Jump to content

Acromelic acid A

From Wikipedia, the free encyclopedia
Acromelic acid A
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
  • InChI=1S/C13H14N2O7/c16-9(17)3-6-7(4-14-10(6)13(21)22)5-1-2-8(12(19)20)15-11(5)18/h1-2,6-7,10,14H,3-4H2,(H,15,18)(H,16,17)(H,19,20)(H,21,22)/t6-,7+,10-/m0/s1checkY
  • Key: CWXNEBSQRIECMV-PJKMHFRUSA-N
  • C1C(C(C(N1)C(=O)O)CC(=O)O)C2=CC=C(NC2=O)C(=O)O
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 andneurotoxicproperties.[6]Ingestion of the Clitocybe acromelalga, causesallodyniawhich can continue for over a month.[7]The systemic administration of acromelic acid A in rats results in selective loss ofinterneuronsin the lowerspinal cord,without causing neuronal damage in thehippocampusand other regions.[8]

Structure and isoforms[edit]

Acromelic acids represent a group of compounds found in various forms. Five distinct molecules have been identified, including twoisoformsdesignated 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,andpyridonecomposition, 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]

Synthesis[edit]

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 successiveprotectionofiminoandcarboxyl groupsof L-alpha-kainic acid, followed by a reduction andsilylation.[12]Subsequently, theoxidationof the methyl group viaepoxidationoccurs. To form the pyridine nucleus,1,4-additionbythiophenol,Horner-Emmons reaction,and aPummerer reactionare 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 thedeprotectionof 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 thecondensationofL-glutamic acidwithpyridones.[14]This method, too, entails numerous steps leading to a yield of only 9%.[14]The construction of the pyridone ring is achieved from acatecholthrough 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 thepyrrolidinering 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.

Mechanism of action[edit]

Followingabsorption,acromelic acid A induces abnormal behavioral symptoms in rats,[8][15]and tactileallodyniain mice.[7]Administration of thistoxincauses 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,anotherglutamatereceptor 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 todepolarizationof 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 thisneurotoxiccompound.[4]Therefore, further investigation into themechanism of actionof acromelic acid A is required to better understand the toxic effects.[7]

Toxicity[edit]

Research has revealed that thelethal dose(LD50) ranges between 5 and 5.5 mg/kg in rats, when acromelic acid A administeredintravenously.[16]

Effects on rats[edit]

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]

  • 30 minutes after injection: All rats began to bite and moved their tails like snails. Theirhindlimbsbecame gradually extended and their back slowly bent forwards, which led them to occasional falls. Further, rats suffered from attacks of intermittent hindlimb cramp, which becametonicover time.
  • 1 hour after injection: Rats were seized by toniccloning convulsions.The Rats which got the lethal dose died during these seizures. The surviving rats developed complete flaccid paraplegia which carried on for 2 hours.
  • Days after injection: Rats developedparaparesisof severe spasticity. They were able to move using their forelimbs.

Effects on mice[edit]

Intrathecaladministration of acromelic acid A provoked tactile allodynia in mice. At an extremely low dose of 1 fg/mouseallodyniawas 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]

Effects on humans[edit]

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]

References[edit]

  1. ^"Acromelic acid A".pubchem.National Center for Biotechnology Information.Retrieved4 March2024.
  2. ^ab"acromelic acid A".Chemspider.Royal society of chemistry.Retrieved4 March2024.
  3. ^"acromelic acid A".chemicalbook.Retrieved4 March2024.
  4. ^abcdefgFuruta, Kyoji; Wang, Guang Xing; Minami, Toshiaki; Nishizawa, Mikio; Ito, Seiji; Suzuki, Masaaki (2004-03-17)."A simple acromelic acid analog potentially useful for receptor photoaffinity labeling and biochemical studies".Tetrahedron Letters.45(20): 3933–3936.doi:10.1016/j.tetlet.2004.03.098.ISSN0040-4039.
  5. ^Shinozaki, H.; Ishida, M.; Gotoh, Y.; Kwak, S. (1990), Lubec, Gert; Rosenthal, Gerald A. (eds.),"Acromelic acid as a tool for the study of specific neurone damages",Amino Acids: Chemistry, Biology and Medicine,Dordrecht: Springer Netherlands, pp. 281–293,doi:10.1007/978-94-011-2262-7_32,ISBN978-94-011-2262-7,retrieved2024-03-04
  6. ^abcdefgYin, Xia; Yang, An-An; Gao, Jin-Ming (2019-05-08)."Mushroom Toxins: Chemistry and Toxicology".Journal of Agricultural and Food Chemistry.67(18): 5053–5071.doi:10.1021/acs.jafc.9b00414.ISSN1520-5118.PMID30986058.S2CID116862463.
  7. ^abcdefgOmoto, Haruka; Matsumura, Shinji; Kitano, Manabu; Miyazaki, Shinichiro; Minami, Toshiaki; Ito, Seiji (2015-08-05)."Comparison of mechanisms of allodynia induced by acromelic acid A between early and late phases".European Journal of Pharmacology.760:42–48.doi:10.1016/j.ejphar.2015.03.075.ISSN0014-2999.PMID25861935.
  8. ^abcdefghiTsuji, K.; Nakamura, Y.; Ogata, T.; Mitani, A.; Kataoka, K.; Shibata, T.; Ishida, M.; Shinozaki, H. (1995-09-01)."Neurotoxicity of acromelic acid in cultured neurons from rat spinal cord".Neuroscience.68(2): 585–591.doi:10.1016/0306-4522(95)00149-d.ISSN0306-4522.PMID7477968.S2CID45027663.
  9. ^Fushiya, Shinji; Sato, Seiichi; Kanazawa, Toshiyuki; Kusano, Genjiro; Nozoe, Shigeo (1990-01-01)."Acromelic acid C. A new toxic constituent of clitocybe acromelalga: An efficient isolation of acromelic acids".Tetrahedron Letters.31(27): 3901–3904.doi:10.1016/S0040-4039(00)97501-4.ISSN0040-4039.
  10. ^PubChem."Acromelic acid A".pubchem.ncbi.nlm.nih.gov.Retrieved2024-03-06.
  11. ^PubChem (2015-04-08)."Kainic acid".pubchem.ncbi.nlm.nih.gov.Retrieved2024-03-06.
  12. ^abcdKonno, Katsuhiro; Hashimoto, Kimiko; Ohfune, Yasufumi; Shirahama, Haruhisa; Matsumoto, Takeshi (1986-01-01)."Synthesis of acromelic acid A, a toxic principle of clitocybe acromelalga".Tetrahedron Letters.27(5): 607–610.doi:10.1016/S0040-4039(00)84053-8.ISSN0040-4039.
  13. ^abcOuchi, Hitoshi; Asahina, Aya; Asakawa, Tomohiro; Inai, Makoto; Hamashima, Yoshitaka; Kan, Toshiyuki (2014-04-04)."Practical Total Syntheses of Acromelic Acids A and B".Organic Letters.16(7): 1980–1983.doi:10.1021/ol500529w.ISSN1523-7060.PMID24660857.
  14. ^abcBaldwin, Jack E.; Fryer, Andrew M.; Pritchard, Gareth J.; Spyvee, Mark R.; Whitehead, Roger C.; Wood, Mark E. (1998-06-25)."A biomimetic approach to the pyridone rings of the acromelic acids: A concise synthesis of acromelic acid A and an approach to acromelic acid B".Tetrahedron.54(26): 7465–7484.doi:10.1016/S0040-4020(98)00377-9.ISSN0040-4020.
  15. ^abcdefghOgata, T.; Nakamura, Y.; Tsuji, K.; Shibata, T.; Kataoka, K.; Ishida, M.; Shinozaki, H. (1994-05-13)."A marked increase in intracellular Ca2+ concentration induced by acromelic acid in cultured rat spinal neurons".Neuropharmacology.33(9): 1079–1085.doi:10.1016/0028-3908(94)90146-5.ISSN0028-3908.PMID7838320.S2CID21165905.
  16. ^abKwak, S.; Aizawa, H.; Ishida, M.; Shinozaki, H. (1991)."Systemic administration of acromelic acid induces selective neuron damage in the rat spinal cord".Life Sciences.49(14): PL91–96.doi:10.1016/0024-3205(91)90307-w.ISSN0024-3205.PMID1890926.
  17. ^abMinami, Toshiaki; Matsumura, Shinji; Nishizawa, Mikio; Sasaguri, Yasuyuki; Hamanaka, Nobuyuki; Ito, Seiji (2004-05-24)."Acute and late effects on induction of allodynia by acromelic acid, a mushroom poison related structurally to kainic acid".British Journal of Pharmacology.142(4): 679–688.doi:10.1038/sj.bjp.0705834.ISSN0007-1188.PMC1575046.PMID15159282.
  18. ^abNakajima, N.; Ueda, M.; Higashi, N.; Katayama, Y. (2013-05-03)."Erythromelalgia associated with Clitocybe acromelalga intoxication".Clinical Toxicology.51(5): 451–454.doi:10.3109/15563650.2013.792933.ISSN1556-9519.PMID23641936.S2CID8004853.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Acromelic_acid_A&oldid=1217743655"