Toxins are busting out all over

Go to the profile of Joshua Finkelstein
Mar 27, 2019
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When it comes to marine natural products, there’s certainly no shortage of chemically-interesting, highly toxic molecules: for example, there’s saxitoxin (“”http://www.bt.cdc.gov/agent/saxitoxin/casedef.asp">Exposure to saxitoxin might cause … muscle weakness, vertigo, and cranial nerve dysfunction. Respiratory failure and death might occur from paralysis.“) and brevetoxin (”Gastrointestinal symptoms include abdominal pain, vomiting, and diarrhea. Neurologic symptoms include paresthesias, reversal of hot and cold temperature sensation, vertigo, and ataxia. Inhalational exposure to brevetoxin results in cough, dyspnea, and bronchospasm.").

So ciguatoxin may seem quite mild by comparison: “”http://www.cdc.gov/ncidod/dbmd/diseaseinfo/marinetoxins_g.htm#whatsort">symptoms include nausea, vomiting, diarrhea, cramps, excessive sweating, headache, and muscle aches. The sensation of burning or “pins-and-needles,” weakness, itching, and dizziness can occur. Patients may experience reversal of temperature sensation in their mouth, … unusual taste sensations, nightmares, or hallucinations. Ciguatera poisoning is rarely fatal."

It can be extremely challenging to isolate these molecules (for example, only “”http://pubs.acs.org/cgi-bin/asap.cgi/jacsat/asap/html/ja063041p.html">0.35 mg of ciguatoxin [was] extracted from 4000 kg of moray eels") and many of these molecules (and other marine toxins) have complex molecular architectures that have fascinated synthetic chemists for years.

Although maitotoxin (one of the largest and most toxic marine natural products) has not been synthesised (yet), many other marine toxins have been made in the lab: the synthesis of (+)-saxitoxin was described earlier this year (Fleming & Du Bois), brevetoxin A and B were synthesized years ago (brevetoxin A; brevetoxin B), and earlier this month, the syntheses of the two most toxic ciguatoxins (ciguatoxin and 51-hydroxyCTX3C) were reported in JACS (Inoue et al.). One highlight of the ciguatoxin synthesis involved a radical cyclization reaction which stereospecifically formed a key seven-membered ring in the middle of the molecule (the ‘G’ ring)…

But have no fear, not every natural product made by a marine organism is ultra toxic: Fuwa et al. just reported the synthesis of the proposed structure of brevenal, a pentacyclic polyether natural product. For some reason, this molecule actually “”http://pubs.acs.org/cgi-bin/asap.cgi/jacsat/asap/html/ja062524q.html">displaces tritiated dihydrobrevetoxin-B … from voltage-sensitive sodium channels in a dose-dependent manner and acts as a natural brevetoxin antagonist in vivo."

After making the proposed structure, the authors noticed that “[u]nfortunately, 1H and 13C NMR data … were not identical to those reported for the natural sample … On the basis of these NMR variations, along with the proposed biosynthetic pathway for marine polycyclic ethers, we think that the correct structure of brevenal is most likely represented by the C26 epimer of the [molecule we synthesized].” But keep your eyes peeled for their next paper, as they say that “efforts toward structural determination and total synthesis of brevenal are underway and will be reported in due course.”

Joshua

Joshua Finkelstein (Associate Editor, Nature)


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