Gelsemine (C20H22N2O2) is an indole alkaloid isolated from flowering plants of the genus Gelsemium, a plant native to the subtropical and tropical Americas, and southeast Asia, and is a highly toxic compound that acts as a paralytic, exposure to which can result in death. It has generally potent activity as an agonist of the mammalian glycine receptor, the activation of which leads to an inhibitory postsynaptic potential in neurons following chloride ion influx, and systemically, to muscle relaxation of varying intensity and deleterious effect. Despite its danger and toxicity, recent pharmacological research has suggested that the biological activities of this compound may offer opportunities for developing treatments related to xenobiotic or diet-induced oxidative stress, and of anxiety and other conditions, with ongoing research including attempts to identify safer derivatives and analogs to make use of gelsemine's beneficial effects.Lin, Lin; Zheng, Jing; Zhu, Weiping; Jia, Ning (2015-03). "Nephroprotective Effect of Gelsemine Against Cisplatin-Induced Toxicity is Mediated Via Attenuation of Oxidative Stress". Cell Biochemistry and Biophysics. 71 (2): 535–541. doi:10.1007/s12013-014-0231-y. ISSN 1085-9195.Liu, Ming; Huang, Hui-Hui; Yang, Jian; Su, Yan-Ping; Lin, Hong-Wei; Lin, Li-Qing; Liao, Wei-Jian; Yu, Chang-Xi (2013-02). "The active alkaloids of Gelsemium elegans Benth. are potent anxiolytics". Psychopharmacology. 225 (4): 839–851. doi:10.1007/s00213-012-2867-x. ISSN 0033-3158
Natural sources
Gelsemine is found in, and can be isolated from, the subtropical to tropical flowering plant genus Gelsemium, family Gelsemiaceae, which as of 2014 included five species, where G. sempervirens Ait., the type species, is prevalent in the Americas and G. elegans Benth. in China and East Asia. The species in the Americas, G. sempervirens, has a number of common names that include yellow or Carolina jasmine (or jessamine), gelsemium, evening trumpetflower, and woodbine. The plant genus is native to the subtropical and tropical Americas, e.g., in Mexico, Honduras, Guatemala, and Belize, as well as to China and southeast Asia. The species is prized for its "heavily fragrant yellow flowers," and has been cultivated since mid-seventeenth century (in Europe). It is found in southeastern and south-central states of the U.S., and as a garden plant in warmer areas where it can be trained to grow over arbors or to cover walls (see image).
All plant parts of the herbage and exudates of this genus, including its sap and nectar, appear to contain gelsemine and related compounds, as well as a wide variety of further alkaloids and other natural products. The plant's herbage, in particular, is known to contain several toxic alkaloids, and is generally known to be poisonous to livestock and humans.
Chemistry
Gelsemine was isolated from G. sempervirens Ait., in 1870. Note, the use of Chen et al. is, in part, for the thorough manner in which it reviews the earlier literature on synthetic efforts toward, and total syntheses of the gelsemine target. Its chemical formula was determined to be C20H22N2O2, thus with a molecular weight of 322.44 g/mol. Its structure was finally determined, by X-ray crystallographic analysis and by nuclear magnetic resonance (NMR) spectroscopy, in 1959 by Conroy and Chakrabarti.
It is a monoterpenoid type of indole alkaloid, and a close relative of the natural product gelseminine, which is also present from the same natural sources. The gelsemine class of alkaloids are some of a wide variety of the alkaloid and other natural products that have been isolated from this genus of plants.
Gelsemine's biosynthesis, as of 1998, is thought to proceed from 3α(S)-strictosidine (isovincoside), the common precursor for essentially all monoterpenoid indole alkaloids—itself deriving directly from mevalonic acid-derived secologanin and tryptamine. From strictosidine, the biosynthesis proceeds through five intermediates—including koumicine (akkuammidine), koumidine, vobasindiol, anhydrovobasindiol, and gelsenidine (humantienine-type). The related alkaloids koumine and gelsemicine also derive from this pathway (koumine from anhydrovobasindiol via oxidation and rearrangement, and gelsemicine from gelsemine itself, via aromatic oxidation and O-methylation).
For the chemical synthesis (natural product synthesis, studies and total synthesis), see the separate section below.
Summary of biological activities Full sections in following are devoted to specific activities of gelsemine. Noted are the facts that it is a highly toxic compound, where exposure can result in paralysis and death. It is reported to be a glycine receptor agonist with significantly higher binding affinity for some of these receptors than its native agonist, glycine. In addition, it has been shown to have effects on pathways/systems in model animals (rat, rabbit), related to xenobiotic- or diet-induced oxidative stress, and in the treatment of anxiety and other conditions.
History Gelsimium extracts, and so gelsemine, indirectly, have been the subject of serious scientific study for over a hundred years. On the medical side, gelsemium tinctures were used in the treatment of neuralgia by physicians in England, in the late 19th century; Arthur Conan Doyle, the noted author who first trained as a physician, after observing the success of such treatments, ingested increasing doses of a tincture daily, to "ascertain how far one might go in taking the drug, and what the primary symptoms of an overdose might be," submitting his first career publication on this in the British Medical Journal.[primary source][primary source] On the chemistry side, the December 1910 meeting of the Division of Pharmaceutical Chemistry, of the American Chemical Society, reports among the papers read, the "Assay of Gelsemium" by L.E. Sayre.[primary source][primary source]
Mechanisms of action Gelsemine is an agonist for the glycine receptor (GlyR) with a much greater affinity for studied examples of this receptor than glycine.Zhang, Jing-Yang; Gong, Nian; Huang, Jin-Lu; Guo, Ling-Chen; Wang, Yong-Xiang (2013-11). "Gelsemine, a principal alkaloid fromGelsemium sempervirensAit., exhibits potent and specific antinociception in chronic pain by acting at spinal α3 glycine receptors". PAIN. 154 (11): 2452. doi:10.1016/j.pain.2013.07.027. ISSN 0304-3959. These receptors are ligand-gated ion channels which affect a variety of physiological processes. When glycine receptors are activated by agonist binding to at least two of the five agonist binding sites, chloride ions enter the neuron. This causes an inhibitory postsynaptic potential, which, systemically, leads to muscle relaxation.Lynch, Joseph W. (2004-10). "Molecular Structure and Function of the Glycine Receptor Chloride Channel". Physiological Reviews. 84 (4): 1051–1095. doi:10.1152/physrev.00042.2003. ISSN 0031-9333.
Toxicity and toxicology In mice, it has been shown to have an LD50 of 56 mg/kg (intraperitoneal), and a lowest lethal dose (LDLo) of 0.1-0.12 mg/kg (intravenous). In rabbits, the LDLo was 0.05-0.06 mg/kg (intravenous). In frogs, the LDLo was 20–30 mg/kg (subcutaneous). In dogs, the LDLo was 0.5-1.0 mg/kg (intravenous).
The sap of the plant may cause skin irritation in sensitive individuals, and there are reports that inhalation from the flowers alone may, in some cases, lead to human poisoning (see below, where insect death at such flowers is likewise reported).
The plant's herbage is known to contain several toxic alkaloids, and while there is report of its feeding to pigs, it is generally considered to be an abortifacient and lethal poison when livestock or other animals feed on its leaves. It has been reportedly used as a fish poison as well, e.g., on the island of Borneo.
Human poisonings are known, including pediatric and adult cases, and in the case of adults, both accidental and intentional poisonings. At lower doses in humans, the inhibitory postsynaptic potential induced by gelsemine action at the glycine receptor can result in nausea, diarrhea and muscle spasms caused by loss of involuntary muscle control; at higher doses, vision impairment or blindness, paralysis, and death can occur. Children, mistaking the flower of G. sempervirens for honeysuckle, have been poisoned by sucking the nectar from the flower; its ingestion has been associated with honey bee (but not bumble bee) fatalities as well (e.g., in the southeast U.S.).In the case of Bombus impatiens (bumblebees), feeding on gelsemine may reduce the load of the parasite Crithidia bombi, which, in improving bee health, increases foraging efficiency, a possible case of selective advantage of a pollinator self-medicating through collection of an otherwise generally toxic secondary metabolite. See [primary source] It has been reportedly used, via ingestion or smoking, as a poison in cases of suicide, in China, Vietnam, and Borneo.
Treatment Gelsemine is a highly toxic and therefore possibly fatal substance for which there is no antidote, but the symptoms can be managed in low dose intoxications. In the case of an oral exposure a gastric lavage is performed, which must be done within approximately one hour of ingestion. Activated charcoal is then administered to bind the free toxin in the gastrointestinal tract to prevent absorption. Benzodiazepine or phenobarbital is also generally administered to help control seizing, and atropine can be used to treat bradycardia. Electrolyte and nutrient levels are monitored and controlled.
In the case of a skin exposure, the area is washed with soap and water for 15 minutes to avoid skin damage.
While there is no current treatment to reverse the effects of gelsemine poisoning, preliminary research done in rats has suggested that strychnine has potential therapeutic applications due to its antagonistic effects at the glycine receptor, resulting in a counteraction of some downstream effects such as the increase in allopregnanolone production associated with gelsemine poisoning.Meyer L; Boujedaini N; Patte-Mensah C; Mensah-Nyagan AG. (2013). "Pharmacological Effect of Gelsemine on Anxiety-Like Behavior in Rat". Behav Brain Res. 253 (September 15): 90–94. doi:10.1016/j.bbr.2013.07.010. PMID 23850351. S2CID 5290737Venard, C.; Boujedaini, N.; Belon, P.; Mensah-Nyagan, A. G.; Patte-Mensah, C. (2008-04-22). "Regulation of neurosteroid allopregnanolone biosynthesis in the rat spinal cord by glycine and the alkaloidal analogs strychnine and gelsemine". Neuroscience. 153 (1): 154–161. doi:10.1016/j.neuroscience.2008.02.009. ISSN 0306-4522.
Chemical synthesis The chemical synthesis of gelsemine has been an active target of interest since the early 1990s, given its place among the alkaloids, and its complex structure (seven contiguous stereocenters and six rings). Although the full mechanism of its biosynthesis is still being investigated, many research groups have successfully synthesized it using chemical means.Chen, Gu-Zhou; Hong, Ran (2022-10-19). "A bioinspired cyclization toward koumine and gelsemine". Cell Reports Physical Science. 3 (10): 101097. doi:10.1016/j.xcrp.2022.101097. ISSN 2666-3864.Yang, Liyan; Wang, Zhonglei. "Advances in the Total Synthesis of Gelsemine". Current Organic Chemistry. 26 (4): 356–368. doi:10.2174/1385272826666220210124835. The first racemic total synthesis of gelsemine was in 1994, by W.N. Speckamp's group, with a remarkable first yield of 0.83% (given the subsequent range, prior to 2014, of 0.02-1.2%).[primary source]Vijn, Robert J.; Hiemstra, Henk; Kok, Joost J.; Knotter, Martin; Speckamp, W.Nico (1987-01). "Synthetic studies towards gelsemine, I The importance of the antiperiplanar effect in the highly regioselective reduction of non-symmetrical cis-hexahydrophthalimides". Tetrahedron. 43 (21): 5019–5030. doi:10.1016/S0040-4020(01)87680-8.