Chemistry:Gymnodimine

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Gymnodimines are marine cyclic imine phycotoxins that are found in mollusks.[1] They are highly potent neurotoxins that block nicotinic acetylcholine receptors, leading to disruption of neuromuscular signal transmission.[2] They are structurally related to other cyclic imine toxins, like pinnatoxins and spirolides, and characterized by a macrocyclic structure containing a spirolinked imine group.[3]

It was first discovered and isolated in 1994 from contaminated oysters in New Zealand during an algal bloom event. The compound was identified after an unexplained shellfish toxicity had occurred in the region. Gymnodimine structure was unique among other marine toxins featuring a cyclic imine moiety.[1]

Initially identified as Gymnodinium cf. Mikimotoi, as it was thought to be associated with a different dinoflagellate.[1] However, later studies confirmed that the toxins are produced by microalga planktonic dinoflagellates Karenia selliformis and Alexandrium ostenfeldii.[4] Subsequently, gymnodimines were also detected in 2002 along the Tunisian coast, as well as in shellfish from Europe and North America.[1]

Several structural analogues of the family of Gymnodimine toxins have since been identified, including GYM-A, GYM-B, GYM-C and GYM-D. These analogues differ slightly in chemical structures, such as carbon chains but share their typical six-member cyclic imine ring that is central in determining their biological activity.[4]

Gymnodimines can accumulate in filter-feeding shellfish, which can then be transferred to humans by the consumption of contaminated seafood.[4]

Structure, reactivity and synthesis

Gymnodimines are part of the marine toxins that have spirocyclic imines and with an ether or polyether subunit.[5] It is a 6 membered spirocyclic imine and has lipophilic character. With the main interest of gymnodimines being the spirocyclic imine ring as its plays a role in the binding to nicotinic acetylcholine receptors.[6] Several structural analogues of the family of Gymnodimine toxins have since been identified, including GYM-A, GYM-B, GYM-C and GYM-D, all having slightly different side groups attached, with GYM-A being the most common variant and most researched one of the gymnodimines.[4] About the reactivity there is not a lot known, but it can be assumed that because of its accumulation in shellfish it would be mainly unreactive. Due to GYM-A being a marine toxin, the synthesis of GYM-A was mainly done by enhancing the growth and GYM-A production in dinoflagellate, Karenia selliformis.[7] Later, the retrosynthetic route of GYM-A was discovered and used as a synthesis pathway of GYM A for studying the mode of action of the marine toxin.[5]

Metabolism and biotransformation

Not a lot is known about the metabolism and biotransformation of GYM-A. GYM-A is accumulated in shellfish, indicating that GYM-A is not broken down rapidly in those organisms. However, a study in 2020 observed that there are two fatty acid metabolites of GYM-A in Mytilus galloprovincialis, which were exposed to Karenia selliformis.[8]

Molecular mechanism of action

The mechanism of GYM-A is related to its high affinity binding with nicotinic acetylcholine receptor (nAChR) subtypes in neuronal and neuromuscular synapses and is therefore a reversible high affinity inhibitor of this receptor.[2] The potency of inhibition by GYM-A is dependent on the subtype of the nAChR.[2] When GYM-A binds to the nAChRs the channel is blocked for activation by acetylcholine. As acetylcholine cannot bind to the receptor, the signal transduction from neuron to neuron junction or neuron to muscle cell junction will not take place. This is because there is no influx of ions, which normally happens when acetylcholine binds to the receptor.[2] A paper published in 2008 discovered that GYM-A targets and binds with high affinity muscle- and neuronal-type nAChRs and thereby making it clear that GYM-A’s mechanism is by inactivation of those receptors.[9] This similar as how other marine toxins of the group of cyclic imines act.[9]

Use and availability

Use

It has no approved medical or commercial use.[10] It is, however, used as a research tool in toxicology because of its high affinity and low specificity for nicotinic acetylcholine receptors.[4] Some studies indicate that gymnodimines could be used therapeutically to enhance anti-cancer effects of chemotherapeutic agents by sensitizing cells to apoptotic stimuli Neuro2a neuroblastoma cell line. Furthermore, it is suggested that gymnodimines could reduce beta-amyloid levels and tau phosphorylation contributing to neurodegenerative disease treatment.[10]

Availability

Gymnodimines naturally occur in marine environments during algal blooms. As it is isolated from dinoflagellates, shellfish and coastal waters during algal blooms and is reported in New Zealand, Tunisia, United States and Europe. For example, these toxins accumulate in the digestive gland of Tunisian clams, some amounts can also be found in the meat.[11] It is thought to remain in the ecosystems for a long period of time, as the toxins have shown a slow depuration rate in oysters.[4] As mentioned in the part about synthesis, it is also synthetically produced in laboratories.[11] No regulations have been established for gymnodimine toxins.[3]

Efficacy and side effects

Efficacy

Gymnodimines are highly potent neurotoxins that block nicotinic acetylcholine receptors.[2] Less toxic when introduced by force-feeding or when consumed with food. Gymnodimine B is 10-fold less toxic than Gymnodimine A to mice. GYM-A was shown to make neurons more sensitive to apoptosis by okadic acid. In addition to mice, it also demonstrated toxicity against freshwater fish Tanichthys albonubes (0.1 ppm at pH 8).[4]

LD50 mice: intraperitoneal administration 80-96 microg/kg.[3]

LD50 mice: subcutaneously 100 micrograms/kg.[4]

LD50 mice: oral administration 755 ug/kg.[12]

LD50 mice GYM-B: intraperitoneal 800 micrograms/kg.[4]

Side effects

Studies done on mice showed rapid onset toxicity, starting with hyperactivity. Then flattening and paralysis of the hind legs happens, and lastly respiratory problems occur with finally death after 3 minutes of injection.[2] So, the poisoning effects are: muscle paralysis, neuromuscular blockade, and respiratory distress.[2] Harmful effects in individuals consuming contaminated shellfish were absent.[12] No long-term exposure effects to subacute doses have been investigated in humans.[3]

References

  1. ↑ 1.0 1.1 1.2 1.3 Seki, Tetsuya; Satake, Masayuki; Mackenzie, Lincoln; Kaspar, Heinrich F.; Yasumoto, Takeshi (1995-09-25). "Gymnodimine, a new marine toxin of unprecedented structure isolated from New Zealand oysters and the dinoflagellate, Gymnodinium sp.". Tetrahedron Letters 36 (39): 7093–7096. doi:10.1016/0040-4039(95)01434-J. ISSN 0040-4039. https://dx.doi.org/10.1016/0040-4039%2895%2901434-J. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Kharrat, Riadh; Servent, Denis; Girard, Emmanuelle; Ouanounou, Gilles; Amar, Muriel; Marrouchi, Riadh; Benoit, Evelyne; Molgó, Jordi (21 October 2008). "The marine phycotoxin gymnodimine targets muscular and neuronal nicotinic acetylcholine receptor subtypes with high affinity" (in en). Journal of Neurochemistry 107 (4): 952–963. doi:10.1111/j.1471-4159.2008.05677.x. ISSN 0022-3042. PMID 18990115. https://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2008.05677.x. 
  3. ↑ 3.0 3.1 3.2 3.3 Harju, Kirsi; Koskela, Harri; Kremp, Anke; Suikkanen, Sanna; de la Iglesia, Pablo; Miles, Christopher O.; Krock, Bernd; Vanninen, Paula (2016-03-15). "Identification of gymnodimine D and presence of gymnodimine variants in the dinoflagellate Alexandrium ostenfeldii from the Baltic Sea". Toxicon 112: 68–76. doi:10.1016/j.toxicon.2016.01.064. ISSN 0041-0101. PMID 26829651. https://www.sciencedirect.com/science/article/pii/S0041010116300150. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Marrouchi, Riadh (2009). "Gymnodimines: a family of phycotoxins contaminating shellfish". https://www.researchgate.net/publication/263852371. 
  5. ↑ 5.0 5.1 Yang, Ju; Cohn, Stephen T.; Romo, Daniel (2000). "Studies toward (−)-Gymnodimine: Concise Routes to the Spirocyclic and Tetrahydrofuran Moieties". Organic Letters 2 (6): 763–766. doi:10.1021/ol005510c. PMID 10754678. https://doi.org/10.1021/ol005510c. Retrieved 2026-03-14. 
  6. ↑ Otero, Alberto; Chapela, María-José; Atanassova, Miroslava; Vieites, Juan M.; Cabado, Ana G. (2011). "Cyclic Imines: Chemistry and Mechanism of Action: A Review". Chemical Research in Toxicology 24 (11): 1817–1829. doi:10.1021/tx200182m. https://doi.org/10.1021/tx200182m. Retrieved 2026-03-14. 
  7. ↑ Mountfort, Douglas; Beuzenberg, Veronica; MacKenzie, Lincoln; Rhodes, Lesley (2006-12-01). "Enhancement of growth and gymnodimine production by the marine dinoflagellate, Karenia selliformis". Harmful Algae 5 (6): 658–664. doi:10.1016/j.hal.2006.02.001. ISSN 1568-9883. https://www.sciencedirect.com/science/article/pii/S1568988306000163. 
  8. ↑ Ji, Ying; Che, Yijia; Wright, Elliott J.; McCarron, Pearse; Hess, Philipp; Li, Aifeng (2020-02-01). "Fatty acid ester metabolites of gymnodimine in shellfish collected from China and in mussels (Mytilus galloprovincialis) exposed to Karenia selliformis". Harmful Algae 92. doi:10.1016/j.hal.2020.101774. ISSN 1568-9883. PMID 32113591. https://www.sciencedirect.com/science/article/pii/S1568988320300548. 
  9. ↑ 9.0 9.1 Molgó, Jordi; Benoit, Evelyne; Aráoz, Rómulo; Zakarian, Armen; Iorga, Bogdan I. (2015), "Spirolides and Cyclic Imines: Toxicological Profile" (in en), Marine and Freshwater Toxins (Springer, Dordrecht): pp. 1–19, doi:10.1007/978-94-007-6650-1_23-1, ISBN 978-94-007-6650-1, https://link.springer.com/rwe/10.1007/978-94-007-6650-1_23-1, retrieved 2026-03-14 
  10. ↑ 10.0 10.1 Assunção, Joana; Guedes, A.; Malcata, F. (2017-12-20). "Biotechnological and Pharmacological Applications of Biotoxins and Other Bioactive Molecules from Dinoflagellates" (in en). Marine Drugs 15 (12): 393. doi:10.3390/md15120393. ISSN 1660-3397. PMID 29261163. 
  11. ↑ 11.0 11.1 Kong, Ke; Moussa, Ziad; Lee, Changsuk; Romo, Daniel (2011). "Total Synthesis of the Spirocyclic Imine Marine Toxin (−)-Gymnodimine and an Unnatural C4-Epimer". Journal of the American Chemical Society 133 (49): 19844–19856. doi:10.1021/ja207385y. PMID 22023219. PMC 3256008. https://doi.org/10.1021/ja207385y. Retrieved 2026-03-14. 
  12. ↑ 12.0 12.1 PubChem. "Gymnodimine" (in en). https://pubchem.ncbi.nlm.nih.gov/compound/11649137. 



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