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Neopeltolide C31H46N2O9 |
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Karl Scheidt has synthesized a natural molecule
with cancer-fighting properties that was isolated from this
deep-sea sponge, a member of the family Neopeltidae. Credit:
Harbor Branch Oceanographic Institution.
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After six months of intense effort, Scheidt,
graduate student Daniel Custar and postdoctoral fellow Thomas Zabawa
successfully built the molecular structure reported in the paper.
That�s when they discovered something strange and unexpected when they
compared the spectra, or unique molecular fingerprints, of their
structure and that of the natural compound: The spectra did not match,
which meant that the structures did not match. Something was wrong.
This story and how the Northwestern team solved the mystery and
determined the real structure of neopeltolide, the natural compound
derived from the marine sponge, is reported in a paper published in
the Jan. 23 issue of the Journal of the American Chemical Society (JACS).
Knowing neopeltolide�s structure will help researchers learn how the
new compound works, which could lead to new, more-effective
anti-cancer drugs.
�The reported biological activity of this new natural compound was
fantastic - two to three orders of magnitude more potent for some
cancer cells than Taxol�, a common chemotherapy drug,� said Scheidt,
assistant professor of chemistry in the Weinberg College of Arts and
Sciences at Northwestern. (Taxol� also has its origins in nature,
having been extracted from the Pacific yew tree.) �Synthetic chemists
are inspired by such structures. Because of the potential benefits to
human health, these are the compounds you want to go after.�
Marine sponges can�t move and escape predators, and they don�t have
claws, teeth or quills, so they have developed a different kind of
defense mechanism: chemical protection. The sponge and/or bacteria
hosted by the sponge produce poisonous compounds to ward off enemies.
This chemical factory makes sponges rich sources of interesting
natural products, many with cell-killing abilities.
After discovering the spectrum of their first built molecule did not
match the natural compound�s spectrum, Scheidt and his team faced two
possibilities - either they had done something wrong while building
the molecule or the structure was reported incorrectly.
The researchers double checked their methods, found they were �spot
on� and concluded the structure was reported incorrectly. Which meant
the right structure still needed to be determined. Custar and Zabawa
decided to set up a cot in the lab�s computer room to cut down on
their commute to the lab and set to work.
Again, using simple starting materials and complex chemical synthesis,
the team built a new molecule, just slightly different from the first
one. This time they perturbed just two carbon atoms, making them
�down� instead of �up,� in chemist speak. The researchers compared the
spectrum of this new structure with that of the natural compound, and
this time the spectra matched perfectly. These results are those
published in the JACS article.
To construct the compound, Scheidt, Custar and Zabawa used an
efficient, convergent synthesis, a bit akin to how a car is put
together on an assembly line - with major parts, like the engine,
built separately and then put together in the final piece. �Our
approach brings three equal fragments together to form the whole,
which is better than building in a linear sequence,� said Scheidt. �We
pushed the envelope of what can be done with organic chemistry to do
it.�
Unbeknownst to the Northwestern researchers, a group led by James S.
Panek, an organic chemist at Boston University, was working on the
neopeltolide structure at the same time as Scheidt and his team. In
their work, Panek�s group also discovered the original published
structure to be incorrect and determined the correct structure, using
steps different from Scheidt�s to get there. Panek�s results were
published a few weeks after the time Scheidt submitted his paper to
JACS.
�The synthetic chemists have done an amazing job in such a short
time,� said Wright, who works at the Harbor Branch Oceanographic
Institution. Wright isolated neopeltolide from a sponge she collected
near Jamaica in 1993; she and her team reported its biological
activity and structure in the 2007 article that inspired Scheidt�s
work.
�I was impressed with the molecular modeling work that Karl�s group
did to propose a variety of structures,� said Wright. �The beauty is
that we can find a compound in nature, and synthetic chemists can then
build the structure in the lab. That structure and related compounds
can then be tested for drug discovery.�
�Nature is the biggest pharmacy around,� said Scheidt. �Sixty to
seventy percent of pharmaceuticals are inspired by natural products.
We learn from nature, but we want to improve on nature, too.�
Neopeltolide stops cell division in an unusual place, and this
activity is different from that of other commonly known and utilized
chemotherapies. �We know there is something different going on with
this new molecule, and we want to start figuring out if this behavior
is the beginning of a new way to treat cancer,� said Scheidt.
In addition to the original structure, Scheidt and his team currently
have six or seven other synthetic compounds to test. The researchers
want to see if they can make a smaller, simpler molecule that is just
as effective against cancer cells but also more selective, leaving
healthy cells alone. A few small chemical tweaks may be all that is
needed.
With the new compound�s correct structure in hand, the real journey
can begin, says Scheidt. He plans to work with Wright and Professor
Craig Crews, a molecular biologist at Yale University, to screen the
tweaked molecules against different cancer cell lines and to discover
how they work so new pathways for treating cancer can be identified.
The Northwestern research was supported by the Sloan Foundation,
Abbott Laboratories, Amgen, AstraZeneca, 3M, GlaxoSmithKline and
Boehringer-Ingelheim.
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