Alkaloid

{{Short description|Class of naturally occurring chemical compounds}} {{About|the class of chemical compounds|the pharmaceutical company|Alkaloid (company)}}

{{Use dmy dates|date=May 2023}} [[File:Papaver_somniferum_2021_G4.jpg|thumb|250px|The first individual alkaloid, morphine, was isolated in 1804 from the opium poppy (''Papaver somniferum'').<ref>{{cite book |url=https://books.google.com/books?id=MtOiLVWBn8cC&pg=PA20 |page=20 |title=Molecular, Clinical and Environmental Toxicology, Volume 1: Molecular Toxicology |volume=1 |first=Andreas |last=Luch |publisher=Springer |year=2009 |oclc=1056390214 |isbn=9783764383367}}</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>{{Cite book |last=Lewis |first=Robert Alan |url=https://books.google.com/books?id=caTqdbD7j4AC |title=Lewis' Dictionary of Toxicology |date=1998-03-23 |publisher=CRC Press |page=51 |oclc=1026521889 |isbn=9781566702232}}</ref>

Alkaloids are produced by a large variety of organisms including bacteria, fungi, plants, and animals.<ref>{{Cite book |title=Alkaloids: Biochemistry, Ecology, and Medicinal Applications |last1=Roberts |first1=M. F. (Margaret F.) |last2=Wink |first2=Michael |date=1998 |publisher=Springer US |isbn=9781475729054 |location=Boston |oclc=851770197}}</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">{{Cite journal |last1=Gonçalves Paterson Fox |first1=Eduardo |last2=Russ Solis |first2=Daniel |last3=Delazari dos Santos |first3=Lucilene |last4=Aparecido dos Santos Pinto |first4=Jose Roberto |last5=Ribeiro da Silva Menegasso |first5=Anally |last6=Cardoso Maciel Costa Silva |first6=Rafael |last7=Sergio Palma |first7=Mario |last8=Correa Bueno |first8=Odair |last9=de Alcântara Machado |first9=Ednildo |date=April 2013 |title=A simple, rapid method for the extraction of whole fire ant venom (Insecta: Formicidae: Solenopsis) |journal=Toxicon |volume=65 |pages=5–8 |doi=10.1016/j.toxicon.2012.12.009 |pmid=23333648 |doi-access=free|bibcode=2013Txcn...65....5G |hdl=11449/74946 |hdl-access=free }}</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">{{cite journal |vauthors=Kittakoop P, Mahidol C, Ruchirawat S |title=Alkaloids as important scaffolds in therapeutic drugs for the treatments of cancer, tuberculosis, and smoking cessation |journal=Curr Top Med Chem |volume=14 |issue=2 |pages=239–252 |year=2014 |pmid=24359196 |doi=10.2174/1568026613666131216105049 |url=https://zenodo.org/record/895681 }}</ref> cholinomimetic (e.g. galantamine),<ref name="PAA2013">{{cite journal |vauthors=Russo P, Frustaci A, Del Bufalo A, Fini M, Cesario A |title=Multitarget drugs of plants origin acting on Alzheimer's disease |journal=Curr Med Chem |volume=20 |issue=13 |pages=1686–93 |year=2013 |pmid=23410167 |doi=10.2174/0929867311320130008 }}</ref> vasodilatory (e.g. vincamine), antiarrhythmic (e.g. quinidine), analgesic (e.g. morphine),<ref name=morphine>{{cite book |author1=Raymond S. Sinatra |author2=Jonathan S. Jahr |author3=J. Michael Watkins-Pitchford |title=The Essence of Analgesia and Analgesics |publisher=Cambridge University Press |year=2010 |pages=82–90 |isbn=978-1139491983}}</ref> antibacterial (e.g. chelerythrine),<ref name=" TBA2014">{{cite journal |vauthors=Cushnie TP, Cushnie B, Lamb AJ |title=Alkaloids: An overview of their antibacterial, antibiotic-enhancing and antivirulence activities |journal=Int J Antimicrob Agents |volume=44 |issue=5 |pages=377–386 |year=2014 |pmid=25130096 |doi=10.1016/j.ijantimicag.2014.06.001 |s2cid=205171789 |url=https://zenodo.org/record/1004771}}</ref> and antihyperglycemic activities (e.g. berberine).<ref>{{Cite journal |last1=Singh |first1=Sukhpal |last2=Bansal |first2=Abhishek |last3=Singh |first3=Vikramjeet |last4=Chopra |first4=Tanya |last5=Poddar |first5=Jit |date=June 2022 |title=Flavonoids, alkaloids and terpenoids: a new hope for the treatment of diabetes mellitus |journal=Journal of Diabetes & Metabolic Disorders |language=en |volume=21 |issue=1 |pages=941–950 |doi=10.1007/s40200-021-00943-8 |issn=2251-6581 |pmc=9167359 |pmid=35673446}}</ref><ref name=":0">{{Cite journal |last1=Behl |first1=Tapan |last2=Gupta |first2=Amit |last3=Albratty |first3=Mohammed |last4=Najmi |first4=Asim |last5=Meraya |first5=Abdulkarim M. |last6=Alhazmi |first6=Hassan A. |last7=Anwer |first7=Md. Khalid |last8=Bhatia |first8=Saurabh |last9=Bungau |first9=Simona Gabriela |date=2022-09-09 |title=Alkaloidal Phytoconstituents for Diabetes Management: Exploring the Unrevealed Potential |journal=Molecules |language=en |volume=27 |issue=18 |pages=5851 |doi=10.3390/molecules27185851 |doi-access=free |issn=1420-3049 |pmc=9501853 |pmid=36144587}}</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>{{cite web |title=Alkaloid |url=http://science.howstuffworks.com/alkaloid-info.htm |date=2007-12-18}}</ref> and have been used in entheogenic rituals or as recreational drugs. Alkaloids can be toxic (e.g. atropine, tubocurarine).<ref name="JMV1996">{{Cite book |vauthors=Robbers JE, Speedie MK, Tyler VE |title=Pharmacognosy and Pharmacobiotechnology |date=1996 |publisher=Lippincott, Williams & Wilkins |location=Philadelphia |isbn=978-0683085006 |pages=143–185 |chapter=Chapter 9: Alkaloids}}</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>{{cite book |year=1979 |author=Rhoades, David F |chapter=Evolution of Plant Chemical Defense against Herbivores |editor1=Rosenthal, Gerald A. |editor2=Janzen, Daniel H |title=Herbivores: Their Interaction with Secondary Plant Metabolites |place=New York |publisher=Academic Press |page=41 |isbn=978-0-12-597180-5}}</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. {{ISBN|0-12-227411-3}}</ref> Most alkaloids are basic, although some have neutral<ref name=GoldBook>{{GoldBookRef |title=alkaloids |file=A00220 }}</ref> and even weakly acidic properties.<ref>{{Cite book |last=Manske |first=R. H. F. |url=https://books.google.com/books?id=WPbJCgAAQBAJ |title=The Alkaloids: Chemistry and Physiology, Volume 8 |date=2014-05-12 |publisher=Elsevier |isbn=9781483222004 |volume=8 |location=Saint Louis |pages=683–695 |oclc=1090491824}}</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>{{Cite web |title=АЛКАЛОИДЫ - Химическая энциклопедия |language=ru |trans-title=Alkaloids - Chemical Encyclopedia |url=https://www.xumuk.ru/encyklopedia/119.html |access-date=2023-05-18 |website=www.xumuk.ru}}</ref> Compounds like amino acid peptides, proteins, nucleotides, nucleic acid, amines, and antibiotics are usually not called alkaloids.{{r|GoldBook}} Natural compounds containing nitrogen in the exocyclic position (mescaline, serotonin, dopamine, etc.) are usually classified as amines rather than as alkaloids.<ref>{{Cite book |last1=Cseke |first1=Leland J. |url=https://books.google.com/books?id=wV2T41nGFc4C&pg=PA30 |title=Natural Products from Plants |last2=Kirakosyan |first2=Ara |last3=Kaufman |first3=Peter B. |last4=Warber |first4=Sara |last5=Duke |first5=James A. |last6=Brielmann |first6=Harry L. |date=2016-04-19 |publisher=CRC Press |isbn=978-1-4200-0447-2 |pages=30 |language=en}}</ref> Some authors, however, consider alkaloids a special case of amines.<ref>{{Cite book |last=Johnson |first=Alyn William |url=https://books.google.com/books?id=0X4cQus2gz8C&pg=PA433 |title=Invitation to Organic Chemistry |date=1999 |publisher=Jones & Bartlett Learning |isbn=978-0-7637-0432-2 |pages=433 |language=en}}</ref><ref>{{Cite book |last=Bansal |first=Raj K. |url=https://books.google.com/books?id=1B6ijcTkD5EC&pg=PA644 |title=A Textbook of Organic Chemistry |date=2003 |publisher=New Age International Limited |isbn=978-81-224-1459-2 |pages=644 |language=en}}</ref><ref name="Aniszewski 110">Aniszewski, p. 110</ref>

==Naming== thumb|160px|The article that introduced the concept of "alkaloid".

The name "alkaloids" ({{langx|de|Alkaloide|links=no}}) was introduced in 1819 by German chemist Carl Friedrich Wilhelm Meissner, and is derived from late Latin root {{lang|la|alkali}} and the Greek-language suffix {{lang|grc|-οειδής}} -('like').<ref group="nb">{{cite journal |last=Meissner |first=W. |year=1819|title=Über Pflanzenalkalien: II. Über ein neues Pflanzenalkali (Alkaloid) |trans-title=About Plant Alkalis: II. About a New Plant Alkali (Alkaloid)|quote=In the penultimate sentence of his article, Meissner wrote: "Überhaupt scheint es mir auch angemessen, die bis jetzt bekannten Pflanzenstoffe nicht mit dem Namen Alkalien, sondern Alkaloide zu belegen, da sie doch in manchen Eigenschaften von den Alkalien sehr abweichen, sie würden daher in dem Abschnitt der Pflanzenchemie vor den Pflanzensäuren ihre Stelle finden." ["In general, it seems appropriate to me to impose on the currently known plant substances not the name 'alkalis' but 'alkaloids', since they differ greatly in some properties from the alkalis; among the chapters of plant chemistry, they would therefore find their place before plant acids (since 'Alkaloid' would precede 'Säure' (acid) but follow 'Alkalien')".] |journal=Journal für Chemie und Physik |volume=25 |pages=379–381 |url=https://babel.hathitrust.org/cgi/pt?id=nyp.33433069069056;view=1up;seq=415 |archive-url=https://web.archive.org/web/20230518130019/https://babel.hathitrust.org/cgi/pt?id=nyp.33433069069056&view=1up&seq=415 |archive-date=2023-05-18}}</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>{{Cite book |last=Ladenburg |first=Albert |url=https://books.google.com/books?id=-9fUAAAAMAAJ&pg=PA213 |title=Handwörterbuch der chemie |date=1882 |publisher=E. Trewendt |pages=213–422 |language=de}}</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): {{Cite web |url=https://webspace.yale.edu/chem125/125/history99/5Valence/Nomenclature/alkanenames.html |title=Development of Systematic Names for the Simple Alkanes |archive-url=https://web.archive.org/web/20120316080546/https://webspace.yale.edu/chem125/125/history99/5Valence/Nomenclature/alkanenames.html |archive-date=2012-03-16 |work=yale.edu}}</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>{{cite journal|last1 = van der Heijden|first1 = Robert|last2 = Jacobs|first2 = Denise I.|last3 = Snoeijer|first3 = Wim|last4 = Hallard|first4 = Didier|last5 = Verpoorte|first5 = Robert|year = 2004|title = The ''Catharanthus'' alkaloids: Pharmacognosy and biotechnology|journal = Current Medicinal Chemistry|volume = 11|issue = 5|pages = 607–628|pmid = 15032608|doi = 10.2174/0929867043455846}}</ref><ref>{{cite book|chapter = Africa's gift to the world|pages = 46–51|chapter-url = https://books.google.com/books?id=aXGmCwAAQBAJ&pg=PA46|title = Botanical Miracles: Chemistry of Plants That Changed the World|first1 = Raymond|last1 = Cooper|first2 = Jeffrey John|last2 = Deakin|publisher = CRC Press|year = 2016|isbn = 9781498704304}}</ref><ref>{{cite book|last = Raviña|first = Enrique|title = The evolution of drug discovery: From traditional medicines to modern drugs|year = 2011|publisher = John Wiley & Sons|isbn = 9783527326693|pages = 157–159|chapter = Vinca alkaloids|chapter-url = https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA157}}</ref>

== History == [[File:Friedrich Wilhelm Adam Sertuerner.jpg|thumb|left|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" ({{langx|la|principium somniferum|links=no}}), 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">{{GSEn|063832|Кониин}}</ref><ref>Hesse, p. 204</ref>

[[File:Bufotenin2DACS.svg|class=skin-invert-image|thumb|160px|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|class=skin-invert-image|thumb|160px|The nicotine molecule contains both pyridine (left) and pyrrolidine (right) rings.]]

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>

# "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> # "Protoalkaloids", which contain nitrogen (but not the nitrogen heterocycle) and also originate from amino acids.<ref name="ref21" /> Examples include mescaline, adrenaline and ephedrine. # Polyamine alkaloids – derivatives of putrescine, spermidine, and spermine. # Peptide and cyclopeptide alkaloids.<ref name="ref27">{{cite journal|author1=Dimitris C. Gournelif |author2=Gregory G. Laskarisb |author3=Robert Verpoorte |title = Cyclopeptide alkaloids|doi = 10.1039/NP9971400075|journal = Nat. Prod. Rep.|year = 1997|volume = 14|pages = 75–82|pmid = 9121730|issue = 1}}</ref> # 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 = "wikitable skin-invert-image" |- ! Class !Major groups !Main synthesis steps !Examples |- | colspan="4" style="text-align:center; background:# DADADA;"|''Alkaloids with nitrogen heterocycles (true alkaloids)'' |- | Pyrrolidine derivatives<ref name="ref34">Plemenkov, p. 224</ref> 50px|center | | 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> |- | Rowspan = "2"|Tropane derivatives<ref name="ref38">{{Cite web |url=http://www.xumuk.ru/encyklopedia/2/4609.html |title=Chemical Encyclopedia: Tropan alkaloids |work=xumuk.ru}}</ref> 100px|center | Atropine group Substitution in positions 3, 6 or 7 | Rowspan = "2"|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> |- | Rowspan = "4"|Pyrrolizidine derivatives<ref name="ref45">{{Cite web |url=http://www.xumuk.ru/encyklopedia/2/3370.html |title=Chemical Encyclopedia: Pyrrolizidine alkaloids |work=xumuk.ru}}</ref> 80px|center | Non-esters | Rowspan = "3"|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">{{cite journal|vauthors=Blankenship JD, Houseknecht JB, Pal S, Bush LP, Grossman RB, Schardl CL |year= 2005|title=Biosynthetic precursors of fungal pyrrolizidines, the loline alkaloids|journal=ChemBioChem|volume=6|pages=1016–1022|pmid=15861432|doi=10.1002/cbic.200400327|issue=6|s2cid= 13461396}}</ref><ref name="Faulkner et al. 2006">{{cite journal|vauthors=Faulkner JR, Hussaini SR, Blankenship JD, Pal S, Branan BM, Grossman RB, Schardl CL |year= 2006|title=On the sequence of bond formation in loline alkaloid biosynthesis|journal=ChemBioChem|volume=7|pages=1078–1088|pmid=16755627|doi=10.1002/cbic.200600066|issue=7|s2cid= 34409048}}</ref> |Loline, ''N''-formylloline, ''N''-acetylloline<ref name="Schardl et al. 2007">{{cite journal|vauthors=Schardl CL, Grossman RB, Nagabhyru P, Faulkner JR, Mallik UP |year=2007|title=Loline alkaloids: currencies of mutualism|journal = Phytochemistry|volume=68|pages=980–996|doi=10.1016/j.phytochem.2007.01.010|pmid=17346759|issue=7|bibcode=2007PChem..68..980S }}</ref> |- | Rowspan = "2"|Piperidine derivatives<ref>Plemenkov, p. 225</ref> 50px|center | | 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" /> |- | Rowspan = "5"|Quinolizidine derivatives<ref name="ref57">{{Cite web |url=http://www.xumuk.ru/encyklopedia/2/5011.html |title=Chemical Encyclopedia: Quinolizidine alkaloids |work=xumuk.ru}}</ref><ref>Saxton, Vol. 1, p. 93</ref> 80px|center | Lupinine group | Rowspan = "5"|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>{{cite journal|author = Joseph P. Michael|title = Indolizidine and quinolizidine alkaloids|doi = 10.1039/b208137g|pmid = 14620842|journal=Nat. Prod. Rep.|year = 2002|volume = 19|issue = 5|pages = 458–475}}</ref> |- | Ormosanine group | Ormosanine, piptantine<ref name="ref57" /><ref>Saxton, Vol. 1, p. 92</ref> |- | Indolizidine derivatives<ref>Dewick, p. 310</ref> 80px|center | | Lysine → δ-semialdehyde of α-aminoadipic acid → pipecolic acid → 1 indolizidinone<ref>Aniszewski, p. 96</ref> | Swainsonine, castanospermine<ref>Aniszewski, p. 97</ref> |- | Rowspan = "4"|Pyridine derivatives<ref name="ref72">Plemenkov, p. 227</ref><ref name="ref73">{{Cite web |url=http://www.xumuk.ru/encyklopedia/2/3336.html |title=Chemical Encyclopedia: pyridine alkaloids |work=xumuk.ru}}</ref> 50px|center | Simple derivatives of pyridine | Rowspan = "3"|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" /> |- | Rowspan = "26"|Isoquinoline derivatives and related alkaloids<ref name="Hesse 36">Hesse, p. 36</ref> 90px|center | Simple derivatives of isoquinoline<ref name="XimE: izoxinolin">{{Cite web |url=http://www.xumuk.ru/encyklopedia/1642.html |title=Chemical Encyclopedia: isoquinoline alkaloids |work=xumuk.ru}}</ref> | Rowspan = "26"|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">{{cite journal|author = Kenneth W. Bentley|title = β-Phenylethylamines and the isoquinoline alkaloids|doi = 10.1039/NP9971400387|journal=Nat. Prod. Rep.|year = 1997|volume = 14|pages = 387–411|pmid = 9281839|issue = 4|url=http://chemistry.mdma.ch/hiveboard/rhodium/pdf/archive/merbst/phenethylamines%20and%20isoquinolines%202001.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://chemistry.mdma.ch/hiveboard/rhodium/pdf/archive/merbst/phenethylamines%20and%20isoquinolines%202001.pdf |archive-date=2022-10-09 |url-status=live}}</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> 80px|center | | Tyrosine → tyramine<ref>Brossi, Vol. 35, p. 261</ref> | Annuloline, halfordinol, texaline, texamine<ref>Brossi, Vol. 35, pp. 260–263</ref> |- | Isoxazole derivatives 80px|center | |Ibotenic acid → Muscimol |Ibotenic acid, Muscimol |- | Thiazole derivatives<ref name="ref114">Plemenkov, p. 242</ref> 80px|center | | 1-Deoxy-D-xylulose 5-phosphate (DOXP), tyrosine, cysteine<ref>Begley, Cofactor Biosynthesis</ref> | Nostocyclamide, thiostreptone<ref name="ref114" /><ref>{{cite journal|author = John R. Lewis|title = Amaryllidaceae, muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids|journal = Nat. Prod. Rep.|year = 2000|volume = 17|pages = 57–84|pmid = 10714899|issue = 1|doi = 10.1039/a809403i}}</ref> |- | Rowspan = "3"|Quinazoline derivatives<ref>{{Cite web |url=http://www.xumuk.ru/encyklopedia/2/5003.html |title=Chemical Encyclopedia: Quinazoline alkaloids |work=xumuk.ru}}</ref> 90px|center | 3,4-Dihydro-4-quinazolone derivatives | Rowspan = "3"|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"/> 100px|center | | Anthranilic acid<ref>{{cite journal|author = Richard B. Herbert|title = The biosynthesis of plant alkaloids and nitrogenous microbial metabolites|journal=Nat. Prod. Rep.|year = 1999|volume = 16|issue = 2|pages = 199–208|doi = 10.1039/a705734b|last2 = Herbert|first2 = Richard B.|last3 = Herbert|first3 = Richard B.}}</ref> | Rutacridone, acronicine<ref>Plemenkov, pp. 231, 246</ref><ref>Hesse, p. 58</ref> |- | Rowspan = "4"|Quinoline derivatives<ref>Plemenkov, p. 231</ref><ref name="ref126">{{Cite web |url=http://www.xumuk.ru/encyklopedia/2/5014.html |title=Chemical Encyclopedia: Quinoline alkaloids |work=xumuk.ru}}</ref> 90px|center | Simple derivatives of quinoline derivatives of 2–quinolones and 4-quinolone | Rowspan = "3"|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" /> |- | Rowspan = "10"|Indole derivatives<ref name="ref104" /> 100px|center | colspan="3" style="text-align:center;"|''Non-isoprene indole alkaloids'' |- | Simple indole derivatives<ref name="ref140">Aniszewski, p. 112</ref> | Rowspan = "3"|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" /> |- | colspan="3" style="text-align:center;"|''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> |- | colspan="3" style="text-align:center;"|''Monoterpenoid indole alkaloids'' |- | ''Corynanthe'' type alkaloids<ref name="ref141" /> | Rowspan = "3"|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"/> 50px|center | | 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> 90px|center | | 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> |- | colspan="4" style="text-align:center; background:# DADADA;"|''Alkaloids with nitrogen in the side chain (protoalkaloids)'' |- | β-Phenylethylamine derivatives<ref name="ref90" /> 110px|center | | 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>{{Cite web |url=http://www.plantcyc.org:1555/PLANT/NEW-IMAGE?type=NIL&object=PWY-5883 |title=PlantCyc Pathway: ephedrine biosynthesis |archive-url=https://web.archive.org/web/20111210040135/http://www.plantcyc.org:1555/PLANT/NEW-IMAGE?type=NIL&object=PWY-5883 |archive-date=December 10, 2011 }}</ref> | Tyramine, ephedrine, pseudoephedrine, mescaline, cathinone, catecholamines (adrenaline, noradrenaline, dopamine)<ref name="Aniszewski 110"/><ref>Hesse, p. 76</ref> |- | Colchicine alkaloids<ref name="ref179">{{Cite web |url=http://www.xumuk.ru/encyklopedia/2069.html |title=Chemical Encyclopedia: colchicine alkaloids |work=xumuk.ru}}</ref> 120px|center | | Tyrosine or phenylalanine → dopamine → autumnaline → colchicine<ref>Aniszewski, p. 77</ref> | Colchicine, colchamine<ref name="ref179" /> |- | Muscarine<ref name="ref182">Hesse, p. 81</ref> 100px|center | | 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> 90px|center | | 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> |- | colspan="4" style="text-align:center; background:# DADADA;"|''Polyamines alkaloids'' |- | Putrescine derivatives<ref name="ref189">Hesse, p. 82</ref> 90px|center | | Rowspan = "3"|ornithine → putrescine → spermidine → spermine<ref>{{Cite web|url=http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/misc/spermine.html/|title=Spermine Biosynthesis|website=www.qmul.ac.uk|archive-url=https://web.archive.org/web/20031113075753/http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/misc/spermine.html/ |archive-date=13 November 2003 }}</ref> | Paucine<ref name="ref189" /> |- | Spermidine derivatives<ref name="ref189" /> 110px|center | | Lunarine, codonocarpine<ref name="ref189" /> |- | Spermine derivatives<ref name="ref189" /> 130px|center | | Verbascenine, aphelandrine<ref name="ref189" /> |- | colspan="4" style="text-align:center; background:# DADADA;"|''Peptide (cyclopeptide) alkaloids'' |- | Rowspan = "2"|Peptide alkaloids with a 13-membered cycle<ref name="ref27" /><ref name="ref196">Plemenkov, p. 243</ref> | Nummularine C type | Rowspan = "8"|From different amino acids<ref name="ref27" /> | Nummularine C, Nummularine S<ref name="ref27" /> |- | Ziziphine type | Ziziphine A, sativanine H<ref name="ref27" /> |- | Rowspan = "5"|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" /> |- | colspan="4" style="text-align:center; background:# DADADA;"|''Pseudoalkaloids (terpenes and steroids)'' |- | Diterpenes<ref name="ref23" /> 80px|center | Lycoctonine type | Mevalonic acid → Isopentenyl pyrophosphate → geranyl pyrophosphate<ref>{{Cite web |url=http://www.xumuk.ru/encyklopedia/2/4392.html |title=Chemical Encyclopedia: Terpenes |work=xumuk.ru}}</ref><ref>Begley, Natural Products: An Overview</ref> | Aconitine, delphinine<ref name="ref23" /><ref>{{cite journal|author = Atta-ur-Rahman and M. Iqbal Choudhary|title = Diterpenoid and steroidal alkaloids|journal=Nat. Prod. Rep.|year = 1997|volume = 14|pages = 191–203|pmid = 9149410|issue = 2|doi = 10.1039/np9971400191}}</ref> |- | Steroidal alkaloids<ref>Hesse, p. 88</ref> 100px|center | | 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>{{GSEn|081823|Никотин}}</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">{{Cite book |last=Spiller |first=Gene A. |url=https://books.google.com/books?id=Rgs_rVOceZwC&pg=PA140 |title=Caffeine |date=2019-04-23 |publisher=CRC Press |isbn=978-1-4200-5013-4 |pages=140 |language=en}}</ref> Many alkaloids dissolve poorly in water but readily dissolve in organic solvents, such as diethyl ether, chloroform or 1,2-dichloroethane. Caffeine,<ref>{{cite web|title=Caffeine|url=http://www.drugbank.ca/drugs/DB00201|work=DrugBank|access-date=12 February 2013}}</ref> cocaine,<ref>{{cite web|title=Cocaine|url=http://www.drugbank.ca/drugs/DB00907|work=DrugBank|access-date=12 February 2013}}</ref> codeine<ref>{{cite web|title=Codeine|url=http://www.drugbank.ca/drugs/DB00318|work=DrugBank|access-date=12 February 2013}}</ref> and nicotine<ref>{{cite web|title=Nicotine|url=http://www.drugbank.ca/drugs/DB00184|work=DrugBank|access-date=12 February 2013}}</ref> are slightly soluble in water (with a solubility of ≥1g/L), whereas others, including morphine<ref>{{cite web|title=Morphine|url=http://www.drugbank.ca/drugs/DB00295|work=DrugBank|access-date=12 February 2013}}</ref> and yohimbine<ref>{{cite web|title=Yohimbine |url=http://www.drugbank.ca/drugs/DB01392 |work=DrugBank |access-date=12 February 2013 |url-status=dead |archive-url=https://web.archive.org/web/20130130101146/http://www.drugbank.ca/drugs/DB01392 |archive-date=30 January 2013 }}</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>{{cite book|page=362|url=https://books.google.com/books?id=nixyqfGIGHcC&pg=PA362|title=Poisonous plants and related toxins, Volume 2001|author1=Thomas Acamovic |author2=Colin S. Stewart |author3=T. W. Pennycott |publisher=CABI|year= 2004|isbn=978-0-85199-614-1}}</ref>

==Distribution in nature== [[File:Strychnos nux-vomica - Köhler–s Medizinal-Pflanzen-266.jpg|thumb|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">{{Cite journal|last1=Touchard|first1=Axel|last2=Aili|first2=Samira|last3=Fox|first3=Eduardo|last4=Escoubas|first4=Pierre|last5=Orivel|first5=Jérôme|last6=Nicholson|first6=Graham|last7=Dejean|first7=Alain|date=2016-01-20|title=The Biochemical Toxin Arsenal from Ant Venoms|journal=Toxins|volume=8|issue=1|pages=30|doi=10.3390/toxins8010030|pmid=26805882|pmc=4728552|issn=2072-6651|doi-access=free}}</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|thumb|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>{{Cite book|last=Fox|first=Eduardo Gonçalves Paterson|chapter=Venom Toxins of Fire Ants|date=2016|title=Venom Genomics and Proteomics|pages=149–167|editor-last=Gopalakrishnakone|editor-first=P.|publisher=Springer Netherlands|doi=10.1007/978-94-007-6416-3_38|isbn=978-94-007-6415-6|editor2-last=Calvete|editor2-first=Juan J.}}</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>{{Cite journal|last1=Fox|first1=Eduardo G. P.|last2=Xu|first2=Meng|last3=Wang|first3=Lei|last4=Chen|first4=Li|last5=Lu|first5=Yong-Yue|date=2018-05-01|title=Speedy milking of fresh venom from aculeate hymenopterans|journal=Toxicon|volume=146|pages=120–123|doi=10.1016/j.toxicon.2018.02.050|pmid=29510162|bibcode=2018Txcn..146..120F |issn=0041-0101}}</ref> followed by silica-gel chromatography purification.<ref>{{Cite journal|last1=Chen|first1=Jian|last2=Cantrell|first2=Charles L.|last3=Shang|first3=Han-wu|last4=Rojas|first4=Maria G.|date=2009-04-22|title=Piperideine Alkaloids from the Poison Gland of the Red Imported Fire Ant (Hymenoptera: Formicidae)|journal=Journal of Agricultural and Food Chemistry|volume=57|issue=8|pages=3128–3133|doi=10.1021/jf803561y|pmid=19326861|issn=0021-8561}}</ref> Tracking and dosing the extracted solenopsin ant alkaloids has been described as possible based on their absorbance peak around 232 nanometers.<ref>{{Cite journal|last1=Fox|first1=Eduardo G. P.|last2=Xu|first2=Meng|last3=Wang|first3=Lei|last4=Chen|first4=Li|last5=Lu|first5=Yong-Yue|date=2018-06-01|title=Gas-chromatography and UV-spectroscopy of Hymenoptera venoms obtained by trivial centrifugation|journal=Data in Brief|volume=18|pages=992–998|doi=10.1016/j.dib.2018.03.101|pmid=29900266|pmc=5996826|bibcode=2018DIB....18..992F |issn=2352-3409}}</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=== {{Main|Schiff base}}

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>

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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"/>

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===Mannich reaction=== {{Main|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.<ref name = "Dewick 19" />

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

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==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).

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>{{cite journal|journal = Molecules|year = 2012|volume = 17|issue = 5|pages = 5893–5914|doi = 10.3390/molecules17055893|title = Modifications on the basic skeletons of vinblastine and vincristine|first1 = Péter|last1 = Keglevich|first2 = Laszlo|last2 = Hazai|first3 = György|last3 = Kalaus|first4 = Csaba|last4 = Szántay|pmid = 22609781|pmc = 6268133|doi-access = free}}</ref> which are formed from the coupling of catharanthine and vindoline.<ref>{{cite book|chapter = ''Catharanthus roseus'' L. (Periwinkle): Production of Vindoline and Catharanthine in Multiple Shoot Cultures|first1 = K.|last1 = Hirata|first2 = K.|last2 = Miyamoto|first3 = Y.|last3 = Miura|title = Biotechnology in Agriculture and Forestry 26|series = Medicinal and Aromatic Plants|volume = VI|editor-first = Y. P. S.|editor-last = Bajaj|publisher = Springer-Verlag|year = 1994|pages = [https://archive.org/details/medicinalaromati0006unse/page/46 46–55]|chapter-url = https://books.google.com/books?id=e64hCDBddowC&pg=PA47|isbn = 9783540563914|url = https://archive.org/details/medicinalaromati0006unse/page/46}}</ref><ref name = TopCurrChem>{{cite book|title = Metal Catalyzed Reductive C—C Bond Formation: A Departure from Preformed Organometallic Reagents|volume = 279|series = Topics in Current Chemistry|pages = 25–52|year = 2007|chapter = Reductive C—C bond formation after epoxide opening via electron transfer|first1 = Andreas|last1 = Gansäuer|first2 = José|last2 = Justicia|first3 = Chun-An|last3 = Fan|first4 = Dennis|last4 = Worgull|first5 = Frederik|last5 = Piestert|doi = 10.1007/128_2007_130|chapter-url = https://books.google.com/books?id=A5xcVmT9iIQC&pg=PA25|editor-link1=Michael J. Krische|editor-first = Michael J.|editor-last = Krische|publisher = Springer Science & Business Media|isbn = 9783540728795}}</ref> The newer semi-synthetic chemotherapeutic agent vinorelbine is used in the treatment of non-small-cell lung cancer.<ref name = MoleculesReview /><ref>{{cite journal|journal = Clinical Medicine Insights: Oncology|year = 2011|volume = 5|pages = 131–144|doi = 10.4137/CMO.S5074|pmc = 3117629|title = Safety and efficacy of vinorelbine in the treatment of non-small cell lung cancer|first1 = Bryan A.|last1 = Faller|first2 = Trailokya N.|last2 = Pandi|pmid=21695100}}</ref> It is another derivative dimer of vindoline and catharanthine and is synthesised from anhydrovinblastine,<ref>{{cite journal|last1 = Ngo|first1 = Quoc Anh|last2 = Roussi|first2 = Fanny|last3 = Cormier|first3 = Anthony|last4 = Thoret|first4 = Sylviane|last5 = Knossow|first5 = Marcel|last6 = Guénard|first6 = Daniel|last7 = Guéritte|first7 = Françoise|title = Synthesis and biological evaluation of ''Vinca alkaloids'' and phomopsin hybrids|journal = Journal of Medicinal Chemistry|year = 2009|volume = 52|issue = 1|pages = 134–142|pmid = 19072542|doi = 10.1021/jm801064y}}</ref> starting either from leurosine<ref name = Anhydro>{{cite journal|title = Concise synthesis of anhydrovinblastine from leurosine|first1 = Christophe|last1 = Hardouin|first2 = Eric|last2 = Doris|first3 = Bernard|last3 = Rousseau|first4 = Charles|last4 = Mioskowski|journal = Organic Letters|year = 2002|volume = 4|issue = 7|pages = 1151–1153|doi = 10.1021/ol025560c|pmid = 11922805}}</ref><ref>{{cite journal|last1 = Morcillo|first1 = Sara P.|last2 = Miguel|first2 = Delia|last3 = Campaña|first3 = Araceli G.|last4 = Cienfuegos|first4 = Luis Álvarez de|last5 = Justicia|first5 = José|last6 = Cuerva|first6 = Juan M.|year = 2014|title = Recent applications of Cp2TiCl in natural product synthesis|journal = Organic Chemistry Frontiers|volume = 1|issue = 1|pages = 15–33|doi = 10.1039/c3qo00024a | url=http://pubs.rsc.org/en/content/articlepdf/2014/qo/c3qo00024a|doi-access = free|hdl = 10481/47295|hdl-access = free}}</ref> or the monomers themselves.<ref name = MoleculesReview /><ref name = TopCurrChem />

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==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. {{ISBN|0195327373}}.</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>{{Cite journal|last1=Castells|first1=Eva|last2=Berenbaum|first2=May R.|date=June 2006|title=Laboratory Rearing of Agonopterix alstroemeriana, the Defoliating Poison Hemlock (Conium maculatum L.) Moth, and Effects of Piperidine Alkaloids on Preference and Performance|url=http://ddd.uab.cat/record/125702|journal=Environmental Entomology|volume=35|issue=3|pages=607–615|via=ResearchGate|doi=10.1603/0046-225x-35.3.607|s2cid=45478867|doi-access=free|url-access=subscription}}</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>{{Cite journal|last1=Fox|first1=Eduardo G. P.|last2=Wu|first2=Xiaoqing|last3=Wang|first3=Lei|last4=Chen|first4=Li|last5=Lu|first5=Yong-Yue|last6=Xu|first6=Yijuan|date=2019-02-01|title=Queen venom isosolenopsin A delivers rapid incapacitation of fire ant competitors|journal=Toxicon|volume=158|pages=77–83|doi=10.1016/j.toxicon.2018.11.428|pmid=30529381|bibcode=2019Txcn..158...77F |s2cid=54481057|issn=0041-0101}}</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>

{| Class = "wikitable" |- ! 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>

<gallery class="center skin-invert-image" widths="200px" perrow="2"> File:Thebaine skeletal.svg|Thebaine File:Naloxone.svg|Naloxone </gallery>

=== 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>{{Cite book |last1=Matolcsy |first1=G. |url=https://books.google.com/books?id=fPiRSsUOpLEC&pg=PA21 |title=Pesticide Chemistry |last2=Nádasy |first2=M. |last3=Andriska |first3=V. |date=1989-01-01 |publisher=Elsevier |isbn=978-0-08-087491-3 |pages=21–22 |language=en}}</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>{{cite book|title=Ibogaine: Proceedings from the First International Conference (The Alkaloids Book 56)|year=1950|publisher=Elsevier Science |isbn=978-0-12-469556-6|at=p. 8}}</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 == {{Div col|colwidth=22em}} * Amine * Base (chemistry) * List of poisonous plants * Mayer's reagent * Natural products * Palau'amine * Secondary metabolite {{div col end}}

== Explanatory notes == {{Reflist|group="nb"}}

== Citations == {{Reflist|25em}}

== General and cited references == * {{Cite book |ref=Aniszewski |author=Aniszewski, Tadeusz |year=2007 |title=Alkaloids: secrets of life |location=Amsterdam |publisher=Elsevier |isbn=978-0-444-52736-3}} * {{Cite book |ref=Begley |author=Begley, Tadhg P. |year=2009 |title=Encyclopedia of Chemical Biology |volume=10 |issue=9 |pages=1569–1570 |publisher=Wiley |isbn=978-0-471-75477-0 |doi=10.1002/cbic.200900262}} * {{Cite book |ref=Brossi |author =Brossi, Arnold |year=1989 |title=The Alkaloids: Chemistry and Pharmacology |publisher=Academic Press}} * {{Cite book |ref=Dewick |author=Dewick, Paul M. |year=2002 |title=Medicinal Natural Products: A Biosynthetic Approach |edition=Second |publisher=Wiley |isbn=978-0-471-49640-3}} * {{Cite book |ref=Fattorusso |author1=Fattorusso, E. |author2=Taglialatela-Scafati, O. |year=2008 |title=Modern Alkaloids: Structure, Isolation, Synthesis and Biology |publisher=Wiley-VCH |isbn=978-3-527-31521-5}} * {{Cite book |ref=Grinkevich |editor1=Grinkevich NI |editor2=Safronich LN |year=1983 |title=The chemical analysis of medicinal plants |language=ru |location=Moscow |publisher=Vysshaya Shkola }} * {{Cite book |ref=Hesse |author=Hesse, Manfred |year=2002 |title=Alkaloids: Nature's Curse or Blessing? |publisher=Wiley-VCH |isbn=978-3-906390-24-6}} * {{Cite book |ref=Knunyants |author=Knunyants, IL |year=1988 |title=Chemical Encyclopedia |url=http://www.cnshb.ru/AKDiL/0048/base/RA/140004.shtm |publisher=Soviet Encyclopedia}} * {{Cite book |ref=Orekhov |author=Orekhov, AP |title=Chemistry alkaloids |year=1955 |edition=Acad. 2nd |location=Moscow |publisher=}} * {{Cite book |ref=Plemenkov |author=Plemenkov, VV |year=2001 |title=Introduction to the Chemistry of Natural Compounds |location=Kazan}} * {{Cite book |ref=Saxton |author=Saxton, J. E. |year=1971 |title=The Alkaloids: A Specialist Periodical Report |place=London |publisher= The Chemical Society}} * {{Cite book |ref=Veselovskaya |author1=Veselovskaya, N. B. |author2=Kovalenko, A. E. |year=2000 |title=Drugs |place=Moscow |publisher=Triada-X}} * {{Cite journal |last=Wink |first=M |title=Mode of action and toxicology of plant toxins and poisonous plants |year=2009 |journal=Mitt. Julius Kühn-Inst. |volume=421 |pages=93–112x }}

== External links == * {{Commons category-inline}} * {{Wikiquote-inline}}

Category:Alkaloids