Solenopsin

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Solenopsin
Solenopsin.svg
Names
Preferred IUPAC name
(2R,6R)-2-Methyl-6-undecylpiperidine [1]
Other names
Solenopsin A
Identifiers
3D model (JSmol)
ChemSpider
PubChem CID
UNII
  • InChI=1S/C17H35N/c1-3-4-5-6-7-8-9-10-11-14-17-15-12-13-16(2)18-17/h16-18H,3-15H2,1-2H3/t16-,17-/m1/s1 Yes check.svgY
    Key: AYJGABFBAYKWDX-IAGOWNOFSA-N Yes check.svgY
  • CCCCCCCCCCC[C@@H]1CCC[C@H](N1)C
Properties
C17H35N
Molar mass 253.474 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Solenopsin is a lipophilic alkaloid with the molecular formula C17H35N found in the venom of fire ants (Solenopsis). It is considered the primary toxin in the venom [2] and may be the component responsible for the cardiorespiratory failure in people who experience excessive fire ant stings. [3]

Contents

Structurally solenopsins are a piperidine ring with a methyl group substitution at position 2 and a long hydrophobic chain at position 6. They are typically oily at room temperature, water-insoluble, and present an absorbance peak at 232 nanometers. [4] Fire ant venom contains other chemically related piperidines which make purification of solenopsin from ants difficult. [5] [6] Therefore, solenopsin and related compounds have been the target of organic synthesis from which pure compounds can be produced for individual study. Originally synthesized in 1993, [7] several groups have designed novel and creative methods of synthesizing enantiopure solenopsin and other alkaloidal components of ant venom.

Total synthesis

The total synthesis of solenopsin has been described by several methods. [8] [ failed verification ] A proposed method of synthesis [9] (Figure 1) starts with alkylation of 4-chloropyridine with a Grignard reagent derived from 1-bromoundecane, followed by reaction with phenyl chloroformate to form 4-chloro-1-(phenoxycarbonyl)-2-n-undecyl-1,2-dihydropyridine. The phenylcarbamate is converted to the BOC protecting group, and then pyridine is methylated at the 6 position. The pyridine ring is then reduced to a tetrahydropyridine via catalytic hydrogenation with Pd/C and then further reduced with sodium cyanoborohydride to a piperidine ring. The BOC group is finally removed to yield solenopsin. A number of analogs have been synthesized using modifications of this procedure.

A shorter method of synthesis stemming from commercially-available lutidine has been more recently proposed. [10]

Figure 1. Example synthesis of racemic solenopsin Solenopsin synthesis.png
Figure 1. Example synthesis of racemic solenopsin

Biological activities

Solenopsins are described as toxic against vertebrates and invertebrates. For example, the compound known as isosolenopsin A has been demonstrated to have strong insecticidal effects [11] which may play a central role in the biology of fire ants.

In addition to its toxicity, solenopsis has a number of other biological activities. It inhibits angiogenesis in vitro via the phosphoinositide 3-kinase (PI3K) signaling pathway, [9] inhibits neuronal nitric oxide synthase (nNOS) in a manner that appears to be non-competitive with L-arginine, [12] and inhibits quorum-sensing signaling in some bacteria. [13] The biological activities of solenopsins have led researchers to propose a number of biotechnological and biomedical applications for these compounds. For instance, mentioned anti-bacterial and interference in quorum-sensing signalling apparently provide solenopsins with considerable anti-biofilm activity, which suggests the potential of analogs as new disinfectants and surface-conditioning agents. [14] Also, solenopsins have been demonstrated to inhibit cell division and viability of Trypanosoma cruzi , the cause of Chagas disease, which suggests these alkaloids as potential chemotherapeutic drugs. [15]

Solenopsin and analogs share structural and biological properties with the sphingolipid ceramide, a major endogenous regulator of cell signaling, inducing mitophagy and anti-proliferative effects in different tumor cell lines. [16]

Synthetic analogs of solenopsin are being studied for the potential treatment of psoriasis. [17]

Related Research Articles

<span class="mw-page-title-main">Alkaloid</span> Class of naturally occurring chemical compounds

Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar structure may also be termed alkaloids. In addition to carbon, hydrogen and nitrogen, alkaloids may also contain oxygen or sulfur. More rarely still, they may contain elements such as phosphorus, chlorine, and bromine.

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

Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor described as objectionable, typical of amines. The name comes from the genus name Piper, which is the Latin word for pepper. Although piperidine is a common organic compound, it is best known as a representative structure element within many pharmaceuticals and alkaloids, such as natural-occurring solenopsins.

<span class="mw-page-title-main">Venom</span> Toxin secreted by an animal

Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved venom apparatus, such as fangs or a stinger, in a process called envenomation. Venom is often distinguished from poison, which is a toxin that is passively delivered by being ingested, inhaled, or absorbed through the skin, and toxungen, which is actively transferred to the external surface of another animal via a physical delivery mechanism.

Most ants are capable of biting, stinging, and spraying irritant chemicals. However, only relatively few species can harm humans; among which some can cause significant injury or, in rare cases, death. Like wasps, individual ants are capable of stinging multiple times as they do not lose their stingers.

<span class="mw-page-title-main">Fire ant</span> Genus of red ants

Fire ants are several species of ants in the genus Solenopsis, which includes over 200 species. Solenopsis are stinging ants, and most of their common names reflect this, for example, ginger ants and tropical fire ants. Many of the names shared by this genus are often used interchangeably to refer to other species of ant, such as the term red ant, mostly because of their similar coloration despite not being in the genus Solenopsis. Both Myrmica rubra and Pogonomyrmex barbatus are common examples of non-Solenopsis ants being termed red ants.

<span class="mw-page-title-main">Red imported fire ant</span> Invasive ant species

Solenopsis invicta, the fire ant, or red imported fire ant (RIFA), is a species of ant native to South America. A member of the genus Solenopsis in the subfamily Myrmicinae, it was described by Swiss entomologist Felix Santschi as a variant of S. saevissima in 1916. Its current specific name invicta was given to the ant in 1972 as a separate species. However, the variant and species were the same ant, and the name was preserved due to its wide use. Though South American in origin, the red imported fire ant has been accidentally introduced in Australia, New Zealand, several Asian and Caribbean countries, Europe and the United States. The red imported fire ant is polymorphic, as workers appear in different shapes and sizes. The ant's colours are red and somewhat yellowish with a brown or black gaster, but males are completely black. Red imported fire ants are dominant in altered areas and live in a wide variety of habitats. They can be found in rainforests, disturbed areas, deserts, grasslands, alongside roads and buildings, and in electrical equipment. Colonies form large mounds constructed from soil with no visible entrances because foraging tunnels are built and workers emerge far away from the nest.

<span class="mw-page-title-main">Epibatidine</span> Toxic chemical from some poison dart frogs

Epibatidine is a chlorinated alkaloid that is secreted by the Ecuadoran frog Epipedobates anthonyi and poison dart frogs from the Ameerega genus. It was discovered by John W. Daly in 1974, but its structure was not fully elucidated until 1992. Whether epibatidine is the first observed example of a chlorinated alkaloid remains controversial, due to challenges in conclusively identifying the compound from the limited samples collected by Daly. By the time that high-resolution spectrometry was used in 1991, there remained less than one milligram of extract from Daly's samples, raising concerns about possible contamination. Samples from other batches of the same species of frog failed to yield epibatidine.

<span class="mw-page-title-main">Poneratoxin</span> Paralyzing neurotoxic peptide

Poneratoxin is a paralyzing neurotoxic peptide made by the bullet ant Paraponera clavata. It prevents inactivation of voltage gated sodium channels and therefore blocks synaptic transmission in the central nervous system. Specifically, poneratoxin acts on voltage gated sodium channels in skeletal muscle fibers, causing paralysis, and nociceptive fibers, causing pain. It is rated as a 4 plus on the Schmidt sting pain index, the highest possible rating with that system, and its effects can cause waves of pain up to twelve hours after a single sting. It is additionally being studied for its uses in biological insecticides.

<span class="mw-page-title-main">Pumiliotoxin 251D</span> Chemical compound

Pumiliotoxin 251D is a toxic organic compound. It is found in the skin of poison frogs from the genera Dendrobates, Epipedobates, Minyobates, and Phyllobates and toads from the genus Melanophryniscus. Its name comes from the pumiliotoxin family (PTXs) and its molecular mass of 251 daltons. When the toxin enters the bloodstream through cuts in the skin or by ingestion, it can cause hyperactivity, convulsions, cardiac arrest and ultimately death. It is especially toxic to arthropods, even at low concentrations.

<span class="mw-page-title-main">Scorpion toxin</span>

Scorpion toxins are proteins found in the venom of scorpions. Their toxic effect may be mammal- or insect-specific and acts by binding with varying degrees of specificity to members of the Voltage-gated ion channel superfamily; specifically, voltage-gated sodium channels, voltage-gated potassium channels, and Transient Receptor Potential (TRP) channels. The result of this action is to activate or inhibit the action of these channels in the nervous and cardiac organ systems. For instance, α-scorpion toxins MeuNaTxα-12 and MeuNaTxα-13 from Mesobuthus eupeus are neurotoxins that target voltage-gated Na+ channels (Navs), inhibiting fast inactivation. In vivo assays of MeuNaTxα-12 and MeuNaTxα-13 effects on mammalian and insect Navs show differential potency. These recombinants exhibit their preferential affinity for mammalian and insect Na+ channels at the α-like toxins' active site, site 3, in order to inactivate the cell membrane depolarization faster[6]. The varying sensitivity of different Navs to MeuNaTxα-12 and MeuNaTxα-13 may be dependent on the substitution of a conserved Valine residue for a Phenylalanine residue at position 1630 of the LD4:S3-S4 subunit or due to various changes in residues in the LD4:S5-S6 subunit of the Navs. Ultimately, these actions can serve the purpose of warding off predators by causing pain or to subdue predators.

<span class="mw-page-title-main">Rasberry crazy ant</span> Species of ant

The tawny crazy ant or Rasberry crazy ant, Nylanderia fulva, is an ant originating in South America. Like the longhorn crazy ant, this species is called "crazy ant" because of its quick, unpredictable movements. It is sometimes called the "Rasberry crazy ant" in Texas after the exterminator Tom Rasberry, who noticed that the ants were increasing in numbers in 2002. Scientists have reorganised the genera taxonomy within this clade of ants, and now it is identified as Nylanderia fulva.

<span class="mw-page-title-main">Ant venom</span> Medical condition

Ant venom is any of, or a mixture of, irritants and toxins inflicted by ants. Most ants spray or inject a venom, the main constituent of which is formic acid only in the case of subfamily Formicinae.

<i>Solenopsis saevissima</i> Species of ant

Solenopsis saevissima, commonly known in Brazil as formiga de fogo, formiga-vermelha, or formiga-lava-pes, is one of more than 185 species in the genus Solenopsis. It, along with 13 other species, is also a member of the Solenopsis saevissima species group which are popularly known as fire ants.

BmKAEP is a neurotoxin from the venom of the Manchurian scorpion (Mesobuthus martensii). It is a β-toxin, which shift the activation voltage of sodium channels towards more negative potentials.

α-Neurotoxin Group of neurotoxic peptides found in the venom of snakes

α-Neurotoxins are a group of neurotoxic peptides found in the venom of snakes in the families Elapidae and Hydrophiidae. They can cause paralysis, respiratory failure, and death. Members of the three-finger toxin protein family, they are antagonists of post-synaptic nicotinic acetylcholine receptors (nAChRs) in the neuromuscular synapse that bind competitively and irreversibly, preventing synaptic acetylcholine (ACh) from opening the ion channel. Over 100 α-neurotoxins have been identified and sequenced.

Euglenophycin is an ichthyotoxic compound isolated from Euglena sanguinea, a protist of the genus Euglena. It exhibits anticancer and herbicidal activity in vitro.

Ichthyotoxins are compounds which are either toxic to fish, or are toxins produced by fish. The former include the algae-produced euglenophycin and prymnesins, which can cause large-scale fish deaths. The latter includes ostracitoxin, produced by boxfish. Many toxin-producing algal species can be found both in marine and fresh water environments when the algae are in bloom. Ichthyotoxic poisoning in humans can cause symptoms ranging in severity dependent on how much toxin was consumed. The symptoms of an ichthyotoxin poisoning from fish venoms can include headache, vomiting, diarrhea, dizziness, and drop in blood pressure.

Hanatoxin is a toxin found in the venom of the Grammostola spatulata tarantula. The toxin is mostly known for inhibiting the activation of voltage-gated potassium channels, most specifically Kv4.2 and Kv2.1, by raising its activation threshold.

A flavonoid alkaloid also known as a flavoalkaloid is a type of natural product produced by plants that contains both a flavonoid core structure and a nitrogen containing substituent so that the substance is also classified as an alkaloid. The most common flavonoid alkaloids contain a nitrogen heterocycle such as a pyridine or piperidine which is covalently bonded to the A-ring of a chromone. One flavonoid alkaloid, lilaline, was isolated from Lilium candidum in 1987. The synthesis of flavonoid alkaloids has been achieved

The toxicology of fire ant venom is relatively well studied. The venom plays a central role in the biology of Red imported fire ants, such as in capturing prey, and in defending itself from competitors, assailants, and diseases. Some 14 million people are stung annually in the United States, suffering reactions that vary from mild discomfort, to pustule formation, swelling, and in rare cases, systemic reactions followed by anaphylactic shock. Fire ant venoms are mainly composed (>95%) of a complex mixture of insoluble alkaloids added to a watery solution of toxic proteins. For the Red imported fire ant Solenopsis invicta Buren there are currently 46 described proteins, of which four are well-characterised as potent allergens.

References

  1. ↑ Stereochemistry per: Leclercq S, Thirionet I, Broeders F, Daloze D, Vander Meer R, Braekman J (1994). "Absolute configuration of the solenopsins, venom alkaloids of the fire ants". Tetrahedron. 50 (28): 8465–8478. doi:10.1016/S0040-4020(01)85567-8.
  2. ↑ Touchard A, Aili SR, Fox EG, Escoubas P, Orivel J, Nicholson GM, Dejean A (2016). "The Biochemical Toxin Arsenal from Ant Venoms". Toxins. 8 (1): 30. doi: 10.3390/toxins8010030 . PMC   4728552 . PMID   26805882.
  3. ↑ Howell G, Butler J, Deshazo RD, Farley JM, Liu HL, Nanayakkara NP, Yates A, Yi GB, Rockhold RW (2005). "Cardiodepressant and neurologic actions of Solenopsis invicta (imported fire ant) venom alkaloids". Ann Allergy Asthma Immunol. 94 (3): 380–6. doi:10.1016/S1081-1206(10)60991-X. PMID   15801250.
  4. ↑ Fox EG, Xu M, Wang L, Chen L, Lu Y (June 2018). "Gas-chromatography and UV-spectroscopy of Hymenoptera venoms obtained by trivial centrifugation". Data in Brief. 18: 992–998. Bibcode:2018DIB....18..992F. doi:10.1016/j.dib.2018.03.101. PMC   5996826 . PMID   29900266.
  5. ↑ Gopalakrishnakone P, Calvete JJ (2021-01-14). Venom genomics and proteomics. Gopalakrishnakone, P.,, Calvete, Juan J. (Living Reference Work ed.). Dordrecht. ISBN   9789400766495. OCLC   968345667.{{cite book}}: CS1 maint: location missing publisher (link)
  6. ↑ Fox EG, Xu M, Wang L, Chen L, Lu Y (May 2018). "Speedy milking of fresh venom from aculeate hymenopterans". Toxicon. 146: 120–123. doi:10.1016/j.toxicon.2018.02.050. PMID   29510162.
  7. ↑ Jefford CW, Bo Wang J (30 April 1993). "An enantiospecific synthesis of solenopsin A". Tetrahedron Letters. 34 (18): 2911–2914. doi:10.1016/S0040-4039(00)60479-3 . Retrieved 20 April 2021.
  8. ↑ Leclercq, S., Daloze, D., Braekman, J.-C. (1996). "A Synthesis of the Fire Ant Alkaloids, Solenopsins". Org. Prep. Proced. Int. 28 (5): 499. doi:10.1080/00304949609458571. Archived from the original on 2003-03-20.
  9. 1 2 Arbiser JL, Kau T, Konar M, Narra K, Ramchandran R, Summers SA, Vlahos CJ, Ye K, Perry BN, Matter W, Fischl A, Cook J, Silver PA, Bain J, Cohen P, Whitmire D, Furness S, Govindarajan B, Bowen JP (2007). "Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis". Blood. 109 (2): 560–5. doi:10.1182/blood-2006-06-029934. PMC   1785094 . PMID   16990598.
  10. ↑ Pianaro A, Fox EG, Bueno OC, Marsaioli AJ (May 2012). "Rapid configuration analysis of the solenopsins". Tetrahedron: Asymmetry. 23 (9): 635–642. doi:10.1016/j.tetasy.2012.05.005.
  11. ↑ Fox EG, Wu X, Wang L, Chen L, Lu Y, Xu Y (February 2019). "Queen venom isosolenopsin A delivers rapid incapacitation of fire ant competitors". Toxicon. 158: 77–83. doi:10.1016/j.toxicon.2018.11.428. PMID   30529381. S2CID   54481057.
  12. ↑ Yi GB, McClendon D, Desaiah D, Goddard J, Lister A, Moffitt J, Meer RK, deShazo R, Lee KS, Rockhold RW (2003). "Fire ant venom alkaloid, isosolenopsin A, a potent and selective inhibitor of neuronal nitric oxide synthase". Int J Toxicol. 22 (2): 81–6. doi:10.1080/10915810305090. PMID   12745988. S2CID   23324548.
  13. ↑ Park J, Kaufmann GF, Bowen JP, Arbiser JL, Janda KD (2008). "Solenopsin A, a Venom Alkaloid from the Fire Ant Solenopsis invicta,Inhibits Quorum-Sensing Signaling in Pseudomonas aeruginosa". The Journal of Infectious Diseases. 198 (8): 1198–201. doi: 10.1086/591916 . PMID   18713055.
  14. ↑ Machado Ed, Castilho LV, Domont GB, Nogueira FC, Freire DM, Sousa JS, Santos DG, Fox EG, Carvalho DB (July 2019). "Fire Ant Venom Alkaloids Inhibit Biofilm Formation". Toxins. 11 (7): 420. doi: 10.3390/toxins11070420 . PMC   6669452 . PMID   31323790.
  15. ↑ Silva RC, Fox EG, Gomes FM, Feijó DF, Ramos I, Koeller CM, Costa TF, Rodrigues NS, Lima AP, Atella GC, Miranda K (December 2020). "Venom alkaloids against Chagas disease parasite: search for effective therapies". Scientific Reports. 10 (1): 10642. Bibcode:2020NatSR..1010642S. doi: 10.1038/s41598-020-67324-8 . ISSN   2045-2322. PMC   7327076 . PMID   32606423.
  16. ↑ Karlsson I, Zhou X, Thomas R, Smith AT, Bonner MY, Bakshi P, Banga AK, Bowen JP, Qabaja G, Ford SL, Ballard MD, Petersen KS, Li X, Chen G, Ogretmen B, Zhang J, Watkins EB, Arnold RS, Arbiser J (2015). "Solenopsin A and analogs exhibit ceramide-like biological activity". Vascular Cell. 7 (5): 5. doi: 10.1186/s13221-015-0030-2 . PMC   4443652 . PMID   26015865.
  17. ↑ Arbiser JL, Nowak R, Michaels K, Skabytska Y, Biedermann T, Lewis MJ, Bonner MY, Rao S, Gilbert LC, Yusuf N, Karlsson I, Fritz Y, Ward NL (2017). "Evidence for biochemical barrier restoration: Topical solenopsin analogs improve inflammation and acanthosis in the KC-Tie2 mouse model of psoriasis". Scientific Reports. 7 (1): 11198. Bibcode:2017NatSR...711198A. doi:10.1038/s41598-017-10580-y. PMC   5593857 . PMID   28894119.

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