|
An elephant ear sponge (Agelas clathrodes). Photo: NURC/UNCW and NOAA/FGBNMS
|
Deep in the ocean, sponges of the Agelas
family, or bacteria living within the sponges, emit chemicals believed to help
them defend their territory. Those chemicals, called agelastatins, have also
shown the ability to kill cancer cells. For that reason, chemists have been
trying to find ways to synthesize agelastatins in the laboratory since the
chemicals were discovered in 1993.
Chemists at MIT, led by Associate
Professor Mohammad Movassaghi, recently discovered the shortest and most
productive way to synthesize all six of the known agelastatins. The team, which
also includes graduate students Dustin Siegel and Sunkyu Han, described the new method in Chemical Science.
“Movassaghi's very elegant synthesis
demonstrates a nicely scalable, multi-gram preparation of all the known
agelastatins,” says Tadeusz Molinski, the chemist who first isolated
agelastatins C and D, the third and fourth agelastatins discovered, in 1998.
Molinski, a professor of chemistry at the University
of California at San Diego, says the new synthesis will allow
researchers to produce enough of the compounds to test them as cancer drugs.
Agelastatins have been shown to inhibit
cancer-cell proliferation by interfering with cell division. They also repress
an enzyme known as glycogen synthase kinase-3, a potential target for treating
Alzheimer’s disease and bipolar disorder.
“They have a very broad range of
biological activity,” says Movassaghi. “The sponges are not interested in
treating cancer or Alzheimer’s, but the agelastatins are potently active
against them.”
Scientists speculate that sponges, or
bacteria that live in symbiosis with them, release agelastatins into their
watery environment to warn other sponge species not to colonize the area.
Copying nature
Agelas sponges, which have been found in the Coral Sea and Indian
Ocean, are difficult to obtain, so researchers have had trouble
generating enough agelastatin to do large-scale experiments in cancer cells.
Since they were first discovered, chemists have reported about a dozen ways to
produce one or more of the compounds, but none of the chemists have been able
to produce all six. The MIT team can do so, and in relatively large quantities—a
gram per reaction batch.
|
The chemical makeup of agelastatin A. Image: Mohammad Movassaghi
|
The reaction begins with a commonly
available starting material, aspartic acid. The synthesis requires seven steps
to produce agelastatin A, the first discovered and most potent of the
compounds. Agelastatin A can then be converted to agelastatins B, C, or E. The
synthesis can also be altered slightly to produce D, which can then be
converted to F.
In designing their synthesis,
Movassaghi, Siegel and Han tried to mimic the way they believe the sponges naturally
produce agelastatins.
Each agelastatin contains four rings,
known as A, B, C, and D, and most chemists have used syntheses in which the C
ring forms before the B ring. The MIT team formed the B ring first, and the C
ring last. The C ring is the only ring made solely of carbon atoms (all of the
others contain at least one nitrogen atom), and it is where all four of the
molecule’s stereocenters are found. (Stereocenters are atoms around which the
molecule can take different three-dimensional orientations.)
Other chemists had theorized that the
biological synthesis of agelastatins would use precursors with an
electron-deficient carbon atom in the fourth carbon position and a carbon atom
that wants to share its electrons in the eighth position. Movassaghi switched
those features.
To show whether sponges do the same
series of steps, more experiments are needed. Researchers could label the
precursors with isotope tags, give them to the sponges, and follow where the
isotopic labels end up. Although some of the steps of Movassaghi’s synthesis
require high temperatures or acidic conditions, those same reactions could
occur under biological conditions if catalyzed by enzymes.
Movassaghi’s lab is now collaborating
with researchers in academia and industry to test the biological activity of
the compounds, with an emphasis on their anti-cancer activity. Using the new
synthesis, the researchers should be able to easily produce variants not found
in nature that might have even more powerful effects, says Movassaghi. The
synthesis should also provide a good starting point for possible future
large-scale production, should there be a need, he says.
SOURCE
