The article that introduced the concept of "alkaloid".
The name "alkaloids" (German:Alkaloide) was introduced in 1819 by German chemistCarl Friedrich Wilhelm Meissner, and is derived from late Latin rootalkali and the Greek-language suffix-οειδής -('like').[nb 1] However, the term came into wide use only after the publication of a review article, by Oscar Jacobsen in the chemical dictionary ofAlbert Ladenburg in the 1880s.[22][23]
There is no unique method for naming alkaloids.[24] Many individual names are formed by adding the suffix "ine" to the species or genus name.[25] For example,atropine is isolated from the plantAtropa belladonna;strychnine is obtained from the seed of theStrychnine tree (Strychnos nux-vomica L.).[17] Where several alkaloids are extracted from one plant their names are often distinguished by variations in the suffix: "idine", "anine", "aline", "inine" etc. There are also at least 86 alkaloids whose names contain the root "vin" because they are extracted fromvinca plants such asVinca rosea (Catharanthus roseus);[26] these are calledvinca alkaloids.[27][28][29]
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 inMesopotamia from about 2000 BC.[30] TheOdyssey of Homer referred to a gift given to Helen by the Egyptian queen, a drug bringing oblivion. It is believed that the gift was an opium-containing drug.[31] A Chinese book on houseplants written in 1st–3rd centuries BC mentioned a medical use ofephedra andopium poppies.[32] Also,coca leaves have been used by Indigenous South Americans since ancient times.[33]
Extracts from plants containing toxic alkaloids, such asaconitine andtubocurarine, were used since antiquity for poisoning arrows.[30]
Studies of alkaloids began in the 19th century. In 1804, the German chemistFriedrich Sertürner isolated from opium a "soporific principle" (Latin:principium somniferum), which he called "morphium", referring toMorpheus, 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 physicistJoseph Louis Gay-Lussac.
The first complete synthesis of an alkaloid was achieved in 1886 by the German chemistAlbert Ladenburg. He producedconiine by reacting 2-methylpyridine withacetaldehyde andreducing the resulting 2-propenyl pyridine with sodium.[36][37]
Bufotenin, an alkaloid from some toads, contains anindole core, and is produced in living organisms from the amino acidtryptophan.
Compared with most other classes of natural compounds, alkaloids are characterized by a great structural diversity. There is no uniform classification.[38] Initially, when knowledge of chemical structures was lacking, botanical classification of the source plants was relied on. This classification is now considered obsolete.[17][39]
Alkaloids are often divided into the following major groups:[42]
"True alkaloids" containnitrogen in theheterocycle and originate fromamino acids.[43] Their characteristic examples areatropine,nicotine, andmorphine. This group also includes some alkaloids that besides the nitrogen heterocycle containterpene (e.g.,evonine[44]) or peptide fragments (e.g.ergotamine[45]). The piperidine alkaloidsconiine andconiceine may be regarded as true alkaloids (rather than pseudoalkaloids: see below)[46] although they do not originate from amino acids.[47]
"Protoalkaloids", which containnitrogen (but not the nitrogen heterocycle) and also originate from amino acids.[43] Examples includemescaline,adrenaline andephedrine.
Some alkaloids do not have the carbon skeleton characteristic of their group. So,galanthamine and homoaporphines do not containisoquinoline fragment, but are, in general, attributed to isoquinoline alkaloids.[53]
Main classes of monomeric alkaloids are listed in the table below:
Class
Major groups
Main synthesis steps
Examples
Alkaloids with nitrogen heterocycles (true alkaloids)
Most alkaloids contain oxygen in their molecular structure; those compounds are usually colorless crystals at ambient conditions. Oxygen-free alkaloids, such asnicotine[160] orconiine,[36] are typically volatile, colorless, oily liquids.[161] Some alkaloids are colored, likeberberine (yellow) andsanguinarine (orange).[161]
Most alkaloids have a bitter taste or are poisonous when ingested. Alkaloid production in plants appeared to have evolved in response to feeding by herbivorous animals; however, some animals have evolved the ability to detoxify alkaloids.[169] Some alkaloids can produce developmental defects in the offspring of animals that consume but cannot detoxify the alkaloids. One example is the alkaloidcyclopamine, produced in the leaves ofcorn 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 tocyclopia. After decades of research, in the 1980s, the compound responsible for these deformities was identified as the alkaloid 11-deoxyjervine, later renamed to cyclopamine.[170]
Alkaloids aregenerated by various living organisms, especially byhigher plants – about 10 to 25% of those contain alkaloids.[171][172] Therefore, in the past the term "alkaloid" was associated with plants.[173]
The alkaloids content in plants is usually within a few percent and is inhomogeneous over the plant tissues. Depending on the type of plants, the maximum concentration is observed in the leaves (for example,black henbane),fruits orseeds (Strychnine tree), root (Rauvolfia serpentina) or bark (cinchona).[174] Furthermore, different tissues of the same plants may contain different alkaloids.[175]
Beside plants, alkaloids are found in certain types offungus, such aspsilocybin in the fruiting bodies of the genusPsilocybe, and in animals, such asbufotenin in the skin of some toads[24] and a number of insects, markedly ants.[176] Many marine organisms also contain alkaloids.[177] Someamines, such asadrenaline andserotonin, which play an important role in higher animals, are similar to alkaloids in their structure and biosynthesis and are sometimes called alkaloids.[178]
Because of the structural diversity of alkaloids, there is no single method of their extraction from natural raw materials.[179] Most methods exploit the property of most alkaloids to be soluble in organic solvents[4] but not in water, and the opposite tendency of their salts.
Most plants contain several alkaloids. Their mixture is extracted first and then individual alkaloids are separated.[180] Plants are thoroughly ground before extraction.[179][181] Most alkaloids are present in the raw plants in the form of salts of organic acids.[179] The extracted alkaloids may remain salts or change into bases.[180] Base extraction is achieved by processing the raw material with alkaline solutions and extracting the alkaloid bases with organic solvents, such as 1,2-dichloroethane, chloroform, diethyl ether or benzene. Then, the impurities are dissolved by weak acids; this converts alkaloid bases into salts that are washed away with water. If necessary, an aqueous solution of alkaloid salts is again made alkaline and treated with an organic solvent. The process is repeated until the desired purity is achieved.
In the acidic extraction, the raw plant material is processed by a weak acidic solution (e.g.,acetic acid in water, ethanol, or methanol). A base is then added to convert alkaloids to basic forms that are extracted with organic solvent (if the extraction was performed with alcohol, it is removed first, and the remainder is dissolved in water). The solution is purified as described above.[179][182]
Alkaloids are separated from their mixture using their different solubility in certain solvents and different reactivity with certain reagents or bydistillation.[183]
A number of alkaloids are identified frominsects, among which thefire antvenom alkaloids known assolenopsins have received greater attention from researchers.[184] These insect alkaloids can be efficiently extracted by solvent immersion of live fire ants[4] or by centrifugation of live ants[185] followed by silica-gel chromatography purification.[186] Tracking and dosing the extracted solenopsin ant alkaloids has been described as possible based on their absorbance peak around 232 nanometers.[187]
An integral component of the Mannich reaction, in addition to an amine and acarbonyl compound, is acarbanion, which plays the role of the nucleophile in thenucleophilic addition to the ion formed by the reaction of the amine and the carbonyl.[190]
The Mannich reaction can proceed both intermolecularly and intramolecularly:[191][192]
In addition to the described above monomeric alkaloids, there are alsodimeric, and eventrimeric andtetrameric alkaloids formed upon condensation of two, three, and four monomeric alkaloids. Dimeric alkaloids are usually formed from monomers of the same type through the following mechanisms:[193]
Alkaloids are among the most important and best-knownsecondary metabolites, i.e. biogenic substances not directly involved in the normalgrowth,development, orreproduction of the organism. Instead, they generally mediate ecologicalinteractions, which may produce a selective advantage for the organism by increasing itssurvivability orfecundity. In some cases their function, if any, remains unclear.[200] An early hypothesis, that alkaloids are the final products ofnitrogenmetabolism in plants, asurea anduric acid are in mammals, was refuted by the finding that their concentration fluctuates rather than steadily increasing.[14]
Most of the known functions of alkaloids are related to protection. For example,aporphine alkaloidliriodenine produced by thetulip tree protects it from parasitic mushrooms. In addition, the presence of alkaloids in the plant prevents insects andchordate animals from eating it. However, some animals are adapted to alkaloids and even use them in their own metabolism.[201] Such alkaloid-related substances asserotonin,dopamine andhistamine are importantneurotransmitters in animals. Alkaloids are also known to regulate plant growth.[202] One example of an organism that uses alkaloids for protection is theUtetheisa ornatrix, more commonly known as the ornate moth. Pyrrolizidine alkaloids render these larvae and adult moths unpalatable to many of their natural enemies like coccinelid beetles, green lacewings, insectivorous hemiptera and insectivorous bats.[203] Another example of alkaloids being utilized occurs in thepoison hemlock moth (Agonopterix alstroemeriana). This moth feeds on its highly toxic and alkaloid-rich host plantpoison 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 ofA. alstroemeriana to recognizeConium maculatum as the correct location for oviposition.[204] Afire antvenom alkaloid known assolenopsin has been demonstrated to protect queens ofinvasive fire ants during the foundation of new nests, thus playing a central role in the spread of this pest ant species around the world.[205]
Medical use of alkaloid-containing plants has a long history, and, thus, when the first alkaloids were isolated in the 19th century, they immediately found application in clinical practice.[206] Many alkaloids are still used in medicine, usually in the form of salts widely used including the following:[14][207]
Many synthetic and semisynthetic drugs are structural modifications of the alkaloids, which were designed to enhance or change the primary effect of the drug and reduce unwanted side-effects.[208] For example,naloxone, anopioid receptorantagonist, is a derivative ofthebaine that is present inopium.[209]
Prior to the development of a wide range of relatively low-toxic syntheticpesticides, some alkaloids, such as salts of nicotine andanabasine, were used asinsecticides. Their use was limited by their high toxicity to humans.[210]
^Meissner, W. (1819)."Über Pflanzenalkalien: II. Über ein neues Pflanzenalkali (Alkaloid)" [About Plant Alkalis: II. About a New Plant Alkali (Alkaloid)].Journal für Chemie und Physik.25:379–381. Archived fromthe original on 18 May 2023.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')".]
^Roberts, M. F. (Margaret F.); Wink, Michael (1998).Alkaloids: Biochemistry, Ecology, and Medicinal Applications. Boston: Springer US.ISBN9781475729054.OCLC851770197.
^Russo P, Frustaci A, Del Bufalo A, Fini M, Cesario A (2013). "Multitarget drugs of plants origin acting on Alzheimer's disease".Curr Med Chem.20 (13):1686–93.doi:10.2174/0929867311320130008.PMID23410167.
^Raymond S. Sinatra; Jonathan S. Jahr; J. Michael Watkins-Pitchford (2010).The Essence of Analgesia and Analgesics. Cambridge University Press. pp. 82–90.ISBN978-1139491983.
^Robbers JE, Speedie MK, Tyler VE (1996). "Chapter 9: Alkaloids".Pharmacognosy and Pharmacobiotechnology. Philadelphia: Lippincott, Williams & Wilkins. pp. 143–185.ISBN978-0683085006.
^Rhoades, David F (1979). "Evolution of Plant Chemical Defense against Herbivores". In Rosenthal, Gerald A.; Janzen, Daniel H (eds.).Herbivores: Their Interaction with Secondary Plant Metabolites. New York: Academic Press. p. 41.ISBN978-0-12-597180-5.
^abcRobert A. MeyersEncyclopedia of Physical Science and Technology – Alkaloids, 3rd edition.ISBN0-12-227411-3
^John R. Lewis (2000). "Amaryllidaceae, muscarine, imidazole, oxazole, thiazole and peptide alkaloids, and other miscellaneous alkaloids".Nat. Prod. Rep.17 (1):57–84.doi:10.1039/a809403i.PMID10714899.
^Richard B. Herbert; Herbert, Richard B.; Herbert, Richard B. (1999). "The biosynthesis of plant alkaloids and nitrogenous microbial metabolites".Nat. Prod. Rep.16 (2):199–208.doi:10.1039/a705734b.
^Atta-ur-Rahman and M. Iqbal Choudhary (1997). "Diterpenoid and steroidal alkaloids".Nat. Prod. Rep.14 (2):191–203.doi:10.1039/np9971400191.PMID9149410.
^Fox, Eduardo Gonçalves Paterson (2016). "Venom Toxins of Fire Ants". In Gopalakrishnakone, P.; Calvete, Juan J. (eds.).Venom Genomics and Proteomics. Springer Netherlands. pp. 149–167.doi:10.1007/978-94-007-6416-3_38.ISBN978-94-007-6415-6.
^Chen, Jian; Cantrell, Charles L.; Shang, Han-wu; Rojas, Maria G. (22 April 2009). "Piperideine Alkaloids from the Poison Gland of the Red Imported Fire Ant (Hymenoptera: Formicidae)".Journal of Agricultural and Food Chemistry.57 (8):3128–3133.doi:10.1021/jf803561y.ISSN0021-8561.PMID19326861.
^W.E. Conner (2009).Tiger Moths and Woolly Bears—behaviour, ecology, and evolution of the Arctiidae. New York: Oxford University Press. pp. 1–10.ISBN0195327373.
