Innovative Molecular Editing Technique Allows New Elements in Organic Molecules
Chemists at Scripps Research have developed a new molecular editing technique that enables them to add new elements to organic molecules in areas that were previously unreachable. In a May 31, 2023 issue of Nature journal, they described using a ligand, a designer molecule, to help a palladium atom catalyst intervene from one side of a carbon atom ring to break a carbon-hydrogen (C-H) bond on the other side, allowing a new set of molecules to bind at that site. This molecule-building achievement was previously impossible for so-called “saturated” rings of carbon atoms that are prevailing features in drug molecules.
Innovations in CH Functionalization
Scripps Research’s Jin-Quan Yu and his team are already known for their inventions in CH functionalization, which they use to build complex organic molecules for creating new pharmaceuticals and other valuable commercial compounds. In this approach, chemists use ligands and catalysts to disconnect a hydrogen atom from a carbon atom at a chosen position in an organic molecule. This disconnection allows a new group of molecules, known as a functional group, to bind where the hydrogen atom had been.
Rings of Carbon Atoms
The majority of molecules used for building new drugs include rings of carbon atoms, also known as carbocycles. Thanks in part to Yu’s group, CH functionalizations of the carbon atoms in these rings have become reasonably easy in many cases. However, this approach is frequently not applicable in cases where the existing functional group required to anchor the ligand and catalyst is directly across the ring from the desired CH functionalization point.
Meeting New Challenges
The most challenging aspect of CH functionalization is when the rings’ carbon structures are “saturated,” indicating that their carbons are connected only by single carbon-carbon bonds. Saturated carbon rings are common in pharmaceutical chemistry but are more difficult targets for CH functionalization. That is because CH bonds have less affinity for metal catalysts, compared to the CC double bonds of unsaturated carbon rings. Yu’s lab has successfully functionalized CH in unsaturated rings, but there has been no way to do this in a saturated ring until now.
Research Development
In the study, Yu and his team—-including co-authors Guowei Kang, Daniel Strassfeld, and Tao Sheng-—developed quinuclidine-pyridone and sulfonamide-pyridone ligands that allow functionalization of crossed rings with saturated carbon rings. They showed that their approach can work for rings containing four to eight carbon atoms in different molecules. The researchers demonstrated their new technique by easily functionalizing molecules that are being used for developing future drugs, including compounds called histone deacetylase inhibitors that are being investigated as potential cancer treatments.
Expanding Chemical Space in Pharmacology
The researchers anticipate that their new tool will greatly simplify the synthesis of a significant class of carbocyclic molecules used in pharmaceutical chemistry. This will expand the chemical space for discovering new and better drugs. This new technique introduces a synthesis of options by including structurally distinctive chemical substrates into the rings without undertaking a de novo approach, also called a cyclization method, which involves forming a new ring structure from an acyclic chain, and that is often a challenging process.
An Engaging Piece
The introduction of a new synthetic approach with “molecular editing” techniques is a cutting-edge innovation that adds tremendous value to the pharmacology industry. This novel method of adding new molecules to existing rings in organic compounds serves to expand potential drug cataloging and recognize potential pharmacological substances that were previously unavailable. This innovative technique helps to expand synthetic options, which opens up the possibilities of finding new revenue streams, creating jobs, and enhancing the already reinforced healthcare system.
The field of pharmacology has come a long way in trying to address the root cause of cancer and other diseases. The discovery of new drugs has led to life-changing solutions for many before-now incurable diseases. However, one of the most significant challenges in the field of medicine has been overcoming the complexity of organic structures. With such innovation, the discovery of new chemical substrates in rings previously unattached allows for the expansion of the chemical space in pharmacology. This development will lead to the creation of new treatments for various ailments, including cancers that have been previously difficult or impossible to treat.
Summarily, the “molecular editing” technique adds to the arsenal of options available for producing new medicines. In a pharmacological world that has long dealt with the complexities of creating new drugs, the technique offers a more efficient and direct approach to modification and avoids difficult cyclization reactions. As more medicines come into circulation and better healthcare delivery made available, it is clear that this innovative molecular editing technique will be more relevant than ever before.
Supported by grants from the National Institute of General Medical Sciences (2R01GM084019 and F32GM143921), this innovative approach brings hope to the industry by expanding the knowledge and options available in the scientific and medical community. With further research in molecular editing techniques, the challenge of curing many diseases will become less daunting, and innovative pharmaceuticals beholden to unique chemical substrates and structures will be within reach.
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A new “molecular editing” technique from Scripps Research allows chemists to add new elements to organic molecules in places previously out of their reach.
The researchers described their new method in an article that appeared on May 31, 2023, in Nature. The method uses a designer molecule called a ligand that helps a palladium atom catalyst reach from one side of a carbon atom ring to break a carbon-hydrogen bond on the other side, allowing a new set of molecules bind at that site. This molecule-building feat was previously impossible for so-called “saturated” rings of carbon atoms, which are common features in drug molecules.
“Previously, to achieve the same result, one would have to undertake a de novo approach, what we call a cyclization reaction, which involves the formation of a new ring structure from an acyclic chain. Using this new method, we can modify directly an existing ring to avoid a cyclization process that can often be challenging,” says lead study author Jin-Quan Yu, PhD, holder of the Bristol Myers Squibb Chair of Chemistry and Frank and Bertha Hupp Professor at the Scripps Research Department of Chemistry. “In addition to saving steps, this unprecedented synthetic approach may introduce a new chemical space for drug discovery as structurally distinct substrates are incorporated into the ring.”
Yu and his lab are already known for their innovations in CH functionalization, which is a powerful way to build complex organic molecules to make new pharmaceuticals and other valuable commercial compounds. In this approach, chemists use ligands and catalysts to disconnect a hydrogen atom (H) from a carbon atom (C) at a desired position in an organic molecule. This disconnection allows a new group of molecules, known as a functional group, to join where the hydrogen atom had been.
Most of the molecules used to build new drugs include rings of carbon atoms, also called carbocycles. Thanks in part to Yu’s group, CH functionalizations of the carbon atoms in these rings have become relatively easy in many cases. However, this approach is often not applicable in cases where the existing functional group needed to anchor the ligand and catalyst is directly across the ring from the desired CH functionalization site.
“We call this scenario ‘crossing the river,’ and it has been extremely challenging because the palladium catalyst must form a tense ‘bridge’ connecting the existing functional group and the desired carbon site on the other side of the ring,” says Yu. .
The most challenging cases are those in which the carbon ring structures are “saturated”, meaning that their carbons are connected only by single carbon-carbon bonds. Saturated carbon rings are common in pharmaceutical chemistry, but are more difficult targets for CH functionalization, in part because CH bonds have less affinity for metal catalysts, compared to the CC double bonds of unsaturated carbon rings. . Yu’s lab has succeeded in functionalizing CH in unsaturated rings, but there has been no way to do it in a saturated ring, until now.
In the study, Yu and his team—including co-authors Guowei Kang, PhD, Daniel Strassfeld, PhD, and Tao Sheng, PhD, all postdoctoral research associates in Yu’s lab—were able, after months of trial and error, to develop quinuclidine-pyridone and sulfonamide-pyridone ligands that allow functionalization of crossed rings with saturated carbon rings. They showed that the approach can work for rings containing four to eight carbon atoms, within a wide variety of molecules.
The researchers demonstrated the new technique by easily functionalizing molecules that are being used to develop future drugs, including compounds called histone deacetylase inhibitors, which are being investigated as potential cancer treatments.
“We anticipate that this new tool will greatly simplify the synthesis of a large class of carbocyclic molecules used in pharmaceutical chemistry, expanding the chemical space for the discovery of new and better drugs,” says Yu.
The research was supported by grants from the National Institute of General Medical Sciences (2R01GM084019 and F32GM143921).
https://www.sciencedaily.com/releases/2023/05/230531150050.htm
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