Names | |
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IUPAC name 5-[(3S,4S,5S)-5-Carboxy-4-(carboxymethyl)pyrrolidin-3-yl]-6-oxo-1H-pyridine-2-carboxylic acid | |
Identifiers | |
3D model (JSmol) | |
Abbreviations | ACRO A |
ChEBI | |
ChEMBL | |
ChemSpider | |
KEGG | |
PubChem CID | |
UNII | |
CompTox Dashboard (EPA) | |
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Properties | |
C13H14N2O7 | |
Molar mass | 310.26 g/mol [1] |
Density | 1.6±0.1 g/cm3 (predicted) [2] |
Boiling point | 740.5±60.0 °C at 760 mmHg (predicted) [2] |
Acidity (pKa) | 1.93±0.60 (predicted) [3] |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
Acromelic acid A (ACRO A) is a toxic compound that is part of a group known as kainoids, characterized by a structure bearing a pyrrolidine dicarboxylic acid, represented by kainic acid. [4] Acromelic acid A has the molecular formula C13H14N2O7. It has been isolated from a Japanese poisonous mushroom, Clitocybe acromelalga . [5] Acromelic acid is responsible for the poisonous aspects of the mushroom because of its potent neuroexcitatory and neurotoxic properties. [6] Ingestion of the Clitocybe acromelalga, causes allodynia which can continue for over a month. [7] The systemic administration of acromelic acid A in rats results in selective loss of interneurons in the lower spinal cord, without causing neuronal damage in the hippocampus and other regions. [8]
Acromelic acids represent a group of compounds found in various forms. Five distinct molecules have been identified, including two isoforms designated acromelic acid A and B. [6] Acromelic acid C-E are recognized toxic analogs. [9] Acromelic acid A, characterized by its pyrrolidine carboxylic acid (L-proline), tricarboxylic acid, and pyridone composition, resembles kainic acid in its chemical makeup. [6] [10] [11]
Acromelic acid A was the first to be isolated from Clitocybe acromelalga, leading to extensive investigation of this type. [6] Comparative studies reveal acromelic acid B, an isoform of A, to exhibit reduced allodynia effects in mice models. [6] Conversely, limited information exists regarding ACROs C, D, and E, though their analogous structure suggests similar functionalities to varying extents. Further research into these compounds is needed, but not without challenges; the synthesis of acromelic acid A presents difficulties for large-scale production required for comprehensive biological studies. [6]
Acromelic acid A can be produced through the synthesis of L-alpha-kainic acid. [12] However, this process involves multiple complicated steps. One way to do this, as outlined by Katsuhiro Konno et al. (1986), initiates with the successive protection of imino and carboxyl groups of L-alpha-kainic acid, followed by a reduction and silylation. [12] Subsequently, the oxidation of the methyl group via epoxidation occurs. To form the pyridine nucleus, 1,4-addition by thiophenol, Horner-Emmons reaction, and a Pummerer reaction are necessary. Following several rearrangements, an unstable compound is obtained, which promptly cyclizes. Treatment with various compounds transforms this compound into a pyridone carboxylic acid derivative. The final steps involve the deprotection of various groups, resulting in the production of acromelic acid A. [12] The yield of this elaborated synthesis is notably low, as expected due to the numerous synthetic steps, which in turn also hinders large-scale biological studies on acromelic acid A. [6] [12] [13]
Alternatively, another synthesis route involves the condensation of L-glutamic acid with pyridones. [14] This method, too, entails numerous steps leading to a yield of only 9%. [14] The construction of the pyridone ring is achieved from a catechol through an oxidative cleavage recyclization strategy, akin to the previously described method. Researchers attempted a similar approach to synthesize acromelic acid B, which proved challenging but feasible. [14]
In a more recent development, a 13-step synthesis with a yield of 36% has been described. [13] Acromelic acids A and B were synthesized from 2,6-dichloropyridine, with the pyrrolidine ring constructed via Ni-catalyzed asymmetric conjugate addition, followed by intramolecular reductive amination. [13] This represents an advancement over previous synthesis methods, offering a higher yield and fewer steps.
Following absorption, acromelic acid A induces abnormal behavioral symptoms in rats, [8] [15] and tactile allodynia in mice. [7] Administration of this toxin causes selective degeneration specifically in lower spinal interneurons. [8] [15]
In the late 20th century, acromelic acid A was initially believed to act as a glutamate receptor agonist, [4] [15] specifically targeting AMPA receptors. [8] [15] This would explain the observed increase in intracellular Ca2+ concentration after administration. [15] However, over the years, a new type of non-NMDA receptor was thought to be the target of acromelic acid A, as the observed effects couldn't completely be explained by AMPA binding. [4] [8] This idea was established through comparative studies with kainic acid, another glutamate receptor agonist. This revealed remarkable differences in behavioral and pathological effects. [4] [8] [15]
Therefore, the proposed mechanism suggests binding of acromelic acid A to a (yet unidentified) non-NMDA receptor. [4] [8] Binding to the target receptor leads to depolarization of the postsynaptic cell. [4] [7] This depolarization subsequently activates NMDA receptors, which in turn become permeable for Ca2+. [7] The increase in intracellular Ca2+ concentration triggers a cascade of downstream signaling events, including activation of various intracellular enzymes. [7] [8] [15] Consequently, neuronal damage [8] [15] and sustained neuronal excitability, particularly in spinal cord neurons, occur [7]
Although researchers know the resulting pathological symptoms and some molecular conditions after administration of acromelic acid A, they have still not been able to unravel the exact mechanism of action of this neurotoxic compound. [4] Therefore, further investigation into the mechanism of action of acromelic acid A is required to better understand the toxic effects. [7]
Research has revealed that the lethal dose (LD50) ranges between 5 and 5.5 mg/kg in rats, when acromelic acid A administered intravenously. [16]
Multiple studies were performed in which rats were injected with acromelic acid A intravenously. Kwak et al. (1991) conducted experiments involving the injection of both 2 mg/kg and the lethal dose (5 mg/kg) of acromelic acid A in rats. The results demonstrated a series of behavioral changes. [16]
Intrathecal administration of acromelic acid A provoked tactile allodynia in mice. At an extremely low dose of 1 fg/mouse allodynia was already provoked and persisted over a month. Furthermore, at a higher dose of 500 ng/kg, injection of acromelic acid A induced strong spontaneous agitation, scratching, jumping and tonic convulsion and caused death within 15 min. [17]
The effects of acromelic acid A on humans have not been studied yet. However, after accidental ingestion of Clitocybe acromelalga, violent pain and marked reddish edema in hands and feet were observed after several days and continued for a month. [17] [18] However, there is no direct evidence these symptoms were caused by acromelic acid A. Findings from experiments in rats and mice suggest a potential association between acromelic acid A and the observed symptoms. [18]
Muscarine, L-(+)-muscarine, or muscarin is a natural product found in certain mushrooms, particularly in Inocybe and Clitocybe species, such as the deadly C. dealbata. Mushrooms in the genera Entoloma and Mycena have also been found to contain levels of muscarine which can be dangerous if ingested. Muscarine has been found in harmless trace amounts in Boletus, Hygrocybe, Lactarius and Russula. Trace concentrations of muscarine are also found in Amanita muscaria, though the pharmacologically more relevant compound from this mushroom is the Z-drug-like alkaloid muscimol. A. muscaria fruitbodies contain a variable dose of muscarine, usually around 0.0003% fresh weight. This is very low and toxicity symptoms occur very rarely. Inocybe and Clitocybe contain muscarine concentrations up to 1.6%.
N-methyl-D-aspartic acid or N-methyl-D-aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike glutamate, NMDA only binds to and regulates the NMDA receptor and has no effect on other glutamate receptors. NMDA receptors are particularly important when they become overactive during, for example, withdrawal from alcohol as this causes symptoms such as agitation and, sometimes, epileptiform seizures.
Muscimol is one of the principal psychoactive constituents of Amanita muscaria and related species of mushroom. Muscimol is a potent and selective orthosteric agonist for the GABAA receptor and displays sedative-hypnotic, depressant and hallucinogenic psychoactivity. This colorless or white solid is classified as an isoxazole.
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.
The Pauson–Khand (PK) reaction is a chemical reaction, described as a [2+2+1] cycloaddition. In it, an alkyne, an alkene and carbon monoxide combine into a α,β-cyclopentenone in the presence of a metal-carbonyl catalyst.
Kainic acid, or kainate, is an acid that naturally occurs in some seaweed. Kainic acid is a potent neuroexcitatory amino acid agonist that acts by activating receptors for glutamate, the principal excitatory neurotransmitter in the central nervous system. Glutamate is produced by the cell's metabolic processes and there are four major classifications of glutamate receptors: NMDA receptors, AMPA receptors, kainate receptors, and the metabotropic glutamate receptors. Kainic acid is an agonist for kainate receptors, a type of ionotropic glutamate receptor. Kainate receptors likely control a sodium channel that produces excitatory postsynaptic potentials (EPSPs) when glutamate binds.
Orellanine or orellanin is a mycotoxin found in a group of mushrooms known as the Orellani of the family Cortinariaceae. Structurally, it is a bipyridine N-oxide compound somewhat related to the herbicide diquat.
Allodynia is a condition in which pain is caused by a stimulus that does not normally elicit pain. For example, bad sunburn can cause temporary allodynia, and touching sunburned skin, or running cold or warm water over it, can be very painful. It is different from hyperalgesia, an exaggerated response from a normally painful stimulus. The term comes from Ancient Greek άλλος (állos) 'other', and οδύνη (odúnē) 'pain'.
Di-tert-butyl dicarbonate is a reagent widely used in organic synthesis. Since this compound can be regarded formally as the acid anhydride derived from a tert-butoxycarbonyl (Boc) group, it is commonly referred to as Boc anhydride. This pyrocarbonate reacts with amines to give N-tert-butoxycarbonyl or so-called Boc derivatives. These carbamate derivatives do not behave as amines, which allows certain subsequent transformations to occur that would be incompatible with the amine functional group. The Boc group can later be removed from the amine using moderately strong acids. Thus, Boc serves as a protective group, for instance in solid phase peptide synthesis. Boc-protected amines are unreactive to most bases and nucleophiles, allowing for the use of the fluorenylmethyloxycarbonyl group (Fmoc) as an orthogonal protecting group.
Quisqualic acid is an agonist of the AMPA, kainate, and group I metabotropic glutamate receptors. It is one of the most potent AMPA receptor agonists known. It causes excitotoxicity and is used in neuroscience to selectively destroy neurons in the brain or spinal cord. Quisqualic acid occurs naturally in the seeds of Quisqualis species.
Seletracetam is a pyrrolidone-derived drug of the racetam family that is structurally related to levetiracetam. It was under development by UCB Pharmaceuticals as a more potent and effective anticonvulsant drug to replace levetiracetam but its development has been halted.
Apamin is an 18 amino acid globular peptide neurotoxin found in apitoxin (bee venom). Dry bee venom consists of 2–3% of apamin. Apamin selectively blocks SK channels, a type of Ca2+-activated K+ channel expressed in the central nervous system. Toxicity is caused by only a few amino acids, in particular cysteine1, lysine4, arginine13, arginine14 and histidine18. These amino acids are involved in the binding of apamin to the Ca2+-activated K+ channel. Due to its specificity for SK channels, apamin is used as a drug in biomedical research to study the electrical properties of SK channels and their role in the afterhyperpolarizations occurring immediately following an action potential.
The Fukuyama coupling is a coupling reaction taking place between a thioester and an organozinc halide in the presence of a palladium catalyst. The reaction product is a ketone. This reaction was discovered by Tohru Fukuyama et al. in 1998.
The Achmatowicz reaction, also known as the Achmatowicz rearrangement, is an organic synthesis in which a furan is converted to a dihydropyran. In the original publication by the Polish Chemist Osman Achmatowicz Jr. in 1971 furfuryl alcohol is reacted with bromine in methanol to 2,5-dimethoxy-2,5-dihydrofuran which rearranges to the dihydropyran with dilute sulfuric acid. Additional reaction steps, alcohol protection with methyl orthoformate and boron trifluoride) and then ketone reduction with sodium borohydride produce an intermediate from which many monosaccharides can be synthesised.
A convulsant is a drug which induces convulsions and/or epileptic seizures, the opposite of an anticonvulsant. These drugs generally act as stimulants at low doses, but are not used for this purpose due to the risk of convulsions and consequent excitotoxicity. Most convulsants are antagonists at either the GABAA or glycine receptors, or ionotropic glutamate receptor agonists. Many other drugs may cause convulsions as a side effect at high doses but only drugs whose primary action is to cause convulsions are known as convulsants. Nerve agents such as sarin, which were developed as chemical weapons, produce convulsions as a major part of their toxidrome, but also produce a number of other effects in the body and are usually classified separately. Dieldrin which was developed as an insecticide blocks chloride influx into the neurons causing hyperexcitability of the CNS and convulsions. The Irwin observation test and other studies that record clinical signs are used to test the potential for a drug to induce convulsions. Camphor, and other terpenes given to children with colds can act as convulsants in children who have had febrile seizures.
Tutin is a poisonous plant derivative found in New Zealand tutu plants. It acts as a potent antagonist of the glycine receptor, and has powerful convulsant effects. It is used in scientific research into the glycine receptor. It is sometimes associated with outbreaks of toxic honey poisoning when bees feed on honeydew exudate from the sap-sucking passion vine hopper insect, when the vine hoppers have been feeding on the sap of tutu bushes. Toxic honey is a rare event and is more likely to occur when comb honey is eaten directly from a hive that has been harvesting honeydew from passionvine hoppers feeding on tutu plants.
The rostral ventromedial medulla (RVM), or ventromedial nucleus of the spinal cord, is a group of neurons located close to the midline on the floor of the medulla oblongata. The rostral ventromedial medulla sends descending inhibitory and excitatory fibers to the dorsal horn spinal cord neurons. There are 3 categories of neurons in the RVM: on-cells, off-cells, and neutral cells. They are characterized by their response to nociceptive input. Off-cells show a transitory decrease in firing rate right before a nociceptive reflex, and are theorized to be inhibitory. Activation of off-cells, either by morphine or by any other means, results in antinociception. On-cells show a burst of activity immediately preceding nociceptive input, and are theorized to be contributing to the excitatory drive. Neutral cells show no response to nociceptive input.
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.
Willardiine (correctly spelled with two successive i's) or (S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione is a chemical compound that occurs naturally in the seeds of Mariosousa willardiana and Acacia sensu lato. The seedlings of these plants contain enzymes capable of complex chemical substitutions that result in the formation of free amino acids (See:#Synthesis). Willardiine is frequently studied for its function in higher level plants. Additionally, many derivates of willardiine are researched for their potential in pharmaceutical development. Willardiine was first discovered in 1959 by R. Gmelin, when he isolated several free, non-protein amino acids from Acacia willardiana (another name for Mariosousa willardiana) when he was studying how these families of plants synthesize uracilyalanines. A related compound, Isowillardiine, was concurrently isolated by a different group, and it was discovered that the two compounds had different structural and functional properties. Subsequent research on willardiine has focused on the functional significance of different substitutions at the nitrogen group and the development of analogs of willardiine with different pharmacokinetic properties. In general, Willardiine is the one of the first compounds studied in which slight changes to molecular structure result in compounds with significantly different pharmacokinetic properties.
Hafnium(IV) triflate or hafnium trifluoromethansulfonate is a salt with the formula Hf(OSO2CF3)4, also written as Hf(OTf)4. Hafnium triflate is used as an impure mixture as a catalyst. Hafnium (IV) has an ionic radius of intermediate range (Al < Ti < Hf < Zr < Sc < Ln) and has an oxophilic hard character typical of group IV metals. This solid is a stronger Lewis acid than its typical precursor hafnium tetrachloride, HfCl4, because of the strong electron-withdrawing nature of the four triflate groups, which makes it a great Lewis acid and has many uses including as a great catalyst at low Lewis acid loadings for electrophilic aromatic substitution and nucleophilic substitution reactions.