mechanisms. These pathways underscore the evolutionary conservation of amino acid-derived alkaloid synthesis across taxa. Beyond origins, certain alkaloids arise from non-amino acid precursors, reflecting integration with other metabolic routes. Steroidal alkaloids, such as and tomatidine found in plants, are biosynthesized from , where the scaffold undergoes at the C-26 position early in the pathway, followed by modifications to introduce nitrogen and form the alkaloid structure. Terpenoid alkaloids, including those like in species, originate from units via the mevalonate or methylerythritol pathways, yielding backbones that are then nitrogenated through incorporation of fragments or . These classes illustrate how alkaloid can hybridize with and . Recent discoveries have revealed hybrid biosynthetic pathways that combine and origins, particularly in fungi. alkaloids, produced by Claviceps species, exemplify this through the of with (DMAPP), an isoprenoid unit, to form dimethylallyltryptophan as the initial intermediate; subsequent cyclizations and modifications yield derivatives like ergotamine. This indole-terpenoid fusion highlights the versatility of fungal metabolism in generating pharmacologically potent alkaloids.

Pharmacological Categories

Alkaloids exhibit a broad spectrum of pharmacological activities, allowing their classification based on primary biological effects and therapeutic potentials, which often stem from interactions with specific molecular targets in human physiology. This categorization highlights their roles as analgesics, antimalarials, stimulants, hallucinogens, antihypertensives, enzyme inhibitors, and emerging agents in anticancer and antimicrobial therapies, with notable overlaps where compounds display multifaceted actions. Such classifications aid in understanding their therapeutic utility while emphasizing the need for careful dosing due to potential toxicity. Prominent among analgesic alkaloids are the opioids, exemplified by , an alkaloid isolated from , which binds to mu-opioid receptors to modulate pain perception in the . Antimalarial alkaloids include , a derivative from bark, that inhibits by disrupting heme polymerization within infected erythrocytes. Stimulants such as , a alkaloid present in and species, promote by blocking A1 and A2A receptors, thereby enhancing neuronal activity. Hallucinogenic effects are characteristic of , a alkaloid from mushrooms, which is dephosphorylated to and activates serotonin 5-HT2A receptors to alter perception and cognition. Antihypertensive properties are seen in , an from Rauwolfia serpentina, which depletes monoamine stores in sympathetic neurons, reducing peripheral . Alkaloids also function through targeted mechanisms, such as receptor or antagonism and inhibition; for example, , an from , reversibly inhibits to increase levels at synapses. In emerging categories, anticancer alkaloids like (Taxol), a diterpenoid originally from but often semi-synthetically produced, stabilize to arrest in rapidly dividing tumor cells. Antimicrobial activity is demonstrated by , a protoberberine alkaloid from species, which compromises bacterial cell membranes and suppresses efflux pumps to combat pathogens including . These categories underscore the pharmacological versatility of alkaloids, though polypharmacology—where a single compound affects multiple targets—complicates precise classification and requires interdisciplinary research for optimization.

Properties

Physical Characteristics

Alkaloids generally manifest as crystalline solids at , frequently presenting as colorless or white powders that reflect their high purity in isolated forms. This crystalline nature arises from their molecular structures, allowing for ordered lattice formation, though exceptions occur; for instance, exists as a colorless, volatile with a of 247 °C. Colored variants are less common but notable, such as , which appears yellow due to its conjugated chromophores. Solubility profiles of alkaloids are influenced by their basic atoms, rendering the free bases sparingly soluble in but highly soluble in organic solvents such as , , and . Formation of salts, particularly hydrochlorides or sulfates, markedly enhances solubility by of the , facilitating their dissolution in aqueous media for pharmaceutical applications. This dual solubility behavior—lipid-soluble in neutral or basic conditions and -soluble when acidified—underpins their extraction and . Melting points for most alkaloids fall within the range of 100–300 °C, varying with molecular weight and intermolecular forces; for example, atropine melts at approximately 115 °C, while requires 254 °C. Volatility differs across the class, with lower-molecular-weight examples like exhibiting liquid states and moderate volatility at ambient conditions. Optically, many alkaloids are chiral and levorotatory, owing to asymmetric centers often involving tertiary nitrogen atoms, as seen in . Additionally, their conjugated systems, such as those in or scaffolds, lead to characteristic UV absorption maxima typically between 200–400 nm, aiding spectroscopic identification.

Chemical Reactivity

Alkaloids exhibit basic character primarily due to the presence of one or more atoms in their structures, which can accept protons to form conjugate acids with pKa values typically ranging from 5 to 12, depending on the type of nitrogen (e.g., aliphatic amines around 9-11, aromatic amines lower near 5) and structural features. This basicity enables alkaloids to react with acids to form water-soluble salts, such as , which enhances their and is a common method for isolation and purification. The basic strength is exploited in analytical detection, where alkaloids are titrated with acids like sulfuric or to determine their concentration based on the endpoint of neutralization. Key reactions of alkaloids involve and at the nitrogen, reversible processes that alter and ; for instance, protonation shifts alkaloids from lipid-soluble free bases to water-soluble salts. Tertiary nitrogen-containing alkaloids can undergo quaternization by reaction with alkyl halides, forming quaternary ammonium salts like , which increases polarity and often enhances pharmacological potency. is prominent in alkaloids with or linkages, such as , which upon alkaline yields , , and , or atropine, which hydrolyzes to and tropic acid. Oxidation and reduction reactions modify alkaloid structures, often targeting methyl groups on or oxygen; a representative example is the O-demethylation of to using reagents like sodium propylmercaptide in , yielding in high efficiency. This transformation highlights reductive demethylation pathways that can be achieved chemically, altering bioactivity. Many alkaloids display limited stability, particularly to and , leading to degradation; for example, undergoes thermal decomposition with approximately 50% loss after 30-40 minutes of heating in food matrices, while ergot alkaloids like ergometrine are rapidly degraded by exposure. , an alkaloid, is notably sensitive to both and elevated temperatures, necessitating protected storage to prevent oxidative breakdown.

Natural Distribution

Occurrence in Plants

Alkaloids are ubiquitous secondary metabolites in the plant kingdom, with more than 20,000 distinct structures identified, predominantly from angiosperm species. These nitrogen-containing compounds occur in approximately 15-30% of flowering plants, where they contribute to ecological defense against herbivores and pathogens. Surveys from the early 2020s, including analyses of diverse herbaceous and woody species, estimate alkaloids in around 20% of plant species globally, reinforcing their role in protective strategies. Taxonomically, alkaloids are more prevalent in dicotyledons than in monocotyledons, with dicots hosting a greater number of alkaloid-producing families and genera. Within angiosperms, certain families exhibit particularly high diversity and abundance, such as the (nightshade family), which is renowned for alkaloids like atropine and found in genera including Atropa and . Similarly, the family is a major source of alkaloids, including and , primarily in species. Other notable examples include , a alkaloid present in plants of the family. Alkaloid concentrations vary widely across plant tissues and species, typically ranging from trace amounts to several percent of dry weight, with the highest levels often observed in reproductive and protective structures such as , bark, and leaves. On average, leaves contain the maximum alkaloid content, followed by fruits and , , and bark, reflecting their accumulation in vulnerable or exposed plant parts for defense. A striking example is the opium latex from capsules, which harbors 10-12% alongside other alkaloids, comprising up to 20% total alkaloid content in crude form.

Presence in Animals and Microbes

Alkaloids are relatively rare in animals compared to their prevalence in plants, where they constitute the primary natural reservoir. In animals, most documented cases involve sequestration from dietary sources rather than de novo biosynthesis. A prominent example is batrachotoxin, a steroidal alkaloid found in the skin secretions of poison dart frogs of the genus Phyllobates, such as P. terribilis. This highly potent neurotoxin, which binds to voltage-gated sodium channels, is acquired through the frogs' diet of alkaloid-containing insects and mites, as captive-raised frogs lack these compounds unless fed wild prey. In microbial organisms, alkaloids are more commonly biosynthesized, serving roles in ecological interactions. Fungi, particularly the ascomycete , produce ergot alkaloids like ergotamine through non-ribosomal synthetases in submerged cultures and sclerotia on infected rye plants. This indole-based alkaloid, derived from L-tryptophan and L-proline, exemplifies fungal , with production yields reaching up to 1000 μg/mL under optimized conditions. Bacteria also contribute, as seen with streptazolin, a tetramic alkaloid isolated from marine species such as S. chartreusis NA02069. This compound, featuring a bicyclic oxazinone ring, arises from a polyketide-nonribosomal hybrid pathway and has been detected in strains from coastal sediments. Marine animals, including sponges, harbor unique alkaloid classes often halogenated for environmental . Bromopyrrole alkaloids, such as oroidin and hymenidin, are abundant in genera like Agelas and Stylissa, where they are biosynthesized via pyrrole-imidazole pathways. These nitrogen-rich metabolites, featuring brominated pyrroles, have been isolated from Indo-Pacific specimens and contribute to . Evolutionarily, animal alkaloids frequently trace to horizontal gene transfer (HGT) from microbial donors or dietary uptake, while microbial variants often involve de novo gene clusters. Genomic studies from the 2020s, including analyses of fungal and bacterial BGCs, reveal HGT events facilitating alkaloid diversification, such as polyketide synthase transfers in actinomycetes and ascomycetes.

Biosynthesis

General Pathways

Alkaloid biosynthesis generally begins with amino acid precursors derived from primary metabolism, such as , , , , and , which are classified into major biogenic groups like ornithine/lysine-derived or tyrosine/phenylalanine-derived alkaloids. These pathways are universal across , microbes, and some animals, involving a series of enzymatic transformations that build nitrogen-containing heterocyclic structures. The core stages of alkaloid biosynthesis follow a sequential framework: initial modification of amino acid precursors through decarboxylation or amination to form biogenic amines, followed by cyclization to establish the characteristic ring systems, and concluding with decoration steps that add functional groups for structural diversity and bioactivity. Decarboxylation typically removes the carboxyl group from amino acids, yielding amines like putrescine or tyramine, while amination introduces additional nitrogen via transaminases. Cyclization then assembles these intermediates into cyclic scaffolds, such as piperidine or indole rings, often through condensation reactions. Decoration involves post-cyclization modifications, including methylation using S-adenosylmethionine-dependent methyltransferases and glycosylation by glycosyltransferases, which enhance solubility, stability, or toxicity. Key enzyme classes driving these pathways include pyridoxal 5'-phosphate (PLP)-dependent decarboxylases, such as , which catalyze the committed step of formation from precursors like L-tyrosine or L-tryptophan. Transaminases facilitate transfer in steps, while monooxygenases perform oxidative modifications, including hydroxylations essential for ring formation or decoration. These enzymes, often part of multienzyme complexes, ensure efficient substrate channeling. Biosynthetic processes are energy-intensive, relying on for activations in and other conjugations, and are spatially compartmentalized in organisms, particularly in where enzymes and intermediates are segregated into organelles like vacuoles to prevent autotoxicity and optimize flux. For instance, storage in vacuoles maintains alkaloid concentrations without disrupting cytosolic metabolism. Regulation of these pathways is tightly controlled at transcriptional and post-transcriptional levels, often induced by environmental stresses such as herbivory, which upregulates genes for in plants via signaling, enhancing defense responses. This stress-responsive mechanism ensures alkaloid production aligns with ecological pressures.

Key Reaction Mechanisms

One of the pivotal reaction mechanisms in alkaloid is the formation of Schiff bases, which involves the of a primary to an , followed by to generate an or intermediate. This creates a reactive that serves as a key precursor in subsequent cyclizations. In the Pictet-Spengler reaction, a hallmark of alkaloid formation, the derived from a β-phenethylamine and an undergoes intramolecular electrophilic attack by the aromatic ring at the ortho position, yielding a cyclic structure with defined . This mechanism is enzyme-catalyzed , such as by in the of alkaloids like , where the enzyme positions substrates to favor the 1S configuration at the new chiral center. The represents another core mechanism, characterized by the three-component coupling of , an , and a carbon to produce β-amino carbonyl compounds. In alkaloid , this proceeds via initial formation of an iminium ion from the amine and , which is then attacked by an enolizable carbon , followed by to yield the product. For tropane alkaloids, such as those in cocaine , an intramolecular variant occurs where N-methyl-Δ¹-pyrrolinium condenses with a polyketide-derived unit, cyclizing to form the bicyclic ring through enamine-imine tautomerism and . This step is facilitated by type III enzymes that generate the necessary acyl intermediates, ensuring efficient scaffold assembly. Beyond these, diverse enzymatic mechanisms underpin other alkaloid classes. In quinolizidine alkaloid biosynthesis, synthase-like enzymes contribute to chain extension and cyclization, where lysine-derived is oxidized to Δ¹-piperideine, which dimerizes via to form the fused ring system, often with enzymatic control over . For alkaloids, strictosidine synthase catalyzes a stereospecific Pictet-Spengler between and secologanin, involving protonation of the aldehyde to enhance electrophilicity, followed by formation and C3 attack, yielding (S)-strictosidine as the universal precursor for over 3,000 monoterpenoid alkaloids. The enzyme's , featuring aspartate residues, facilitates proton transfers and stabilizes the for high-fidelity stereocontrol. Stereoselectivity in alkaloid biosynthesis is critically governed by enzymes that dictate chiral center formation during complex assemblies. In the dimerization leading to , an anticancer , catharanthine undergoes enzymatic oxidation to an ion, which couples with vindoline via at C16', with the ensuring >95% diastereoselectivity for the natural (3R,4S) configuration through substrate binding and stabilization. This enzymatic control contrasts with non-enzymatic couplings, which yield mixtures, highlighting the role of oxidoreductases and peroxidases in achieving the bioactive stereoisomer.

Isolation and Synthesis

Extraction Techniques

Alkaloids, being basic nitrogen-containing compounds, are typically extracted from plant materials by methods that exploit their solubility in organic s and ability to form salts with acids, facilitating separation from aqueous phases. Classical extraction techniques rely on -based processes to isolate alkaloids from natural matrices. extraction often involves maceration or using polar s such as or , which dissolve alkaloids due to their moderate polarity. For instance, is extracted from by dissolving the raw material in hot water, adding lime to precipitate non-alkaloid impurities, and then extracting the alkaloids with an immiscible organic like or . Another foundational approach is acid-base partitioning, exemplified by the Stas-Otto process, where the plant material is first defatted with a non-polar like , then extracted with an acidified (e.g., tartaric or ) to form soluble alkaloid salts, followed by basification to liberate the free bases, and final extraction into an immiscible organic such as . This method, originally developed for , remains widely used for alkaloids like from plant seeds. Modern techniques enhance efficiency, reduce solvent use, and minimize thermal degradation through advanced energy inputs or green solvents. Supercritical carbon dioxide (CO₂) extraction, conducted above its critical point (31.1°C, 73.8 bar), selectively extracts non-polar alkaloids but often requires a polar co-solvent like ethanol (5-20%) to improve yields of more polar compounds such as mitragynine from Mitragyna speciosa leaves, though extraction efficiency varies and may be limited for certain polar alkaloids without further optimization. Microwave-assisted extraction accelerates the process by dielectric heating, disrupting cell walls and releasing alkaloids in minutes; for example, it yields 33 mg/g total alkaloids from Sophora flavescens roots under pressurized hot water conditions. Ultrasound-assisted extraction employs acoustic cavitation to enhance mass transfer, extracting alkaloids like berberine from Coptis chinensis with yields improved by 20-30% compared to conventional methods, using solvents such as deep eutectic mixtures at 40-60°C. Extraction faces challenges due to alkaloids' low natural abundance (typically 0.1-5% dry weight) and co-extraction of impurities like , waxes, and pigments, which reduce purity and complicate . These issues often necessitate pre-treatments such as grinding or defatting to boost yields and selectivity. At industrial scales, processes are optimized for high-volume alkaloids like and . extraction from beans employs supercritical CO₂ in commercial , recycling the to achieve over 99% removal while preserving flavor compounds. is industrially isolated from bark via large-scale extraction with ethanol or acetone, followed by acid-base partitioning, producing 300-500 tons annually for antimalarial applications.

Synthetic Methods

The synthesis of alkaloids in the laboratory encompasses , which constructs the molecule from simple precursors, and semi-synthesis, which modifies naturally derived intermediates to produce analogs or derivatives. has historically targeted complex alkaloids to validate structures and enable structure-activity studies, while semi-synthesis leverages abundant natural sources for efficient production of therapeutically relevant variants. One landmark achievement in is the first preparation of by Marshall Gates and Gilbert Tschudi in 1952, accomplished in a 31-step route from simple precursors such as 3-hydroxyphenethylamine, involving key steps such as a Bischler-Napieralski cyclization and a final phenolic coupling to form the skeleton, with a low overall yield of 0.06%. This synthesis confirmed morphine's structure and paved the way for subsequent syntheses, though its low overall yield highlighted the challenges of assembling the fused ring system with multiple stereocenters. Another seminal was that of by Robert B. Woodward and William von E. Doering in 1944, a formal route that advanced to d-quinotoxine via a series of condensations and reductions starting from 7-hydroxyisoquinoline, relying on earlier degradative work by Paul Rabe to connect to the natural product. Modern asymmetric total syntheses of these alkaloids incorporate catalytic methods, such as chiral complexes for enantioselective ring closures, reducing step counts and improving enantiopurity to over 95% ee in some cases. Semi-synthesis typically begins with extracted natural alkaloids as precursors, allowing targeted modifications to enhance potency or reduce side effects. For instance, is prepared from through a two-step process: oxidation with or to form codeinone, followed by allylic oxidation and catalytic to introduce the 14-hydroxy group, yielding in 70-80% overall efficiency from commercial . This approach exploits the opium poppy's natural abundance of , avoiding the inefficiencies of for morphinan derivatives. Common strategies in alkaloid synthesis include biomimetic approaches that replicate enzymatic processes and convergent assemblies that build polycyclic cores from preformed fragments. Biomimetic routes often employ the , where an or condenses with an ion and a carbon to forge beta-amino carbonyl motifs central to many alkaloids, as demonstrated in the synthesis of pyrrolidine-based structures mimicking pathways. Convergent strategies enhance efficiency by coupling advanced intermediates late in the sequence; for example, in diterpenoid alkaloid syntheses, aziridine openings and radical cyclizations assemble bridged ring systems from two- or three-ring fragments, minimizing manipulations and achieving overall yields up to 15% for complex scaffolds. Recent advances in the 2020s have focused on organocatalysis for , enabling asymmetric construction of quaternary centers and fused rings with high stereocontrol. Chiral secondary amine catalysts, such as derivatives, facilitate enantioselective Michael additions and Pictet-Spengler cyclizations in monoterpenoid syntheses, boosting yields beyond 20% for targets like aspidosperma alkaloids while using mild conditions and substoichiometric loadings. These methods, exemplified in collective syntheses of over 30 derivatives, prioritize by avoiding metal catalysts and enabling gram-scale operations. As of 2025, biocatalytic semi-syntheses using engineered enzymes have further improved yields for derivatives like , achieving up to 90% conversion in continuous flow systems.

Biological Role

Functions in Organisms

Alkaloids primarily serve defensive roles in producing organisms, deterring herbivores through toxicity and unpalatability. In , these nitrogen-containing compounds often impart a bitter or direct physiological harm to animals and , thereby reducing herbivory and enhancing . For instance, , produced by plants (Nicotiana spp.), acts as a potent that repels herbivores such as and leafhoppers by disrupting their nervous systems, with field studies demonstrating that nicotine-deficient mutants suffer significantly higher damage compared to wild-type plants. Similarly, alkaloids contribute to pathogen resistance by exhibiting antimicrobial properties; , found in species like and Coptis, inhibits bacterial and fungal growth through membrane disruption and interference, thereby protecting plant tissues from infections. Beyond direct defense, alkaloids facilitate , where they inhibit the growth of neighboring plants to reduce competition for resources. , an alkaloid synthesized by coffee plants ( spp.) and tea plants (), is released into the via root exudates or leaf litter, suppressing and development in competing species through interference with and activity. This chemical inhibition promotes the producer's dominance in ecosystems, as evidenced by reduced growth rates in sensitive plants exposed to concentrations typical of natural soils around producer species. Alkaloids also function in internal signaling and within organisms, particularly as nitrogen reservoirs during nutrient-limited conditions. In many plants, alkaloids store excess in a metabolically accessible form, allowing rapid remobilization for growth or stress responses when is scarce. Under abiotic stresses like , alkaloid biosynthesis is upregulated to bolster tolerance; for example, in medicinal plants such as , induces increased production of alkaloids via pathways involving signaling, which helps mitigate oxidative damage and maintain cellular . In microbial contexts, alkaloids play key roles in symbiotic interactions, enhancing mutualistic relationships. Fungal endophytes, particularly those in the genus Epichloë colonizing cool-season grasses, produce alkaloids like ergovaline and lolitrem B that deter herbivores and pathogens, indirectly benefiting the host by improving its fitness and resistance without harming the symbiont. This exemplifies how alkaloids mediate beneficial plant-microbe partnerships, with the fungi gaining nutrients from the host while providing chemical .

Evolutionary Aspects

Alkaloid production in is believed to have originated through , drawing from primary metabolic pathways such as those involving , , and , during the transition to terrestrial environments approximately 400 million years ago. This timeline aligns with the diversification of early vascular , where specialized , including alkaloid , evolved independently in lineages like lycopodiophytes and euphyllophytes to adapt to new ecological pressures on land. Convergent mechanisms, such as the parallel recruitment of bacterial-like decarboxylases for alkaloid initiation, underscore how these pathways arose multiple times across clades from shared precursors. Recent studies (as of ) have identified of alkaloid involving bacterial-like transketolases and decarboxylases, recruited independently in diverse lineages. The genetic foundation of alkaloid often involves clustered genes that facilitate coordinated expression and evolution, with examples like the pathway in opium poppy encompassing 15–17 genes organized in syntenic blocks. These clusters, typically comprising 10–20 genes, enable efficient pathway assembly and duplication events that drive structural diversification. In microbial systems, has played a key role in alkaloid evolution, with ancient transfers from to introducing critical biosynthetic enzymes, such as those for or pyrrolizidine alkaloids. This transfer mechanism has accelerated by integrating microbial cassettes into eukaryotic genomes. Diversity in alkaloid structures and distributions has been propelled by coevolutionary dynamics between plants and herbivores, manifesting as an where plants develop novel compounds to deter feeding, prompting herbivores to evolve countermeasures. In the case of alkaloids, this interaction has led to repeated innovations in biosynthetic pathways across species, enhancing chemical variety as a defense strategy against specialized herbivores. Such reciprocal selection pressures explain the proliferation of alkaloid types, with phylogenetic patterns showing escalation in defense over time. Recent phylogenomic analyses reveal multiple independent evolutionary losses of alkaloid biosynthetic pathways, including in some crop lineages. For example, quinolizidine alkaloid production has been reduced in domesticated like lupins to improve . In , tropane alkaloid pathways (e.g., for and ) have been lost repeatedly since the family's ancestral origin, diminishing chemical diversity compared to wild relatives, with syntenic blocks often retained as pseudogenes. These findings highlight conservation challenges, as the erosion of alkaloid-producing traits in cultivated varieties threatens the genetic reservoir of wild plants, which harbor greater biosynthetic potential for and potential medicinal rediscovery.

Applications

Medicinal Applications

Alkaloids represent a cornerstone of modern , with numerous compounds derived from plant sources serving as the basis for essential drugs in . These natural products, often isolated from genera such as (opium poppy) and , target diverse physiological pathways to treat conditions ranging from pain to cancer. Their therapeutic efficacy stems from interactions with receptors and enzymes, though clinical applications are tempered by issues of and dependency. In , opioid alkaloids like and , extracted from , remain foundational for analgesia in moderate to severe acute and . , the prototypic opioid, binds to mu-opioid receptors to alleviate pain by modulating nociceptive signaling in the , and it is routinely used for postoperative and cancer-related pain. , a milder derivative, provides antitussive and effects through its metabolism to via CYP2D6. Synthetic analogs such as , a potent opioid alkaloid derivative, offer rapid-onset relief for breakthrough pain and are administered via patches or injections, though its high potency necessitates careful dosing to avoid respiratory depression. Anticancer applications leverage alkaloids that disrupt microtubule dynamics essential for . Vinca alkaloids, including and from , inhibit by binding to and preventing microtubule , making them effective against hematologic malignancies like and . , in particular, is a key component in regimens for childhood , achieving remission rates exceeding 95% when combined with other chemotherapeutics as of 2025. Cardiovascular therapeutics include alkaloids that modulate autonomic and functions. Reserpine, isolated from , treats by depleting catecholamines from sympathetic nerve terminals, thereby reducing peripheral ; it was historically significant in the for lowering blood pressure in , though its use has declined due to side effects. Quinidine, an alkaloid from bark, manages cardiac arrhythmias by prolonging the action potential via sodium and potassium channel blockade, serving as a class Ia antiarrhythmic for and . Other notable applications encompass and alkaloids for specific indications. Atropine, derived from Atropa belladonna, counters by competitively antagonizing muscarinic acetylcholine receptors, increasing heart rate in acute settings like vagally mediated . , from Pilocarpus jaborandi, treats by stimulating muscarinic receptors to enhance aqueous humor outflow and reduce intraocular pressure, available as ophthalmic drops for open-angle glaucoma. , an alkaloid from species approved by the FDA in 2001, inhibits to elevate levels, providing symptomatic relief in mild to moderate by improving cognition and daily function. Despite their efficacy, alkaloid-based drugs face significant challenges including potential, particularly with opioids, which contribute to tolerance, dependence, and overdose risks through mu-receptor desensitization. Side effects such as , , and (e.g., vincristine's ) limit long-term use and require monitoring. In the 2020s, research has intensified on non-opioid alternatives and novel analgesics, such as the 2025 FDA approval of suzetrigine, a non-opioid inhibitor, to address without addiction liability, signaling a shift toward safer pharmacotherapies.

Agricultural and Other Uses

Alkaloids have found significant applications in as natural pesticides, leveraging their toxicity to target pests while minimizing environmental impact. , extracted from , served as one of the earliest commercial insecticides in the , applied as nicotine sulfate to control , beetles, and other soft-bodied on crops like fruits and . Its use declined with the advent of synthetic chemicals but persists in due to its biodegradable nature and low persistence in soil. Similarly, ryanodine, a ryanoid alkaloid derived from the stems of Ryania speciosa, acts as a botanical by disrupting muscle function in , particularly effective against codling moths and weevils in systems. This compound is approved for , where it provides targeted control without broad-spectrum harm to beneficial or residues in harvested produce. Certain derivatives also function as plant growth regulators, influencing key physiological processes in crops. derivatives inhibit and elongation, aiding in suppression and precise establishment. For instance, these compounds can be applied to to delay emergence, allowing desired plants a during early growth stages, as demonstrated in studies on and crops. Commercial extraction techniques from sources scale these regulators for field use, ensuring consistent efficacy in . In industrial applications, alkaloids contribute to food and beverage processing, enhancing product quality and functionality. , a alkaloid primarily sourced from beans and leaves, is extracted on a large scale for addition to soft drinks, beverages, and instant products, where it imparts bitterness and stimulates . This industrial process involves solvent extraction and purification to meet food-grade standards, supporting a multi-billion-dollar market. , another methylxanthine alkaloid from cacao, is isolated from husks during manufacturing through water decoction and precipitation, then utilized in flavor enhancement and as a precursor for synthesis. Its role in processing helps optimize 's sensory profile while recycling byproducts efficiently. Veterinary medicine employs alkaloids for animal health, particularly in parasite control. , the active levo-enantiomer derived from tetramisole, functions as a broad-spectrum against gastrointestinal and lung nematodes in such as , sheep, and , administered via injection or oral drench to expel worms and prevent infestations. It works by paralyzing parasites through nicotinic receptor stimulation, with dosages typically at 7.5-10 mg/kg body weight for effective clearance without significant residue in or . Emerging biotechnological approaches are crops to produce elevated levels of defensive alkaloids, such as or types, to create biofortified varieties that bolster with natural properties or improved nutritional profiles. These genetically modified , like enhanced or poppy relatives, aim to reduce reliance on chemical dewormers in sustainable farming systems.

Psychoactive Effects

Alkaloids represent a significant class of psychoactive substances that alter , perception, and mood through interactions with systems in the . These compounds are categorized pharmacologically into stimulants, depressants, and hallucinogens, each exerting distinct effects on neural signaling pathways. Stimulants enhance and energy, depressants induce relaxation and , while hallucinogens provoke profound alterations in sensory and cognitive experiences. Such effects have driven both recreational use and emerging therapeutic explorations, though they are tempered by risks of and . Among stimulants, , derived from plants like and , acts primarily as a non-selective at receptors, particularly A1 and A2A subtypes, thereby blocking 's inhibitory effects on neuronal activity and promoting and psychomotor stimulation. , found in , functions as an at nicotinic acetylcholine receptors (nAChRs), facilitating the release of and other neurotransmitters in reward pathways, which results in heightened attention, mood elevation, and reinforcing sensations that contribute to its addictive potential. Opium alkaloids, such as and extracted from the poppy, serve as depressants and sedatives by binding to mu-opioid receptors in the brain, triggering euphoria through dopamine release in the while suppressing pain perception and inducing sedation. These effects mimic endogenous but can lead to rapid tolerance and dependence with repeated use. Hallucinogenic alkaloids include , an from the shrub, which produces dissociative and visionary states by modulating multiple neurotransmitter systems, including sigma receptors and NMDA channels, often resulting in introspective, dream-like experiences. , sourced from certain mushrooms, is metabolized to , which acts as a at serotonin 5-HT2A receptors, mimicking serotonin's role to disrupt activity and induce perceptual distortions, , and emotional insights. Culturally, alkaloids have been integral to rituals and social practices for millennia; ayahuasca, a brew combining (a beta-carboline alkaloid) from with DMT from , has been used by Indigenous Amazonian communities for spiritual healing and , producing synergistic visionary effects through inhibition that enables DMT's oral . Similarly, betel nut () containing , a agonist, has been chewed in South and Southeast Asian traditions for its mild euphoric and stimulating properties, fostering social bonding despite associated health risks. Many psychoactive alkaloids face stringent legal restrictions; for instance, precursors to , such as , are classified as Schedule III controlled substances in the United States, while itself is Schedule I, reflecting high abuse potential and lack of accepted medical use. Risks include via reinforcement of pathways, as seen with and opioids, and such as or cardiovascular strain from hallucinogens like DMT-containing preparations. Nonetheless, therapeutic potential is evident in 2020s FDA-guided trials, where psilocybin-assisted therapy has shown rapid and sustained reductions in depressive symptoms, with phase 3 studies—including positive results announced in June 2025—reporting significant improvements in treatment-resistant cases.

Special Alkaloid Forms

Dimer Alkaloids

Dimer alkaloids represent a specialized subclass of natural alkaloids characterized by the covalent linkage of two monomeric alkaloid units, typically through oxidative coupling reactions that forge carbon-carbon (C-C) or carbon-nitrogen (C-N) bonds. These dimers arise primarily in via enzymatic processes involving oxidative coupling of precursors derived from common biosynthetic pathways, such as those involving strictosidine in indole alkaloid production. Unlike the more prevalent monomeric alkaloids, dimer forms are relatively rare. A prominent example of dimer alkaloids is the vinca series, including and , produced in the Madagascar periwinkle (). These bisindole alkaloids result from the enzymatic coupling of vindoline and catharanthine monomers; specifically, a hydrogen peroxide-dependent peroxidase-like catalyzes the formation of an initial C-C bond between the rings, yielding α-3′,4′-anhydrovinblastine as an intermediate, which is then rearranged to the final dimeric structure. This process exemplifies oxidative dimerization in nature, where the activates catharanthine to an intermediate that reacts with vindoline. Other notable examples include conophylline and conophyllidine, dimeric alkaloids isolated from the leaves of , formed through similar oxidative mechanisms linking two aspidosperma-type units via a C-C bond. These structures highlight the diversity of dimer linkages, from symmetric to asymmetric arrangements, enhancing molecular complexity beyond simple monomers. In general, dimerization imparts greater structural intricacy and often amplifies bioactivity, such as through interactions that monomers lack; for instance, the extended scaffold in vinca dimers enables more effective modulation of protein targets compared to their individual components.

Hybrid Alkaloids

Hybrid alkaloids represent a specialized subclass of naturally occurring alkaloids characterized by the integration of structural motifs from multiple distinct alkaloid skeletons or the fusion of alkaloid cores with elements from other biosynthetic pathways, such as or systems. This structural complexity arises during , often through enzymatic coupling of precursors from divergent metabolic routes, resulting in molecules with enhanced or multifaceted biological activities. Unlike simple alkaloids derived from a single precursor, hybrid forms exemplify evolutionary innovation in , enabling organisms to produce compounds with broader ecological roles or therapeutic potential. Prominent examples include the benzophenanthridine-protopine hybrid alkaloids macleayins A and B, isolated from the Australian plant Macleaya cordata, which combine the tetracyclic benzophenanthridine framework—derived from tyrosine—with the benzyltetrahydroisoquinoline protopine scaffold. Their biosynthesis likely involves the condensation of isoquinoline units with protopine intermediates, yielding quaternary ammonium structures with antimicrobial properties. Similarly, spiroindimicins E and F, discovered in the marine-derived actinomycete Streptomyces sp. MP131-18 from Norwegian fjord sediments, feature a spiro-fused bisindole-pyrrole architecture, arising from the coupling of indole and pyrrole units derived from separate pathways. These hybrids exhibit cytotoxic activities against cancer cell lines, highlighting their pharmacological relevance. Another notable class involves polyketide-peptide-alkaloid hybrids, such as penisimplicins A and B from the Penicillium simplicissimum JXCC5, which merge a chain with -derived thiazole rings and an alkaloid nitrogen heterocycle, potentially assembled by non-ribosomal synthetases (NRPS) and synthases (PKS). In contrast, steroid-alkaloid hybrids like trichosterol A, isolated from the endophytic Trichoderma koningiopsis in centipede , display a rare 6/6/6/5/6-fused pentacyclic system incorporating a steroidal backbone with an oxazine-containing alkaloid moiety, demonstrating herbicidal activity against Medicago sativa. These examples underscore the diversity of hybrid alkaloids across fungal and plant sources, with biosynthetic gene clusters often identified through genome mining to elucidate their assembly.

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