The discovery by MIT Associate Professor Timothy Jamison and graduate
student Ivan Vilotijevic not only could shed light on how algae known
as dinoflagellates generate red tides, but could also help speed up
efforts to develop cystic fibrosis drugs from a compound closely
related to the toxin. Red tides, also known as algal blooms, strike
unpredictably and poison shellfish, making them dangerous for humans
to eat. It is unknown what causes dinoflagellates to produce the red
tide toxins, but it may be a defense mechanism, possibly provoked by
changes in the tides, temperature shifts or other environmental
stresses.
One of the primary toxic components of red tide is brevetoxin, a large
and complex molecule that is very difficult to synthesize.
Twenty-two years ago, chemist Koji Nakanishi of Columbia University
proposed a cascade, or series of chemical steps, that dinoflagellates
could use to produce brevetoxin and other red tide toxins. However,
chemists have been unable to demonstrate such a cascade in the
laboratory, and many came to believe that the "Nakanishi Hypothesis"
would never be proven.
"A lot of people thought that this type of cascade may be impossible,"
said Jamison. "Because Nakanishi's hypothesis accounts for so much of
the complexity in these toxins, it makes a lot of sense, but there
hasn't really been any evidence for it since it was first proposed."
Jamison and Vilotijevic's work offers the first evidence that
Nakanishi's hypothesis is feasible. Their work could also help
accelerate drug discovery efforts. Brevenal, another dinoflagellate
product related to the red tide toxins, has shown potential as a
powerful treatment for cystic fibrosis (CF). It can also protect
against the effects of the toxins.
"Now that we can make these complex molecules quickly, we can
hopefully facilitate the search for even better protective agents and
even more effective CF therapies," said Jamison.
Until now, synthesizing just a few milligrams of red tide toxin or
related compounds, using a non-cascade method, required dozens of
person-years of effort.
The new synthesis depends on two critical factors-giving the reaction
a jump start and conducting the reaction in water.
Many red tide toxins possess a long chain of six-membered rings.
However, the starting materials for the cascades, epoxy alcohols, tend
to form five-membered rings. To overcome that, the researchers
attached a "template" six-membered ring to one end of the epoxy
alcohol. That simple step effectively launches the cascade of
reactions that leads to the toxin chain, known as a ladder polyether.
"The trick is to give it a little push in the right direction and get
it running smoothly," said Jamison.
The researchers speculate that in dinoflagellates, the initial jump
start is provided by an enzyme instead of a template.
Conducting the reaction in water is also key to a successful
synthesis. Water is normally considered a poor solvent for organic
reactions, so most laboratory reactions are performed in organic
solvents. However, when Vilotijevic introduced water into the
reaction, he noticed that it proceeded much more quickly and
selectively.
Although it could be a coincidence that these cascades work best in
water and that dinoflagellates are marine organisms, water may
nevertheless be directly involved in the biosynthesis of the toxins or
emulating an important part of it, said Jamison. Because of this
result, the researchers now believe that organic chemists should
routinely try certain reactions in water as well as organic solvents.
The research was funded by the National Institute of General Medical
Sciences, Merck Research Laboratories, Boehringer Ingelheim, and MIT.
"This is an elegant piece of work with multiple levels of impact,"
said John Schwab, who manages organic chemistry research for the
National Institute of General Medical Sciences. "Not only will it
allow chemists to synthesize this important class of complex molecules
much more easily, but it also provides key insights into how nature
may make these same molecules. This is terrific bang for the
taxpayers' buck!"
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