Calotropin

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Calotropin
Calotropin.svg
Names
Systematic IUPAC name
(1R,3aS,3bR,5aS,6aR,7aS,9R,11S,11aS,12aR,13aR,13bS,15aR)-3a,11,11a-Trihydroxy-9,15a-dimethyl-1-(5-oxo-2,5-dihydrofuran-3-yl)icosahydro-9H,13aH-cyclopenta[7,8]phenanthro[2,3-b]pyrano[3,2-e][1,4]dioxine-13-carbaldehyde
Other names
Pecilocerin A, Pekilocerin A
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
PubChem CID
UNII
  • InChI=1S/C29H40O9/c1-15-9-23(31)29(34)25(36-15)37-21-11-17-3-4-20-19(27(17,14-30)12-22(21)38-29)5-7-26(2)18(6-8-28(20,26)33)16-10-24(32)35-13-16/h10,14-15,17-23,25,31,33-34H,3-9,11-13H2,1-2H3/t15-,17+,18-,19+,20-,21-,22-,23+,25+,26-,27-,28+,29+/m1/s1
    Key: OWPWFVVPBYFKBG-NYVHBPEFSA-N
  • CC1CC(C2(C(O1)OC3CC4CCC5C(C4(CC3O2)C=O)CCC6(C5(CCC6C7=CC(=O)OC7)O)C)O)O
Properties
C29H40O9
Molar mass 532.630 g·mol−1
Melting point 223 °C (433 °F; 496 K)
Hazards
Lethal dose or concentration (LD, LC):
9800 μg/kg (mouse) [1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Calotropin is a toxic cardenolide found in plants in the family Asclepiadoideae . In extreme cases, calotropin poisoning can cause respiratory and cardiac failure. Accidental poisoning is common in livestock who have ingested milkweed. Calotropin is commonly stored as a defense mechanism by insects that eat milkweeds as their main food source.

Contents

Chemistry

Calotropin is a toxic compound and is classified as a cardenolide-type cardiac glycoside. These molecules are related to steroids, and have a similar carbon backbone. Calotropin, like calactin, calotoxin, and uscharin, is based on calotropagenin, the precursor to these molecules. They have similar activity and are often found together in plants of the genus Calotropis . [2]

Biosynthesis of digitoxigenin Digitoxigenin Biosynthesis.png
Biosynthesis of digitoxigenin

Biosynthesis

It is thought that the biosynthesis of calotropin is similar to that of digitoxin, another cardenolide. Digitoxin is more established as a medicine for cardiac insufficiency, and therefore the biosynthesis has been further studied. However, it is believed that many cardenolides are synthesized in plants by a similar process, but this process is not yet well understood. The sterol precursor for this process is similar to precursors for steroidal alkaloids. Two suggested pathways, the pregnane pathway and norcholanic acid pathway are possible for the conversion of the sterol precursor to digitoxigenin, the precursor to digitoxin. Both the pregnane and norcholanic acid pathways use progesterone 5β-reductases, the P5βR and P5βR2 respectively. In the pregnane pathway, a plant analog of the mitochondrial cytochrome P450 (CYP11A in humans), is thought to catalyze the conversion of pregnenolone to progesterone. Progesterone is further processed by P5βR to 5β-Pregnane-3,20-dione, and then to digitoxigenin. Less is known about the norcholanic acid pathway. At this point the similarities between digitoxin and calotropin end. Calotropagenin may be produced by the same process as digitoxigenin, however the mechanism for production of calotropin and digitoxin from these genins diverges. It is not well studied how calotropin is produced from its calotropagenin precursor. [3] [4]

Toxicity

Sodium-potassium pump Sodium-Potassium Pump.jpg
Sodium-potassium pump

Mechanism of action

Cardenolides such as calotropin inhibit the sodium-potassium pump, Na+/K+-ATPase. This enzyme is responsible for active transport of sodium and potassium ions across the cell membrane. This process also helps to regulate the resting potential and cell volume. Inhibition of this enzyme in cardiac tissue is proposed as the receptor for calotropin and cardiac glycosides in general, and this is responsible for the toxic effects. [3] [5] Inhibition of the Na+/K+-ATPase causes an increase of sodium inside the cell, and by the action of the sodium-calcium exchanger (NCX) also raises the calcium concentration. Calotropin has a more noticeable effect on the myocardium than it does on skeletal muscles, as these cells have more active NCX proteins. [6] This can allow for higher cardiac output by the cardiac muscles, but can also lead to arrhythmia, which is aggravated by the charge buildup that develops when Na+/K+-ATPase is inhibited. [7]

Symptoms and bioactivity

Poisoning can cause a variety of unpleasant symptoms including abdominal pain, bloating, diarrhoea, muscle tremors, seizures, and death. [8] Death can be caused by hemorrhages in the lungs, respiratory failure, or cardiac failure. Symptoms can begin as early as two hours after ingestion, and may persist for hours or days. [5] Ingestion is not always lethal, and plants in the genus Calotropis have long been used as a folk remedy in India. [9]

Natural sources

Monarch butterfly caterpillars feeding on milkweed leaves Monarch Butterfly Caterpillars.JPG
Monarch butterfly caterpillars feeding on milkweed leaves

Plants

Calotropin is primarily generated by plants in the Asclepiadoideae family, and can be obtained or isolated from plant extracts of Calotropis gigantea and Calotropis procera . Asclepiadoideae plants are commonly regarded as poisonous, and are common around the world. Calotropin is found in the latex, [9] leaves, and root bark. [2] Ingestion of these plants is toxic to mammals, and can be life-threatening. [8]

Insects

Monarch butterflies are one of many insects that feed on milkweed plants. [10] These butterflies feed on the North American milkweed ( Asclepias) plants. These milkweeds are related to the Indian and North African milkweeds ( Calotropis ), which are consumed by the North African grasshopper Poekilocerus bufonis . [11] These insects have adapted to the toxicity of the milkweed, are capable of safely sequestering cardenolides from the milkweed in glands or tissues during their early stages of development. [12] The insects primarily retain calotropin and calactin (a configurational isomer), even though other cardenolides exist in the plant latex and leaves. These poisons, while not harmful to the insect, make it unpalatable to birds and mammals, and therefore serve as a defense mechanism. Monarch butterflies also store several volatile pyrazines, which give off an odor, which is a warning signal to predators to avoid the insect. [11] P. bufonis is capable of utilizing calotropin in its defensive spray. [3]

See also

Related Research Articles

<span class="mw-page-title-main">Cardiac glycoside</span> Class of organic compounds

Cardiac glycosides are a class of organic compounds that increase the output force of the heart and decrease its rate of contractions by inhibiting the cellular sodium-potassium ATPase pump. Their beneficial medical uses are as treatments for congestive heart failure and cardiac arrhythmias; however, their relative toxicity prevents them from being widely used. Most commonly found as secondary metabolites in several plants such as foxglove plants, these compounds nevertheless have a diverse range of biochemical effects regarding cardiac cell function and have also been suggested for use in cancer treatment.

<i>Erysimum</i> Genus of flowering plants

Erysimum, or wallflower, is a genus of flowering plants in the cabbage family, Brassicaceae. It includes more than 150 species, both popular garden plants and many wild forms. The genus Cheiranthus is sometimes included here in whole or in part. Erysimum has since the early 21st century been ascribed to a monogeneric cruciferous tribe, Erysimeae, characterised by sessile, stellate (star-shaped) and/or malpighiaceous (two-sided) trichomes, yellow to orange flowers and multiseeded siliques.

<i>Asclepias tuberosa</i> Species of flowering plant

Asclepias tuberosa, commonly known as butterfly weed, is a species of milkweed native to eastern and southwestern North America. It is commonly known as butterfly weed because of the butterflies that are attracted to the plant by its color and its copious production of nectar.

<span class="mw-page-title-main">Monarch butterfly</span> Milkweed butterfly in the family Nymphalidae

The monarch butterfly or simply monarch is a milkweed butterfly in the family Nymphalidae. Other common names, depending on region, include milkweed, common tiger, wanderer, and black-veined brown. It is among the most familiar of North American butterflies and an iconic pollinator, although it is not an especially effective pollinator of milkweeds. Its wings feature an easily recognizable black, orange, and white pattern, with a wingspan of 8.9–10.2 cm (3.5–4.0 in). A Müllerian mimic, the viceroy butterfly, is similar in color and pattern, but is markedly smaller and has an extra black stripe across each hindwing.

<span class="mw-page-title-main">Digitoxin</span> Chemical compound

Digitoxin is a cardiac glycoside used for the treatment of heart failure and certain kinds of heart arrhythmia. It is a phytosteroid and is similar in structure and effects to digoxin, though the effects are longer-lasting. Unlike digoxin, which is eliminated from the body via the kidneys, it is eliminated via the liver, and so can be used in patients with poor or erratic kidney function. While several controlled trials have shown digoxin to be effective in a proportion of patients treated for heart failure, the evidence base for digitoxin is not as strong, although it is presumed to be similarly effective.

<i>Asclepias</i> Genus of flowering plants

Asclepias is a genus of herbaceous, perennial, flowering plants known as milkweeds, named for their latex, a milky substance containing cardiac glycosides termed cardenolides, exuded where cells are damaged. Most species are toxic to humans and many other species, primarily due to the presence of cardenolides. However, as with many such plants, some species feed upon them or from them. The most notable of them is the monarch butterfly, which uses and requires certain milkweeds as host plants for their larvae.

<span class="mw-page-title-main">Ouabain</span> Chemical substance

Ouabain or also known as g-strophanthin, is a plant derived toxic substance that was traditionally used as an arrow poison in eastern Africa for both hunting and warfare. Ouabain is a cardiac glycoside and in lower doses, can be used medically to treat hypotension and some arrhythmias. It acts by inhibiting the Na/K-ATPase, also known as the sodium–potassium ion pump. However, adaptations to the alpha-subunit of the Na+/K+-ATPase via amino acid substitutions, have been observed in certain species, namely some herbivore- insect species, that have resulted in toxin resistance.

<span class="mw-page-title-main">Cerberin</span> Chemical compound

Cerberin is a type of cardiac glycoside, a steroidal class found in the seeds of the dicotyledonous angiosperm genus Cerbera; including the suicide tree and the sea mango. This class includes digitalis-like agents, channel-blockers that as a group have found historic uses as cardiac treatments, but which at higher doses are extremely toxic; in the case of cerberin, consumption of the C. odollam results in poisoning with presenting nausea, vomiting, and abdominal pain, often leading to death. The natural product has been structurally characterized, its toxicity is clear—it is often used as an intentional human poison in third-world countries, and accidental poisonings with fatalities have resulted from individuals even indirectly consuming the agent—but its potentially therapeutic pharmacologic properties are very poorly described.

<i>Calotropis procera</i> Species of plant

Calotropis procera is a species of flowering plant in the family Apocynaceae that is native to North Africa, Pakistan, tropical Africa, Western Asia, South Asia and Indochina. It typically grows to a height of 6 feet (1.8 m) to 8 feet (2.4 m) in sunny and partly shaded habitats, including overgrazed pastures, rangeland, roadsides, river flats and coastal dunes. Its green fruits contain a toxic milky sap that is extremely bitter and turns into a gluey coating which is resistant to soap.

<i>Calotropis</i> Genus of flowering plants

Calotropis is a genus of flowering plants in the family Apocynaceae, first described as a genus in 1810. It is native to southern Asia and North Africa.

<span class="mw-page-title-main">Queen (butterfly)</span> Species of butterfly

The queen butterfly is a North and South American butterfly in the family Nymphalidae with a wingspan of 80–85 mm. It is orange or brown with black wing borders and small white forewing spots on its dorsal wing surface, and reddish ventral wing surface fairly similar to the dorsal surface. The ventral hindwings have black veins and small white spots in a black border. The male has a black androconial scent patch on its dorsal hindwings. It can be found in meadows, fields, marshes, deserts, and at the edges of forests.

<i>Asclepias curassavica</i> Species of flowering plant

Asclepias curassavica, commonly known as tropical milkweed, is a flowering plant species of the milkweed genus, Asclepias. It is native to the American tropics and has a pantropical distribution as an introduced species. Other common names include bloodflower or blood flower, cotton bush, hierba de la cucaracha, Mexican butterfly weed, redhead, scarlet milkweed, and wild ipecacuanha.

<span class="mw-page-title-main">Cardenolide</span> Chemical compound

A cardenolide is a type of steroid. Many plants contain derivatives, collectively known as cardenolides, including many in the form of cardenolide glycosides (cardenolides that contain structural groups derived from sugars). Cardenolide glycosides are often toxic; specifically, they are heart-arresting. Cardenolides are toxic to animals through inhibition of the enzyme Na+/K+‐ATPase, which is responsible for maintaining the sodium and potassium ion gradients across the cell membranes.

<i>Calotropis gigantea</i> Species of plant

Calotropis gigantea, the crown flower, is a species of Calotropis native to Cambodia, Vietnam, Bangladesh, Indonesia, Malaysia, Thailand, Sri Lanka, India, China, Pakistan, and Nepal.

k-Strophanthidin Chemical compound

k-Strophanthidin is a cardenolide found in species of the genus Strophanthus. It is the aglycone of k-strophanthin, an analogue of ouabain. k-strophanthin is found in the ripe seeds of Strophanthus kombé and in the lily Convallaria.

<span class="mw-page-title-main">Arenobufagin</span> Chemical compound

Arenobufagin is a cardiotoxic bufanolide steroid secreted by the Argentine toad Bufo arenarum. It has effects similar to digitalis, blocking the Na+/K+ pump in heart tissue.

<span class="mw-page-title-main">Convallatoxin</span> Chemical compound

Convallatoxin is a glycoside extracted from Convallaria majalis.

<i>Asclepias curtissii</i> Species of plant

Asclepias curtissii, or Curtiss's milkweed, is a rare species of flowering milkweed that is endemic to Florida's sandy areas. Curtiss's milkweed belongs to the subfamily Asclepiadoideae and the genus Asclepias. This dicotyledonous, perennial plant was placed on the endangered species list by the state of Florida to protect this rare milkweed. Although Curtiss milkweed is found all over Florida, the populations are very isolated and concentrated.

<span class="mw-page-title-main">Cassaine</span> Chemical compound

Cassaine is a toxic compound found within the tree genus Erythrophleum. This genus has a range from Senegal to Sudan and Kenya in the east, and south to Zimbabwe and Mozambique. Cassaine was first isolated by the G. Dalma group in 1935 from the Erythrophleum guinneese tree. Since ancient times cassaine has been used as an ordeal poison by African tribes. It has also been utilized extensively as an arrow poison by the Casamance people of Senegal.

<i>Erysimum crepidifolium</i> Species of plant

Erysimum crepidifolium, the pale wallflower, is a plant species in the crucifer family, Brassicaceae. It is a member of the genus Erysimum, which includes between 150 and 350 species in the Northern Hemisphere.

References

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