Source: Scripps
Research Institute
Sientists at The Scripps Research Institute
(TSRI) have developed a method for modifying organic molecules that
significantly expands the possibilities for developing new pharmaceuticals and
improving old ones.
A method
for modifying organic molecules has been developed that significantly expands
the possibilities for developing new pharmaceuticals and improving old ones.
The innovation makes it easier to modify existing organic compounds by
attaching biologically active "functional group" to drug molecules. A
typical small-molecule drug derives its activity from such functional groups,
which are bound to a relatively simple backbone structure consisting chiefly of
carbon atoms.
Pushing the Boundaries
Chemists over the past half-century or so have devised various
methods for adding functional groups to carbon atoms, to make new compounds and
to modify old ones. But a certain type of modification has remained largely out
of reach.
Known as a "meta" C-H activation, this modification
involves the temporary attachment of a helper molecule to one carbon atom, in
such a way that the helper molecule extends past the nearest-neighbor carbon
atom to the next-nearest carbon atom, and there mediates the addition of a
functional group. It is a tricky task for a number of reasons, but mostly
because the targeted attachment site is so far away and inaccessible. The carbon
in the backbone of a typical organic compound is arranged in rings of six or so
carbon atoms -- and thus to reach from one such carbon over a second to a third
means reaching almost to the far side of the ring.
In 2012, Yu and his colleagues published a landmark paper, also
in Nature, which described a way to accomplish this feat with one
set of compounds. They devised a helper molecule, with a long segment called a
nitrile, that could attach to one carbon atom on the compound, arch over the
next-door carbon atom, and in effect swing a palladium atom at its far end back
-- a bit like a crane swinging a wrecking ball -- to the targeted carbon atom.
There the palladium atom would act as a catalyst to dislodge the existing
occupant, a hydrogen atom, enabling the attachment of the new functional group.
Following the same principle, Yu's team recently came up with a
new template for making meta-C-H activations on a much more challenging set of
organic compounds. Now, in the new study, the researchers have demonstrated the
same task with a major family of compounds known as amines, including
medicinally important heterocyclic amines. In so doing, the researchers found a
way to use a helper molecule -- also called a template -- that is chemically
simpler and more user-friendly than the ones they have described in previous
work.
A Boost to Drug Discovery
Unusually for such a project, the TSRI chemists analyzed the 3D
atomic structure of their template compound using X-ray crystallography as well
as nuclear magnetic resonance spectroscopy. These studies revealed that the new
template's ability to mediate the attachment of a new functional group to a
distant carbon atom can be "tuned" by making slight changes to its
chemical composition, including the choice of the proper metal catalyst at its
working end.
"The key is to tune the shape of the template to create a
subtle bias towards the targeted carbon hydrogen bond," said Yu. "At
the same time the template's movement towards the target site has to be
exploited effectively by a super-reactive catalyst."
Compounds that can be modified using the new technique include
tetrahydroquinoline, benzooxazines, anilines, benzylamines,
2-phenylpyrrolidines and 2-phenylpiperidines. "All these are commonly used
in medicinal chemistry either as final drug compounds or intermediate compounds
from which the final compounds are made," Yu said.
"Techniques like this one that enable controlled, remote
C-H activation are just beginning to be adopted by industry, and should provide
a boost to drug discovery and development efforts for many years to come,"
Yu said.
Posted by:
Gauri Shah
Faculty BII
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