Steroidal Alkaloids
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Steroidal alkaloids have the basic
steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...
al skeleton with nitrogen-based functional groups attached to the skeleton. More specifically, they are distinguished by their tetracyclic cyclopentanoperhydrophenanthrene skeleton that marks their close relationship with
sterol A sterol is any organic compound with a Skeletal formula, skeleton closely related to Cholestanol, cholestan-3-ol. The simplest sterol is gonan-3-ol, which has a formula of , and is derived from that of gonane by replacement of a hydrogen atom on ...
s. They fall in two major categories: Solanum alkaloids and Veratrum alkaloids. A Steroidal alkaloid has also been found in ''
Chonemorpha fragrans ''Chonemorpha fragrans'', the frangipani vine or climbing frangipani, is a plant species in the genus ''Chonemorpha''. It is a vigorous, generally evergreen, climbing shrub producing stems or more long that can climb to the tops of the tallest ...
'' (Frangipani vine), 'chonemorphine' was used to treat intestinal infections in
Wistar rats Laboratory rats or lab rats are strains of the rat subspecies '' Rattus norvegicus domestica'' (Domestic Norwegian rat) which are bred and kept for scientific research. While less commonly used for research than laboratory mice, rats have ser ...
. (Chatterjee DK et al (1987) Parasitol Res 74, 1, 30-33).


Examples


Apocynaceae steroid alkaloids

The family of apocynaceae alkaloids can be categorized based on their backbone structure, which may include the 5α-pregnane, Δ5-pregnane, or conanine backbone. Typically, these alkaloids feature an amino group or an oxygen compound at the 3rd carbon atom. An illustrative example is latifolinin, which is derived from the conanine backbone. This distinctive structure is characterized by a five-membered ring formed by an amino group bonded to both the 18th and 20th carbon atoms. Latifolinin is a compound that is naturally present in the bark of ''Funtumia latifolia''. Additionally, the leaves of this plant contain two other compounds, namely funtumin and funtumidin. These compounds belong to the Apocynaceae steroid alkaloids family and share the 5α-pregnan backbone structure. Latifolinin V2.svg, Latifolinin Funtumia africana-1906.jpg, Funtumia africana (heterosynonym: Funtumia latifolia)


Batrachotoxins

Batrachotoxins are neurotoxins that are naturally occurring on the dermal surface of
poison dart frog Poison dart frog (also known as dart-poison frog, poison frog or formerly known as poison arrow frog) is the common name of a group of frogs in the family Dendrobatidae which are native to tropical Central and South America. These species are ...
s. The photo shows the ''Phyllobates terribilis''. Batrachotoxins share a structural foundation with
pregnanes Pregnane, also known as 17β-ethylandrostane or as 10β,13β-dimethyl-17β-ethylgonane, is a C21 steroid and, indirectly, a parent of progesterone. It is a parent hydrocarbon for two series of steroids stemming from 5α-pregnane (originally all ...
, consisting of 21 carbon atoms, and are distinctive for the amino group attached to the 18th carbon atom, exemplified by batrachotoxin A (see image). Batrachotoxinin A V2.svg, Batrachotoxinin A Schrecklicherpfeilgiftfrosch-01.jpg,
poison dart frog Poison dart frog (also known as dart-poison frog, poison frog or formerly known as poison arrow frog) is the common name of a group of frogs in the family Dendrobatidae which are native to tropical Central and South America. These species are ...


Bufotoxins

The bufotoxins are named after the genus of ''Bufo''. The α-pyranones at the 17th carbon atom are specific for the bufotoxins. The
bufotoxin Bufotoxins are a family of toxic steroid lactones or substituted Substituted tryptamine, tryptamines of which some are toxic. They occur in the parotoid glands, skin, and poison of many toads (True toad, Bufonidae family) and other amphibians, an ...
shown here is a sterane derivative with an α-pyranone at the 17th carbon atom and an esterified
succinic acid Succinic acid () is a dicarboxylic acid with the chemical formula (CH2)2(CO2H)2. In living organisms, succinic acid takes the form of an anion, succinate, which has multiple biological roles as a metabolic intermediate being converted into fum ...
at the 3rd carbon atom with
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidinium, guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) a ...
attached. Bufotoxin V2.svg,
Bufotoxin Bufotoxins are a family of toxic steroid lactones or substituted Substituted tryptamine, tryptamines of which some are toxic. They occur in the parotoid glands, skin, and poison of many toads (True toad, Bufonidae family) and other amphibians, an ...
2009-03-13Bufo alvarius067Glande.jpg, Bufotoxin is found on the skin of toads of the genus
true toad A true toad is any member of the family Bufonidae, in the order Anura (frogs and toads). This is the only family of anurans in which all members are known as toads, although some may be called frogs (such as harlequin frogs). The bufonids now ...
(''Bufo'').


Buxus steroid alkaloids

Buxus steroid alkaloids are present in the leaves of the common boxwood (''Buxus sempervirens''). This plant primarily thrives in southern and central Europe. These alkaloids are characterized by an amino group attached to the 3rd and/or 20th carbon atom. Methylation of the amino groups can be partial, complete, or absent. Buxus steroid alkaloids constitute a substantial group of bases, most of which can be categorized into three distinct groups. Another subgroup of Buxus steroid alkaloids possesses a tetracyclic structure. In these compounds, a bond exists between the 9th and 19th carbon atoms, forming a seven-membered ring (ring B). Buxamine E serves as an example of this group. The third major group is distinguished by the absence of additional carbon atoms bonded to the 4th carbon atom of the A ring. Buxandonin L is an illustrative member of this category. The largest group consists of pentacyclic Buxus steroid alkaloids, featuring a core structure based on 4,4,14-trimethyl-9,19-cyclopregnan. Cyclobuxin D is a representative of this particular group. The Buxus steroid alkaloids buxamine E, buxandoline L, and cyclobuxin D are found in the leaves of common boxwood (buxus sempervirens).
Buxamin E V2.svg, Buxamine E Buxandonin L V2.svg, Buxandonin L Cyclobuxin D V2.svg, Cyclobuxin D Buxus sempervirens (sapling).jpg, Common boxwood (Buxus sempervirens)


Salamander alkaloids

The toxic salamander alkaloids occur naturally in organisms classified within the genus Salamandra. These alkaloids are derived from 3-aza-''A''-homo-5β-androstane. One notable example is samandarin (see figure), which may serve as the primary alkaloid depending on the species, although it may not be present in some other organisms at all. Samandarin possesses a distinctive oxazolidine structure within the A ring. Besides samandarin, there are several other steroid alkaloids in Salamandra organisms such as samandaridin, samandarone, and cycloneosamandione. Samandarin V2.svg, Samandarin Salamandra salamandra MHNT 1.jpg, Salamander alkaloids, such as samandarin, occur on the skin of animals of the genus
Salamandra ''Salamandra'' is a genus of six species of salamanders localized in central and southern Europe, Northern Africa, and western Asia. List of species References External links Salamandraat Fauna Europaea * Salamandraat Animal Diversity We ...
.


''Solanum'' alkaloids

These compounds generally appear as their corresponding
glycoside In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. ...
in plants of the genus ''Solanum''. ''Solanum'' includes plants like
potato The potato () is a starchy tuberous vegetable native to the Americas that is consumed as a staple food in many parts of the world. Potatoes are underground stem tubers of the plant ''Solanum tuberosum'', a perennial in the nightshade famil ...
es,
tomato The tomato (, ), ''Solanum lycopersicum'', is a plant whose fruit is an edible Berry (botany), berry that is eaten as a vegetable. The tomato is a member of the nightshade family that includes tobacco, potato, and chili peppers. It originate ...
es, and various nightshades Starting with cholesterol, the biosynthesis of these compounds follow a similar general mechanism including
hydroxylation In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...
,
oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
, and transamination before differentiating. Alkaloids found in these plants include
chaconine α-Chaconine is a steroidal glycoalkaloid that occurs in plants of the family Solanaceae. It is a natural toxicant produced in green potatoes and gives the potato a bitter taste. Tubers produce this glycoalkaloid in response to stress, providing ...
,
solanine Solanine is a glycoalkaloid poison found in species of the Solanaceae, nightshade family within the genus ''Solanum'', such as the potato (''Solanum tuberosum''). It can occur naturally in any part of the plant, including the Leaf, leaves, frui ...
,
solasodine Solasodine is a poisonous alkaloid chemical compound that occurs in plants of the family Solanaceae such as potatoes and tomatoes. Solasonine and solamargine are glycoalkaloid derivatives of solasodine. Solasodine is teratogenic to hamster fe ...
, tomatidine, tomatine, and
solanidine Solanidine is a poisonous steroidal alkaloid chemical Chemical compound, compound that occurs in plants of the family Solanaceae, such as potato and ''Solanum americanum''. The sugar portion of glycoalkaloids hydrolyses in the body, leaving the so ...
. The Itkin group has found several of the biosynthetic gene clusters for these. In Itkin ''et al.'' 2011 and Itkin ''et al.'' 2013 they find several BSGs for
α-tomatine Tomatine (sometimes called tomatin or lycopersicin) is a glycoalkaloid, found in the stems and leaves of tomato plants, and in the fruits at much lower concentrations. Chemically pure tomatine is a white crystalline solid at standard temperature ...
in tomato and
α-solanine Solanine is a glycoalkaloid poison found in species of the nightshade family within the genus ''Solanum'', such as the potato (''Solanum tuberosum''). It can occur naturally in any part of the plant, including the leaves, fruit, and tubers. Sol ...
in potato. Typically they are used in plants as a protection mechanism against animals. Due to the typical anti-
cholinesterase The enzyme cholinesterase (EC 3.1.1.8, choline esterase; systematic name acylcholine acylhydrolase) catalyses the hydrolysis of choline-based esters: : an acylcholine + H2O = choline + a carboxylate Several of these serve as neurotransmitte ...
activity, they can be used as poisons against the plants' predators. They can be used as starting materials for steroidal drugs. There are various tests for identifying these alkaloids. The characteristic test involves dissolving the compound in hot amyl alcohol or ethanol and watching for the formation of a jelly-like product as the mixture cools.


Solanidan skeleton

Steroidal alkaloids with a solanidan backbone exhibit a distinctive bicyclic structure, which replaces the cholesterol side chain on the D-ring. A notable example is solanocapsin, as discovered in the coral shrub (''Solanum pseudocapsicum''). Solanocapsin V1.svg, Solanocapsin Solanum pseudocapsicum.jpg, Solanocapsin is found, among other things, in the fruits of the Jerusalem cherry ('' Solanum pseudocapsicum'').


Spirosolan backbone

Another category of solanum alkaloids is based on the spirosolane skeleton. In these compounds, the E-ring is a
tetrahydrofuran Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...
to which a piperidine is directly attached via a spiro compound. An example of such a steroid alkaloid is tomatidenol, which is prevalent across various species within the genus ''Solanum''. Tomatidenol V3.svg, Tomatidenol Solanum dulcamara 0002.JPG, Tomatidenol is found, among other things, in the leaves of the bittersweet nightshade (''
Solanum dulcamara ''Solanum dulcamara'' is a species of vine in the genus ''Solanum'' (which also includes the potato and the tomato) of the family Solanaceae. Common names include bittersweet, bittersweet nightshade, bitter nightshade, blue bindweed, Amara Dulci ...
''). This plant species belongs to the nightshade genus. Tomatidenol forms the main alkamin in the species of ''Solanum dulcarama'', which are native to Europe.


Veratrum alkaloids


Veratrum alkaloids of white/green chervil

The veratrum alkaloids derive their name from the white and green germer plants (''Veratrum album'' and ''Veratrum viride'', respectively). These plants belong to the Liliaceae family. Among them, procevin is a special case, as it features a nitrogen atom from piperidine connected to the 18th carbon. Veratramine is an example of veratrum steroid alkaloids, characterized by a 22,26-epimino-14-''abeo''-cholestane ring system as their basis. Procevin V2.svg, Procevin Veratramin V2.svg, Veratramin Veratrum album Dachstein.jpg, Procevin and veratramin occur, among other things, in white veratrum ('' Veratrum album grandiflorum'').


Veratrum alkaloids of sabadill

Veracevin is a member of the veratrum alkaloids group. However, this occurs in the sabadilla (''Schoenocaulon officinale''), which also belongs to the Liliaceae family. The veracevin is based on the cevan skeleton, in which the C-ring is a five-membered instead of a six-membered ring and the D-ring is a six-membered ring. Furthermore, the high number of hydroxy groups is still remarkable. Veracevin V2.svg, Veracevin Schoenocaulon officinale - Köhler–s Medizinal-Pflanzen-262.jpg, Veracevin occurs in the Sabadilla ('' Schoenocaulon officinale'').


Veratrum alkaloids

True to their name, Veratrum alkaloids come from plants of the genus ''Veratrum''. Alkaloids are found in the roots and
rhizome In botany and dendrology, a rhizome ( ) is a modified subterranean plant stem that sends out roots and Shoot (botany), shoots from its Node (botany), nodes. Rhizomes are also called creeping rootstalks or just rootstalks. Rhizomes develop from ...
s of these plants. They include veratridine,
cyclopamine Cyclopamine (11-deoxojervine) is a naturally occurring steroidal alkaloid. It is a teratogenic component of corn lily ('' Veratrum californicum''), which when consumed during gestation has been demonstrated to induce birth defects, including the ...
, and
jervine Jervine is a steroidal alkaloid with molecular formula C27H39NO3 which is derived from the plant genus ''Veratrum''. Similar to cyclopamine, which also occurs in the genus ''Veratrum'', it is a teratogen implicated in birth defects when consumed ...
. Because of their actions on the cardiovascular, neuromuscular, and respiratory systems, Veratrum alkaloids have been used for the treatment of various conditions like
myasthenia gravis Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, ...
,
hypotension Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...
, and
eclampsia Eclampsia is the onset of seizures (convulsions) in a pregnant woman with pre-eclampsia. Pre-eclampsia is a hypertensive disorder of pregnancy that presents with three main features: new onset of high blood pressure, large amounts of proteinuria ...
.


Bioactivity

Steroidal alkaloids have been investigated for a wide range of potential bioactivities including
antimicrobial An antimicrobial is an agent that kills microorganisms (microbicide) or stops their growth (bacteriostatic agent). Antimicrobial medicines can be grouped according to the microorganisms they are used to treat. For example, antibiotics are used aga ...
,
anti-inflammatory Anti-inflammatory is the property of a substance or treatment that reduces inflammation, fever or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs reduce pain by inhibiting mechan ...
, anti-estrogenic, and
chemotherapeutic Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a curat ...
activity. These bioactivities are the result of a wide array of mechanisms across different compounds. For example,
solasodine Solasodine is a poisonous alkaloid chemical compound that occurs in plants of the family Solanaceae such as potatoes and tomatoes. Solasonine and solamargine are glycoalkaloid derivatives of solasodine. Solasodine is teratogenic to hamster fe ...
antimicrobial bioactivity is accomplished by interfering with the synthesis of genetic substances in ''
Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungal microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have be ...
'' and ''
Prototheca wickerhamii ''Prototheca wickerhamii'' is a ubiquitous green alga that does not have chlorophyll. It is widely present in the environment but is a rare cause of opportunistic infection in humans ( protothecosis). Biology ''P. wickerhamii'' has a round to el ...
''. Solasodine inhibits growth signaling in ''Geim original algal''. On the other hand, tomatidine synergistically works with
aminoglycoside Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer ...
s as antibiotics against '' S. aureus''. Antiinflammation is similarly accomplished with a variety of mechanisms.
Solasodine Solasodine is a poisonous alkaloid chemical compound that occurs in plants of the family Solanaceae such as potatoes and tomatoes. Solasonine and solamargine are glycoalkaloid derivatives of solasodine. Solasodine is teratogenic to hamster fe ...
, for example, reduces interleukin-2 and -8 production whereas tomatidine inhibits specific nuclear translocation,
JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are r ...
activation, as well as induce
nitrous oxide Nitrous oxide (dinitrogen oxide or dinitrogen monoxide), commonly known as laughing gas, nitrous, or factitious air, among others, is a chemical compound, an Nitrogen oxide, oxide of nitrogen with the Chemical formula, formula . At room te ...
synthase. Lastly, nine steroidal alkaloids have significant antiestrogenic activity whereas seven inhibit estrone sulfatase. However, in addition to their therapeutic benefits, steroidal alkaloids, specifically veratrum alkaloids, are potentially deadly. Veratrum alkaloid compounds act by attaching to voltage-gated sodium ion channels, altering their permeability. Veratrum alkaloids cause affected sodium channels to reactivate 1000x slower than unaffected channels. Furthermore, veratrum alkaloids block inactivation of sodium channels and lower their activation threshold so they remain open even at resting potential. As a result, sodium concentrations within the cell rise, leading to increased nerve and muscle excitability. These biochemical channels cause muscle contractions, repetitive firing of the nerves and an irregular heart rhythm caused by stimulation of vagal nerves which control the parasympathetic functions of the heart, lungs and digestive tract.


References

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