Alkaloid

File:Papaver somniferum 2021 G4.jpg

The first individual alkaloid, morphine, was isolated in 1804 from the opium poppy (Papaver somniferum).<ref>Template:Cite book</ref>

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.<ref>Template:Cite book</ref>

Alkaloids are produced by a large variety of organisms including bacteria, fungi, plants, and animals.<ref>Template:Cite book</ref> They can be purified from crude extracts of these organisms by acid-base extraction, or solvent extractions followed by silica-gel column chromatography.<ref name="G. P. Fox et al 2013">Template:Cite journal</ref> Alkaloids have a wide range of pharmacological activities including antimalarial (e.g. quinine), antiasthma (e.g. ephedrine), anticancer (e.g. homoharringtonine),<ref name="PCS2014">Template:Cite journal</ref> cholinomimetic (e.g. galantamine),<ref name="PAA2013">Template:Cite journal</ref> vasodilatory (e.g. vincamine), antiarrhythmic (e.g. quinidine), analgesic (e.g. morphine),<ref name=morphine>Template:Cite book</ref> antibacterial (e.g. chelerythrine),<ref name=" TBA2014">Template:Cite journal</ref> and antihyperglycemic activities (e.g. berberine).<ref>Template:Cite journal</ref><ref name=":0">Template:Cite journal</ref> 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),<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and have been used in entheogenic rituals or as recreational drugs. Alkaloids can be toxic (e.g. atropine, tubocurarine).<ref name="JMV1996">Template:Cite book</ref> Although alkaloids act on a diversity of metabolic systems in humans and other animals, they almost uniformly evoke a bitter taste.<ref name=Rhoades1979>Template:Cite book</ref>

The boundary between alkaloids and other nitrogen-containing natural compounds is not clear-cut.<ref name="Meyers">Robert A. Meyers Encyclopedia of Physical Science and Technology – Alkaloids, 3rd edition. Template:ISBN</ref> Most alkaloids are basic, although some have neutral<ref name=GoldBook>Template:GoldBookRef</ref> and even weakly acidic properties.<ref>Template:Cite book</ref> 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.<ref name=xumuk.ru>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Compounds like amino acid peptides, proteins, nucleotides, nucleic acid, amines, and antibiotics are usually not called alkaloids.Template:R Natural compounds containing nitrogen in the exocyclic position (mescaline, serotonin, dopamine, etc.) are usually classified as amines rather than as alkaloids.<ref>Template:Cite book</ref> Some authors, however, consider alkaloids a special case of amines.<ref>Template:Cite book</ref><ref>Template:Cite book</ref><ref name="Aniszewski 110">Aniszewski, p. 110</ref>

Naming

File:Meissner alkalod definition article 1819.png

The article that introduced the concept of "alkaloid".

The name "alkaloids" (Template:Langx) was introduced in 1819 by German chemist Carl Friedrich Wilhelm Meissner, and is derived from late Latin root {{#invoke:Lang|lang}} and the Greek-language suffix {{#invoke:Lang|lang}} -('like').<ref group="nb">Template:Cite journal</ref> 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.<ref>Hesse, pp. 1–3</ref><ref>Template:Cite book</ref>

There is no unique method for naming alkaloids.<ref name="Hesse 5">Hesse, p. 5</ref> Many individual names are formed by adding the suffix "ine" to the species or genus name.<ref>The suffix "ine" is a Greek feminine patronymic suffix and means "daughter of"; hence, for example, "atropine" means "daughter of Atropa" (belladonna): {{#invoke:citation/CS1|citation |CitationClass=web }}</ref> For example, atropine is isolated from the plant Atropa belladonna; strychnine is obtained from the seed of the Strychnine tree (Strychnos nux-vomica L.).<ref name=xumuk.ru /> 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);<ref>Hesse, p. 7</ref> these are called vinca alkaloids.<ref name = CurrMedChem-VA>Template:Cite journal</ref><ref>Template:Cite book</ref><ref>Template:Cite book</ref>

History

File:Friedrich Wilhelm Adam Sertuerner.jpg

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.<ref name="Aniszewski 182">Aniszewski, p. 182</ref> 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.<ref>Hesse, p. 338</ref> A Chinese book on houseplants written in 1st–3rd centuries BC mentioned a medical use of ephedra and opium poppies.<ref>Hesse, p. 304</ref> Also, coca leaves have been used by Indigenous South Americans since ancient times.<ref>Hesse, p. 350</ref>

Extracts from plants containing toxic alkaloids, such as aconitine and tubocurarine, were used since antiquity for poisoning arrows.<ref name="Aniszewski 182"/>

Studies of alkaloids began in the 19th century. In 1804, the German chemist Friedrich Sertürner isolated from opium a "soporific principle" (Template:Langx), 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).<ref>Hesse, pp. 313–316</ref> 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.<ref>Begley, Natural Products in Plants.</ref>

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.<ref name="BSE: koniin">Template:GSEn</ref><ref>Hesse, p. 204</ref>

File:Bufotenin.svg

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

Classifications

File: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. There is no uniform classification.<ref name="ref15">Hesse, p. 11</ref> Initially, when knowledge of chemical structures was lacking, botanical classification of the source plants was relied on. This classification is now considered obsolete.<ref name=xumuk.ru /><ref>Orekhov, p. 6</ref>

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.).<ref name=xumuk.ru /> However, they require compromises in borderline cases;<ref name="ref15" /> for example, nicotine contains a pyridine fragment from nicotinamide and a pyrrolidine part from ornithine<ref>Aniszewski, p. 109</ref> and therefore can be assigned to both classes.<ref name="ref19">Dewick, p. 307</ref>

Alkaloids are often divided into the following major groups:<ref>Hesse, p. 12</ref>

1. "True alkaloids" contain nitrogen in the heterocycle and originate from amino acids.<ref

name="ref21">Plemenkov, p. 223</ref> Their characteristic examples are atropine, nicotine, and morphine. This group also includes some alkaloids that besides the nitrogen heterocycle contain terpene (e.g., evonine<ref>Aniszewski, p. 108</ref>) or peptide fragments (e.g. ergotamine<ref name="ref23">Hesse, p. 84</ref>). The piperidine alkaloids coniine and coniceine may be regarded as true alkaloids (rather than pseudoalkaloids: see below)<ref name="ref24">Hesse, p. 31</ref> although they do not originate from amino acids.<ref name="ref25">Dewick, p. 381</ref>

1. "Protoalkaloids", which contain nitrogen (but not the nitrogen heterocycle) and also originate from amino acids.<ref name="ref21" /> Examples include mescaline, adrenaline and ephedrine.
2. Polyamine alkaloids – derivatives of putrescine, spermidine, and spermine.
3. Peptide and cyclopeptide alkaloids.<ref name="ref27">Template:Cite journal</ref>
4. Pseudoalkaloids – alkaloid-like compounds that do not originate from amino acids.<ref>Aniszewski, p. 11</ref> This group includes terpene-like and steroid-like alkaloids,<ref>Plemenkov, p. 246</ref> as well as purine-like alkaloids such as caffeine, theobromine, theacrine and theophylline.<ref name="ref30">Aniszewski, p. 12</ref> 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.<ref name="ref30" /><ref name="ref31">Dewick, p. 382</ref>

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.<ref>Hesse, pp. 44, 53</ref>

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<ref name="ref34">Plemenkov, p. 224</ref> File:Pyrrolidine structure.svg		Ornithine or arginine → putrescine → N-methylputrescine → N-methyl-Δ1-pyrroline<ref name="ref35">Aniszewski, p. 75</ref>	Cuscohygrine, hygrine, hygroline, stachydrine<ref name="ref34" /><ref>Orekhov, p. 33</ref>
Tropane derivatives<ref name="ref38">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref> File:Tropane numbered.svg	Atropine group Substitution in positions 3, 6 or 7	Ornithine or arginine → putrescine → N-methylputrescine → N-methyl-Δ1-pyrroline<ref name = "ref35 "/>	Atropine, scopolamine, hyoscyamine<ref name="ref34" /><ref name="ref38" /><ref>Hesse, p. 34</ref>
	Cocaine group Substitution in positions 2 and 3	Cocaine, ecgonine<ref name="ref38" /><ref>Aniszewski, p. 27</ref>
Pyrrolizidine derivatives<ref name="ref45">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref> File:Pyrrolizidine.svg	Non-esters	In plants: ornithine or arginine → putrescine → homospermidine → retronecine<ref name="ref35" />	Retronecine, heliotridine, laburnine<ref name="ref45" /><ref>Plemenkov, p. 229</ref>
	Complex esters of monocarboxylic acids	Indicine, lindelophin, sarracine<ref name="ref45" />
	Macrocyclic diesters	Platyphylline, trichodesmine<ref name="ref45" />
	1-aminopyrrolizidines (lolines)	In fungi: L-proline + L-homoserine → N-(3-amino-3-carboxypropyl)proline → norloline<ref name="Blankenship">Template:Cite journal</ref><ref name="Faulkner et al. 2006">Template:Cite journal</ref>	Loline, N-formylloline, N-acetylloline<ref name="Schardl et al. 2007">Template:Cite journal</ref>
Piperidine derivatives<ref>Plemenkov, p. 225</ref> File:Piperidin.svg		Lysine → cadaverine → Δ1-piperideine<ref>Aniszewski, p. 95</ref>	Sedamine, lobeline, anaferine, piperine<ref name="ref24" /><ref>Orekhov, p. 80</ref>
		Octanoic acid → coniceine → coniine<ref name="ref25" />	Coniine, coniceine<ref name="ref25" />
Quinolizidine derivatives<ref name="ref57">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref><ref>Saxton, Vol. 1, p. 93</ref> File:Quinolizidine.svg	Lupinine group	Lysine → cadaverine → Δ1-piperideine<ref>Aniszewski, p. 98</ref>	Lupinine, nupharidin<ref name="ref57" />
	Cytisine group	Cytisine<ref name="ref57" />
	Sparteine group	Sparteine, lupanine, anahygrine<ref name="ref57" />
	Matrine group.	Matrine, oxymatrine, allomatridine<ref name="ref57" /><ref>Saxton, Vol. 1, p. 91</ref><ref>Template:Cite journal</ref>
	Ormosanine group	Ormosanine, piptantine<ref name="ref57" /><ref>Saxton, Vol. 1, p. 92</ref>
Indolizidine derivatives<ref>Dewick, p. 310</ref> File:Indolizidine.svg		Lysine → δ-semialdehyde of α-aminoadipic acid → pipecolic acid → 1 indolizidinone<ref>Aniszewski, p. 96</ref>	Swainsonine, castanospermine<ref>Aniszewski, p. 97</ref>
Pyridine derivatives<ref name="ref72">Plemenkov, p. 227</ref><ref name="ref73">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref> File:Pyridine.svg	Simple derivatives of pyridine	Nicotinic acid → dihydronicotinic acid → 1,2-dihydropyridine<ref name="ref74">Aniszewski, p. 107</ref>	Trigonelline, ricinine, arecoline<ref name="ref72" /><ref name="ref76">Aniszewski, p. 85</ref>
	Polycyclic noncondensing pyridine derivatives	Nicotine, nornicotine, anabasine, anatabine<ref name="ref72" /><ref name="ref76" />
	Polycyclic condensed pyridine derivatives	Actinidine, gentianine, pediculinine<ref>Plemenkov, p. 228</ref>
	Sesquiterpene pyridine derivatives	Nicotinic acid, isoleucine<ref name="Aniszewski 110"/>	Evonine, hippocrateine, triptonine<ref name="ref73" /><ref name="ref74" />
Isoquinoline derivatives and related alkaloids<ref name="Hesse 36">Hesse, p. 36</ref> File:Isoquinoline numbered.svg	citation	CitationClass=web }}</ref>	Tyrosine or phenylalanine → dopamine or tyramine (for alkaloids Amarillis)<ref>Aniszewski, pp. 77–78</ref><ref name="Begley">Begley, Alkaloid Biosynthesis</ref>	Salsoline, lophocerine<ref name="Hesse 36"/><ref name="XimE: izoxinolin"/>
	Derivatives of 1- and 3-isoquinolines<ref name="Saxton 122">Saxton, Vol. 3, p. 122</ref>	N-methylcoridaldine, noroxyhydrastinine<ref name="Saxton 122"/>
	Derivatives of 1- and 4-phenyltetrahydroisoquinolines<ref name="XimE: izoxinolin"/>	Cryptostilin<ref name="XimE: izoxinolin"/><ref name="Hesse 54">Hesse, p. 54</ref>
	Derivatives of 5-naftil-isoquinoline<ref name="ref83">Hesse, p. 37</ref>	Ancistrocladine<ref name="ref83" />
	Derivatives of 1- and 2-benzyl-izoquinolines<ref>Hesse, p. 38</ref>	Papaverine, laudanosine, sendaverine
	Cularine group<ref name="ref86">Hesse, p. 46</ref>	Cularine, yagonine<ref name="ref86" />
	Pavines and isopavines<ref name="ref88">Hesse, p. 50</ref>	Argemonine, amurensine<ref name="ref88" />
	Benzopyrrocolines<ref name="ref90">Template:Cite journal</ref>	Cryptaustoline<ref name="XimE: izoxinolin"/>
	Protoberberines<ref name="XimE: izoxinolin"/>	Berberine, canadine, ophiocarpine, mecambridine, corydaline<ref name="ref91">Hesse, p. 47</ref>
	Phthalidisoquinolines<ref name="XimE: izoxinolin"/>	Hydrastine, narcotine (Noscapine)<ref>Hesse, p. 39</ref>
	Spirobenzylisoquinolines<ref name="XimE: izoxinolin"/>	Fumaricine<ref name="ref88" />
	Ipecacuanha alkaloids<ref name="ref94">Hesse, p. 41</ref>	Emetine, protoemetine, ipecoside<ref name="ref94" />
	Benzophenanthridines<ref name="XimE: izoxinolin"/>	Sanguinarine, oxynitidine, corynoloxine<ref name="ref96">Hesse, p. 49</ref>
	Aporphines<ref name="XimE: izoxinolin"/>	Glaucine, coridine, liriodenine<ref>Hesse, p. 44</ref>
	Proaporphines<ref name="XimE: izoxinolin"/>	Pronuciferine, glaziovine<ref name="XimE: izoxinolin"/><ref name="ref90" />
	Homoaporphines<ref name="ref99">Saxton, Vol. 3, p. 164</ref>	Kreysiginine, multifloramine<ref name="ref99" />
	Homoproaporphines<ref name="ref99" />	Bulbocodine<ref name="ref86" />
	Morphines<ref name="ref103">Hesse, p. 51</ref>	Morphine, codeine, thebaine, sinomenine,<ref name="ref104">Plemenkov, p. 236</ref> heroin
	Homomorphines<ref>Saxton, Vol. 3, p. 163</ref>	Kreysiginine, androcymbine<ref name="ref103" />
	Tropoloisoquinolines<ref name="XimE: izoxinolin"/>	Imerubrine<ref name="XimE: izoxinolin"/>
	Azofluoranthenes<ref name="XimE: izoxinolin"/>	Rufescine, imeluteine<ref>Saxton, Vol. 3, p. 168</ref>
	Amaryllis alkaloids<ref>Hesse, p. 52</ref>	Lycorine, ambelline, tazettine, galantamine, montanine<ref>Hesse, p. 53</ref>
	Erythrina alkaloids<ref name="Hesse 54"/>	Erysodine, erythroidine<ref name="Hesse 54"/>
	Phenanthrene derivatives<ref name="XimE: izoxinolin"/>	Atherosperminine<ref name="XimE: izoxinolin"/><ref name="ref91" />
	Protopines<ref name="XimE: izoxinolin"/>	Protopine, oxomuramine, corycavidine<ref name="ref96" />
	Aristolactam<ref name="XimE: izoxinolin"/>	Doriflavin<ref name="XimE: izoxinolin"/>
Oxazole derivatives<ref name="Plemenkov 241">Plemenkov, p. 241</ref> File:Oxazole structure.svg		Tyrosine → tyramine<ref>Brossi, Vol. 35, p. 261</ref>	Annuloline, halfordinol, texaline, texamine<ref>Brossi, Vol. 35, pp. 260–263</ref>
Isoxazole derivatives File:Isoxazole structure.png		Ibotenic acid → Muscimol	Ibotenic acid, Muscimol
Thiazole derivatives<ref name="ref114">Plemenkov, p. 242</ref> File:Thiazole structure.svg		1-Deoxy-D-xylulose 5-phosphate (DOXP), tyrosine, cysteine<ref>Begley, Cofactor Biosynthesis</ref>	Nostocyclamide, thiostreptone<ref name="ref114" /><ref>Template:Cite journal</ref>
Quinazoline derivatives<ref>{{#invoke:citation/CS1|citation	CitationClass=web }}</ref> File:Quinazoline numbered.svg	3,4-Dihydro-4-quinazolone derivatives	Anthranilic acid or phenylalanine or ornithine<ref>Aniszewski, p. 106</ref>	Febrifugine<ref name="ref120">Aniszewski, p. 105</ref>
	1,4-Dihydro-4-quinazolone derivatives	Glycorine, arborine, glycosminine<ref name="ref120" />
	Pyrrolidine and piperidine quinazoline derivatives	Vazicine (peganine)<ref name="Plemenkov 241"/>
Acridine derivatives<ref name="Plemenkov 241"/> File:Acridine.svg		Anthranilic acid<ref>Template:Cite journal</ref>	Rutacridone, acronicine<ref>Plemenkov, pp. 231, 246</ref><ref>Hesse, p. 58</ref>
Quinoline derivatives<ref>Plemenkov, p. 231</ref><ref name="ref126">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref> File:Quinoline numbered.svg	Simple derivatives of quinoline derivatives of 2–quinolones and 4-quinolone	Anthranilic acid → 3-carboxyquinoline<ref name="ref127">Aniszewski, p. 114</ref>	Cusparine, echinopsine, evocarpine<ref name="ref126" /><ref>Orekhov, p. 205</ref><ref>Hesse, p. 55</ref>
	Tricyclic terpenoids	Flindersine<ref name="ref126" /><ref name="ref131">Plemenkov, p. 232</ref>
	Furanoquinoline derivatives	Dictamnine, fagarine, skimmianine<ref name="ref126" /><ref>Orekhov, p. 212</ref><ref>Aniszewski, p. 118</ref>
	Quinines	Tryptophan → tryptamine → strictosidine (with secologanin) → korinanteal → cinhoninon<ref name="Begley"/><ref name = " ref127 "/>	Quinine, quinidine, cinchonine, cinhonidine<ref name="ref131" />
Indole derivatives<ref name="ref104" /> File:Indole numbered.svg	Non-isoprene indole alkaloids
	Simple indole derivatives<ref name="ref140">Aniszewski, p. 112</ref>	Tryptophan → tryptamine or 5-Hydroxytryptophan<ref name="ref141">Aniszewski, p. 113</ref>	Serotonin, psilocybin, dimethyltryptamine (DMT), bufotenin<ref>Hesse, p. 15</ref><ref>Saxton, Vol. 1, p. 467</ref>
	Simple derivatives of β-carboline<ref>Dewick, pp. 349–350</ref>		Harman, harmine, harmaline, eleagnine<ref name="ref140" />
	Pyrroloindole alkaloids<ref name="ref152">Aniszewski, p. 119</ref>		Physostigmine (eserine), etheramine, physovenine, eptastigmine<ref name="ref152" />
	Semiterpenoid indole alkaloids
	Ergot alkaloids<ref name="ref104" />	Tryptophan → chanoclavine → agroclavine → elimoclavine → paspalic acid → lysergic acid<ref name="ref152" />	Ergotamine, ergobasine, ergosine<ref>Hesse, p. 29</ref>
	Monoterpenoid indole alkaloids
	Corynanthe type alkaloids<ref name="ref141" />	Tryptophan → tryptamine → strictosidine (with secologanin)<ref name="ref141" />	Ajmalicine, sarpagine, vobasine, ajmaline, yohimbine, reserpine, mitragynine,<ref>Hesse, pp. 23–26</ref><ref>Saxton, Vol. 1, p. 169</ref> group strychnine and (Strychnine brucine, aquamicine, vomicine<ref>Saxton, Vol. 5, p. 210</ref>)
	Iboga-type alkaloids<ref name="ref141" />		Ibogamine, ibogaine, voacangine<ref name="ref141" />
	Aspidosperma-type alkaloids<ref name="ref141" />		Vincamine, vinca alkaloids,<ref name = CurrMedChem-VA /><ref name = MoleculesReview /> vincotine, aspidospermine<ref>Hesse, pp. 17–18</ref><ref>Dewick, p. 357</ref>
Imidazole derivatives<ref name="Plemenkov 241"/> File:Imidazole structure.svg		Directly from histidine<ref name="Aniszewski 104">Aniszewski, p. 104</ref>	Histamine, pilocarpine, pilosine, stevensine<ref name="Plemenkov 241"/><ref name="Aniszewski 104"/>
Purine derivatives<ref>Hesse, p. 72</ref> File:9H-Purine.svg		Xanthosine (formed in purine biosynthesis) → 7 methylxantosine → 7-methylxanthine → theobromine → caffeine<ref name="Begley"/>	Caffeine, theobromine, theophylline, saxitoxin<ref>Hesse, p. 73</ref><ref>Dewick, p. 396</ref>
Alkaloids with nitrogen in the side chain (protoalkaloids)
β-Phenylethylamine derivatives<ref name="ref90" /> File:Phenylethylamine numbered.svg		Tyrosine or phenylalanine → dioxyphenilalanine → dopamine → adrenaline and mescaline tyrosine → tyramine phenylalanine → 1-phenylpropane-1,2-dione → cathinone → ephedrine and pseudoephedrine<ref name="Aniszewski 110"/><ref name="ref31" /><ref>{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	Tyramine, ephedrine, pseudoephedrine, mescaline, cathinone, catecholamines (adrenaline, noradrenaline, dopamine)<ref name="Aniszewski 110"/><ref>Hesse, p. 76</ref>
Colchicine alkaloids<ref name="ref179">{{#invoke:citation/CS1|citation	CitationClass=web }}</ref> File:Colchicine.svg		Tyrosine or phenylalanine → dopamine → autumnaline → colchicine<ref>Aniszewski, p. 77</ref>	Colchicine, colchamine<ref name="ref179" />
Muscarine<ref name="ref182">Hesse, p. 81</ref> File:Muscarine.svg		Glutamic acid → 3-ketoglutamic acid → muscarine (with pyruvic acid)<ref>Brossi, Vol. 23, p. 376</ref>	Muscarine, allomuscarine, epimuscarine, epiallomuscarine<ref name="ref182" />
Benzylamine<ref name="ref185">Hesse, p. 77</ref> File:Benzylamine.svg		Phenylalanine with valine, leucine or isoleucine<ref>Brossi, Vol. 23, p. 268</ref>	Capsaicin, dihydrocapsaicin, nordihydrocapsaicin, vanillylamine<ref name="ref185" /><ref>Brossi, Vol. 23, p. 231</ref>
Polyamines alkaloids
Putrescine derivatives<ref name="ref189">Hesse, p. 82</ref> File:Putrescine.svg		ornithine → putrescine → spermidine → spermine<ref>{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>	Paucine<ref name="ref189" />
Spermidine derivatives<ref name="ref189" /> File:Spermidine.svg			Lunarine, codonocarpine<ref name="ref189" />
Spermine derivatives<ref name="ref189" /> File:Spermine.svg			Verbascenine, aphelandrine<ref name="ref189" />
Peptide (cyclopeptide) alkaloids
Peptide alkaloids with a 13-membered cycle<ref name="ref27" /><ref name="ref196">Plemenkov, p. 243</ref>	Nummularine C type	From different amino acids<ref name="ref27" />	Nummularine C, Nummularine S<ref name="ref27" />
	Ziziphine type		Ziziphine A, sativanine H<ref name="ref27" />
Peptide alkaloids with a 14-membered cycle<ref name="ref27" /><ref name="ref196" />	Frangulanine type		Frangulanine, scutianine J<ref name="ref196" />
	Scutianine A type		Scutianine A<ref name="ref27" />
	Integerrine type		Integerrine, discarine D<ref name="ref196" />
	Amphibine F type		Amphibine F, spinanine A<ref name="ref27" />
	Amfibine B type		Amphibine B, lotusine C<ref name="ref27" />
Peptide alkaloids with a 15-membered cycle<ref name="ref196" />	Mucronine A type		Mucronine A<ref name="ref23" /><ref name="ref196" />
Pseudoalkaloids (terpenes and steroids)
Diterpenes<ref name="ref23" /> File:Isoprene.svg	Lycoctonine type	Mevalonic acid → Isopentenyl pyrophosphate → geranyl pyrophosphate<ref>{{#invoke:citation/CS1|citation	CitationClass=web }}</ref><ref>Begley, Natural Products: An Overview</ref>	Aconitine, delphinine<ref name="ref23" /><ref>Template:Cite journal</ref>
Steroidal alkaloids<ref>Hesse, p. 88</ref> File:Cyclopentenophenanthrene.svg		Cholesterol, arginine<ref>Dewick, p. 388</ref>	Solanidine, cyclopamine, batrachotoxin<ref>Plemenkov, p. 247</ref>

Properties

Most alkaloids contain oxygen in their molecular structure; those compounds are usually colorless crystals at ambient conditions. Oxygen-free alkaloids, such as nicotine<ref>Template:GSEn</ref> or coniine,<ref name="BSE: koniin"/> are typically volatile, colorless, oily liquids.<ref name="ref222">Grinkevich, p. 131</ref> Some alkaloids are colored, like berberine (yellow) and sanguinarine (orange).<ref name="ref222" />

Most alkaloids are weak bases, but some, such as theobromine and theophylline, are amphoteric.<ref name="ref225">Template:Cite book</ref> Many alkaloids dissolve poorly in water but readily dissolve in organic solvents, such as diethyl ether, chloroform or 1,2-dichloroethane. Caffeine,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> cocaine,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> codeine<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and nicotine<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> are slightly soluble in water (with a solubility of ≥1g/L), whereas others, including morphine<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and yohimbine<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="ref222" />

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.<ref>Fattorusso, p. 53</ref> 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.<ref>Template:Cite book</ref>

Distribution in nature

File:Strychnos nux-vomica - Köhler–s Medizinal-Pflanzen-266.jpg

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.<ref>Aniszewski, p. 13</ref><ref>Orekhov, p. 11</ref> Therefore, in the past the term "alkaloid" was associated with plants.<ref name="Hesse 4">Hesse, p.4</ref>

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).<ref>Grinkevich, pp. 122–123</ref> Furthermore, different tissues of the same plants may contain different alkaloids.<ref>Orekhov, p. 12</ref>

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<ref name="Hesse 5" /> and a number of insects, markedly ants.<ref name=":1">Template:Cite journal</ref> Many marine organisms also contain alkaloids.<ref>Fattorusso, p. XVII</ref> 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.<ref>Aniszewski, pp. 110–111</ref>

Extraction

File:Piperine crystals.jpg

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.<ref name="Hesse 116">Hesse, p. 116</ref> Most methods exploit the property of most alkaloids to be soluble in organic solvents<ref name="G. P. Fox et al 2013" /> 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.<ref name="ref236">Grinkevich, p. 132</ref> Plants are thoroughly ground before extraction.<ref name="Hesse 116"/><ref>Grinkevich, p. 5</ref> Most alkaloids are present in the raw plants in the form of salts of organic acids.<ref name="Hesse 116"/> The extracted alkaloids may remain salts or change into bases.<ref name="ref236" /> 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.<ref name="Hesse 116"/><ref>Grinkevich, pp. 132–134</ref>

Alkaloids are separated from their mixture using their different solubility in certain solvents and different reactivity with certain reagents or by distillation.<ref>Grinkevich, pp. 134–136</ref>

A number of alkaloids are identified from insects, among which the fire ant venom alkaloids known as solenopsins have received greater attention from researchers.<ref>Template:Cite book</ref> These insect alkaloids can be efficiently extracted by solvent immersion of live fire ants<ref name="G. P. Fox et al 2013" /> or by centrifugation of live ants<ref>Template:Cite journal</ref> followed by silica-gel chromatography purification.<ref>Template:Cite journal</ref> Tracking and dosing the extracted solenopsin ant alkaloids has been described as possible based on their absorbance peak around 232 nanometers.<ref>Template:Cite journal</ref>

Biosynthesis

Biological precursors of most alkaloids are amino acids, such as ornithine, lysine, phenylalanine, tyrosine, tryptophan, histidine, aspartic acid, and anthranilic acid.<ref name="Plemenkov 253">Plemenkov, p. 253</ref> Nicotinic acid can be synthesized from tryptophan or aspartic acid. Ways of alkaloid biosynthesis are too numerous and cannot be easily classified.<ref name="Begley"/> However, there are a few typical reactions involved in the biosynthesis of various classes of alkaloids, including synthesis of Schiff bases and Mannich reaction.<ref name="Plemenkov 253"/>

Synthesis of Schiff bases

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Schiff bases can be obtained by reacting amines with ketones or aldehydes.<ref>Plemenkov, p. 254</ref> These reactions are a common method of producing C=N bonds.<ref name="Dewick 19">Dewick, p. 19</ref>

File:Schiff base formation.svg

In the biosynthesis of alkaloids, such reactions may take place within a molecule,<ref name="Plemenkov 253"/> such as in the synthesis of piperidine:<ref name="ref19"/>

File:Schiff base formation intramolecular.svg

Mannich reaction

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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.<ref name = "Dewick 19" />

File:Mannich.png

The Mannich reaction can proceed both intermolecularly and intramolecularly:<ref>Plemenkov, p. 255</ref><ref>Dewick, p. 305</ref>

File:Mannich reaction intramolecular.svg

Dimer alkaloids

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:<ref>Hesse, pp. 91–105</ref>

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

• Voacamine chemical structure.png

  Voacamine

• Villalstonine.svg

  Villalstonine

• Toxiferine I.png

  Toxiferine

• Dauricine.svg

  Dauricine

• Tubocurarine.svg

  Tubocurarine

• Carpaine.png

  Carpaine

There are also dimeric alkaloids formed from two distinct monomers, such as the vinca alkaloids vinblastine and vincristine,<ref name = CurrMedChem-VA /><ref name = MoleculesReview>Template:Cite journal</ref> which are formed from the coupling of catharanthine and vindoline.<ref>Template:Cite book</ref><ref name = TopCurrChem>Template:Cite book</ref> The newer semi-synthetic chemotherapeutic agent vinorelbine is used in the treatment of non-small-cell lung cancer.<ref name = MoleculesReview /><ref>Template:Cite journal</ref> It is another derivative dimer of vindoline and catharanthine and is synthesised from anhydrovinblastine,<ref>Template:Cite journal</ref> starting either from leurosine<ref name = Anhydro>Template:Cite journal</ref><ref>Template:Cite journal</ref> or the monomers themselves.<ref name = MoleculesReview /><ref name = TopCurrChem />

File:Vinorelbine from leurosine and from catharanthine plus vindoline.jpg

Biological role

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.<ref>Aniszewski, p. 142</ref> 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.<ref name="Meyers"/>

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.<ref>Hesse, pp. 283–291</ref> Such alkaloid-related substances as serotonin, dopamine and histamine are important neurotransmitters in animals. Alkaloids are also known to regulate plant growth.<ref>Aniszewski, pp. 142–143</ref> 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.<ref>W.E. Conner (2009). Tiger Moths and Woolly Bears—behaviour, ecology, and evolution of the Arctiidae. New York: Oxford University Press. pp. 1–10. Template:ISBN.</ref> 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.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Applications

In medicine

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.<ref>Hesse, p. 303</ref> Many alkaloids are still used in medicine, usually in the form of salts widely used including the following:<ref name="Meyers"/><ref>Hesse, pp. 303–309</ref>

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<ref name=":0" />

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.<ref>Hesse, p. 309</ref> For example, naloxone, an opioid receptor antagonist, is a derivative of thebaine that is present in opium.<ref>Dewick, p. 335</ref>

• Thebaine skeletal.svg

  Thebaine

• Naloxone.svg

  Naloxone

In agriculture

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.<ref>Template:Cite book</ref>

Use as psychoactive drugs

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.<ref>Veselovskaya, p. 75</ref><ref>Hesse, p. 79</ref> Mescaline and many indole alkaloids (such as psilocybin, dimethyltryptamine and ibogaine) have hallucinogenic effect.<ref>Veselovskaya, p. 136</ref><ref>Template:Cite book</ref> Morphine and codeine are strong narcotic pain killers.<ref>Veselovskaya, p. 6</ref>

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.<ref>Veselovskaya, pp. 51–52</ref> Thebaine is used in the synthesis of many painkillers such as oxycodone.

See also

• Amine
• Base (chemistry)
• List of poisonous plants
• Mayer's reagent
• Natural products
• Palau'amine
• Secondary metabolite

General and cited references

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External links

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