Death-cap mushroom toxin synthesized
Death-cap mushroom toxin synthesized
Route devised for α-amanitin, one of the deadliest known toxins
by Celia Henry Arnaud
March 30, 2018
| APPEARED IN
VOLUME 96, ISSUE 14
α-Amanitin, a bicyclic octapeptide
produced by the death-cap mushroom, is one of the deadliest known
peptide toxins. Researchers are exploring antibody-drug conjugates of it
as possible anticancer agents.
“α-Amanitin has been the subject of thousands of published studies due to its exceptional toxicity,” says Steven L. Castle
of Brigham Young University, who synthesizes bioactive peptides but
wasn’t involved with the work. “The generation of analogs or
antibody-drug conjugates has been greatly hampered by the absence of a
practical synthetic route.”
David M. Perrin and coworkers at the University of British Columbia have devised a synthesis of α-amanitin to fill that void (J. Am. Chem. Soc. 2018, DOI: 10.1021/jacs.7b12698). Before achieving success, they needed to overcome three challenges.
First, they needed to make a delicate 6-hydroxy-tryptathionine
cross-link that could easily form an unwanted oxindole. They achieved
the desired transformation by installing a boronate ester on tryptophan
until after performing a fluorocyclization reaction.
The second challenge was devising an enantioselective synthesis of the toxin’s (2S,3R,4R)-4,5-dihydroxyisoleucine group, which they surmounted using a Strecker amino acid reaction.
The final requirement was forming a sulfoxide with the correct
stereochemistry, which they achieved with a bulky oxidant and judicious
solvent selection. Although researchers already knew that the sulfoxide
isn’t important for the toxin’s activity, Perrin’s team found that it
protects the hydroxyindole from oxidation in air.
“All the pieces fall together, and then it sort of looks obvious,”
Perrin says of the overall synthesis. “But it’s like everything else: It
only looks obvious after you’ve solved the puzzle.”
Now that Perrin and coworkers have a synthetic route for making
α-amanitin, they plan to use it to make antibody-drug conjugates and to
study the chemical biology of the toxin.
The solutions to the synthetic challenges “are both creative and
practical,” Castle says. “I look forward to seeing the results of future
studies enabled by their work.”
Chemical & Engineering News
ISSN 0009-2347
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