A better-fitting molecular `belt' for making new drugs
Chemistry invention could affect the most common medications

Date:
November 16, 2021
Source:
Ohio State University
Summary:
The most common pharmaceuticals on the market are made by chaining
together rings of molecules to create the drugs that treat
conditions including pain, depression and leukemia. But creating
those rings and forming them in a way that is tailored to each
individual disease has always been a cumbersome and expensive
process in medicinal chemistry.

New research proposes a way to simplify that transformation. The
discovery will likely make it easier to produce new drug candidates,
the researchers say.



FULL STORY ==========================================================================
The most common pharmaceuticals on the market are made by chaining
together rings of molecules to create the drugs that treat conditions
including pain, depression and leukemia.


==========================================================================
But creating those rings and forming them in a way that is tailored
to each individual disease has always been a cumbersome and expensive
process in medicinal chemistry.

New research, published today in the journal Chem, proposes a way to
simplify that transformation. The discovery will likely make it easier
to produce new drug candidates, the researchers say.

David Nagib, senior author of the study and associate professor of
chemistry at The Ohio State University, likened the chain of molecules to
a belt with no holes: With no way to fasten the circle and no measurements
for where holes might go, the belt can't be assembled in a way that
keeps it closed.

"The problem we were trying to solve is how do you punch the hole so
that it fits you perfectly, and get it right on the first try without measuring," Nagib said. "The trick here was we had to put the holes
in just the right place, but we had to figure out precisely where the
holes should go, without any markings to tell us where that might be."
The "belt" in this case is a string of carbon-hydrogen bonds, the most ubiquitous bonds in all of nature and medicines. Most drugs contain
rings of carbon-hydrogen bonds, linked together by a "bridging" nitrogen
atom, within complex structures that interact precisely with cellular components in the body -- like a key fitting into a lock. The most common
ring found in all medications are six-sided ones, called a piperidine.

But piperidines have long been difficult and expensive to produce,
primarily because chemists could not quickly or cheaply replace a carbon-hydrogen bond with other chemical bonds.

Researchers in Nagib's lab at Ohio State found a way to replace that
bond - - establishing the "hole" that allowed them to close the belt --
by oxidizing two carbon-hydrogen bonds. Doing that allowed them to select hydrogen molecules and remove them from the molecule chain. Then, they
used light and a copper catalyst to turn one of those bonds into the
needed nitrogen ring. The light worked to excite catalysts in a chain
process similar to photosynthesis, the way plants use light to create
food for themselves.

The process solves a problem for making early-stage drug candidates still
in development - it is still too expensive to be used to mass-produce medication.

Nagib said future work will focus on using a cheaper starting material
to scale up production.

"This discovery is something that can make it possible to more rapidly
create a library of drug candidates for testing, so you can identify
the right, most potent, most effective one more quickly," Nagib said.

Ohio State researchers Leah M. Stateman, now at Merck and Co., Ross
M. Dare and Alyson N. Paneque contributed to this work. The research
was funded by the National Institutes of Health.

========================================================================== Story Source: Materials provided by Ohio_State_University. Original
written by Laura Arenschield. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Leah M. Stateman, Ross M. Dare, Alyson N. Paneque, David
A. Nagib. Aza-
heterocycles via copper-catalyzed, remote C-H desaturation of
amines.

Chem, 2021; DOI: 10.1016/j.chempr.2021.10.022 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211116131733.htm

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