Nitrogen Relocated While Preserving Drug Scaffold... "Molecular Editing" Technology Developed to Find New Drug Candidates [Reading Science]

IBS Develops Synthetic Method to Rearrange Nitrogen in Pyridine; Applied to Actual Anticancer and Anti-Inflammatory Drugs

A Novel Approach: Moving Nitrogen Instead of Substituents

Yield Reaches Up to 88% and Published in Nature

A new "molecular editing" technology has been developed that enables the creation of new drug candidates by changing the specific position of certain atoms while retaining the complex scaffold of an existing drug molecule. Rather than resynthesizing a new drug from scratch, this approach allows researchers to alter the structure of existing drugs at the atomic level, compare their efficacy and properties, and thereby broaden the scope of drug candidate discovery.

The Ministry of Science and ICT and the Institute for Basic Science (IBS) announced on the 18th that a research team led by Seungwoo Hong, Acting Director of the Molecular Active Catalysis Research Group at IBS and Professor of Chemistry at KAIST, developed a “nitrogen atom transposition” synthetic method that allows free rearrangement of the nitrogen atom within a pyridine framework. The research findings were published the same day in the international journal 'Nature.'

Positional Isomerization through Nitrogen Position Rearrangement in Pyridine. Pyridine is a ring structure widely used in pharmaceuticals, and the relative positions of nitrogen and substituents can affect drug efficacy. Previously, positional isomers were created by directly moving the substituents, but the research team developed a method to keep the substituents in place and instead change the position of the nitrogen atom. By inserting a new nitrogen at the desired position and removing the original nitrogen as nitrogen gas (N₂), they can create new isomers with different nitrogen positions while maintaining the complex drug skeleton. Provided by the research team

Pyridine is a compound composed of five carbon atoms and one nitrogen atom forming a hexagonal ring. It is widely used as a basic scaffold in pharmaceuticals as well as in various other chemicals. Even if a compound contains the same types of atoms and substituents, differences in the relative positions of the nitrogen atom and substituents can dramatically alter solubility, absorption, permeability, binding properties, and ultimately, efficacy.

For this reason, in drug development, it is crucial to create “position isomers”—molecules with different spatial relationships between the nitrogen and substituents—and to compare their respective properties. The challenge, however, is that with conventional synthetic methods a separate starting material and synthetic route must be designed for each desired positional isomer, requiring the molecule to be synthesized from the beginning every time. Although it is theoretically possible to directly move substituents on a finished molecule, the reaction conditions required vary depending on the type of substituent, making it difficult to apply such methods to complex molecules containing multiple substituents.

The substituents remain, but the 'reference point' nitrogen is moved

Instead of moving each substituent individually, the research team opted to move the nitrogen atom itself, which serves as the reference point that determines the relative positions of the substituents. By changing only the position of the nitrogen atom while leaving all substituents untouched, the relative positions of the substituents with respect to the nitrogen atom are simultaneously altered.

The researchers developed a method in which a new nitrogen atom is introduced into the pyridine ring from an external nitrogen source while the original nitrogen is removed. During this process, the original six-membered ring temporarily expands to a seven-membered ring before rearranging, resulting in a new pyridine where the nitrogen position has shifted.

Isotope tracing experiments confirmed that the newly introduced nitrogen remains in the pyridine ring, while the original nitrogen is released in the form of nitrogen gas (N₂). In this way, the team was able to exchange and reposition a single atom within the core framework of a molecule with minimal modification to the surrounding structure.

The team successfully applied this technology to both simple pyridine molecules with a single substituent as well as more complex structures with multiple substituents. Under optimized reaction conditions, the yield for the synthesis of positional isomers reached up to 88 percent. Even when scaling up the reaction to a 10-millimole (mmol) scale, a yield of 74 percent was maintained.

Photo of research team. From left to right: Seungwoo Hong, Director of Molecular Activation Catalysis Reaction Group at IBS (Corresponding Author), Wonjun Choi, Postdoctoral Researcher at Molecular Activation Catalysis Reaction Group at IBS (First Author), Jiyong Park, Research Fellow at Molecular Activation Catalysis Reaction Group at IBS (Co-Second Author), Hwawon Joo, Student Researcher at Molecular Activation Catalysis Reaction Group at IBS (Co-Second Author). Courtesy of IBS

In particular, the technique was successfully applied to existing pharmaceuticals such as the anticancer drugs vismodegib and abiraterone acetate, as well as the anti-inflammatory analgesic etoricoxib. The researchers synthesized new molecules in which only the nitrogen position of pyridine was changed, while retaining the complex scaffolds of these existing drugs. This means that it is now possible to rapidly create new candidate molecules with slightly different structures from already developed drugs or drug candidates and compare their properties and efficacy.

The research team also confirmed that simply changing the solvent could control the proportion of each positional isomer generated. Computational chemistry analysis showed that the energy barrier required for the reaction varied depending on the solvent, and this effect could be harnessed to drive the reaction to favor the desired positional isomer.

Acting Director Hong commented, "This research originated from a paradigm shift—moving away from traditional methods and instead directly altering the atomic positions within the core structure of a molecule. By editing the atomic arrangement inside a completed molecular scaffold, we can explore changes in physical properties and efficacy from multiple perspectives and dramatically expand the search space for new drug candidates."

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