Thursday, March 1, 2012

This Just In - File Under "Huge Marine Polyethers"


K. brevisculata
Source: Te Ara - Encyclopedia of New Zealand
Maggy Wassilieff
There's a new red tide in town: Karenia brevisulcata, a dinoflagellate first discovered in New Zealand in 1998. This ocean denizen was pegged for a wave of fish kills and human illnesses, which cued curious natural products chemists to have a peek at their toxin profile. The scientists noted that several of the cell extracts had molecular masses well above 2000 - large polyether territory - and were lethal to lab mice.


Et voilà! Say hello to brevisulcenal-F, their first solved structure from the algal cells. This toxin, tipping the scales at 2076 amu (M + Na), sets a record in its own right: it has seventeen contiguous 6- and 7-membered rings, A-Q, the most yet identified in a single marine ladder toxin (I can almost hear Mori, Nicolaou, Hirama, and Crimmins sharpening their swords, ready for action!).
Brevisulcenal-F spectrum and structure overlay
Source: JACS and M. Satake, U. of Tokyo


But how big is big? This new natural product certainly contends, but still doesn't approach two of the 850-lb gorillas in the room: palytoxin (PTX) and maitotoxin (MTX). First synthesized from PTX-COOH by Kishi in 1994, palytoxin, a soft-coral isolate from Hawaii, weighs in at 2680 amu. Although not specifically a ladder polyether, it was for decades considered the largest known non-peptide natural product. But PTX pales still in comparison to the largest known non-peptide np, maitotoxin, which totals 3422 amu, with 32 total ether rings. Isolated from Tahitian fish in 1976, maitotoxin eluded full structural characterization until the mid-1990s.
I'm glad my NMRs don't look like maitotoxin.
Source: Murata, JACS 1994


Where are these huge marine toxins coming from, exactly? Nakanishi advanced a polyepoxide cascade theory as early as 1985, which suggested that long, polyunsaturated terpenes (olefin biopolymers) were being somehow oxidized by the microorganisms, then cyclized into long ether "ladders," like a falling stack of dominos. It took another 20 years for experimental confirmation, but new cascade research by Jamison and others has shown that this might indeed be the case. 

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