 | |
| Names | |
|---|---|
| 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 | |
| UNII | |
| |
| |
| 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 theirstandard 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 bykainic acid.[4] Acromelic acid A has the molecular formulaC13H14N2O7. 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 andneurotoxic properties.[6] Ingestion of the Clitocybe acromelalga, causesallodynia which can continue for over a month.[7] The systemic administration of acromelic acid A in rats results in selective loss ofinterneurons in the lowerspinal cord, without causing neuronal damage in thehippocampus and other regions.[8]
Acromelic acids represent a group of compounds found in various forms. Five distinct molecules have been identified, including twoisoforms designated acromelic acid A and B.[6] Acromelic acid C-E are recognized toxicanalogs.[9] Acromelic acid A, characterized by its pyrrolidine carboxylic acid (L-proline),tricarboxylic acid, andpyridone composition, resembles kainic acid in its chemical makeup.[6][10][11]
Acromelic acid A was the first to be isolated fromClitocybe 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 successiveprotection ofimino andcarboxyl groups of L-alpha-kainic acid, followed by a reduction andsilylation.[12] Subsequently, theoxidation of the methyl group viaepoxidation occurs. To form the pyridine nucleus,1,4-addition bythiophenol,Horner-Emmons reaction, and aPummerer 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 thedeprotection 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 thecondensation ofL-glutamic acid withpyridones.[14] This method, too, entails numerous steps leading to a yield of only 9%.[14] The construction of the pyridone ring is achieved from acatechol 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 from2,6-dichloropyridine, with thepyrrolidine ring constructed via Ni-catalyzed asymmetricconjugate addition, followed by intramolecularreductive amination.[13] This represents an advancement over previous synthesis methods, offering a higher yield and fewer steps.
Followingabsorption, acromelic acid A induces abnormal behavioral symptoms in rats,[8][15] and tactileallodynia in mice.[7] Administration of thistoxin causes selective degeneration specifically in lowerspinal interneurons.[8][15]
In the late 20th century, acromelic acid A was initially believed to act as aglutamate receptoragonist,[4][15] specifically targetingAMPA 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 withkainic acid, anotherglutamate 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 todepolarization of thepostsynaptic cell.[4][7] This depolarization subsequently activatesNMDA 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 intracellularenzymes.[7][8][15] Consequently, neuronal damage[8][15] and sustained neuronal excitability, particularly inspinal cordneurons, 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 thisneurotoxic compound.[4] Therefore, further investigation into themechanism of action of acromelic acid A is required to better understand the toxic effects.[7]
Research has revealed that thelethal dose (LD50) ranges between 5 and 5.5 mg/kg in rats, when acromelic acid A administeredintravenously.[16]
Multiple studies were performed in which rats were injected with acromelic acid A intravenously. Kwaket 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/mouseallodynia 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 ofClitocybe 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]
