Positional isomerization achieved by relocating the nitrogen atom within a pyridine ring. [Provided by IBS]
Positional isomerization achieved by relocating the nitrogen atom within a pyridine ring. [Provided by IBS]

Scientists have developed a technology that can dramatically expand the search for new drug candidates by repositioning specific atoms within complex pharmaceutical molecules while leaving the core framework intact.

The Institute for Basic Science said Tuesday that a research team led by Hong Seung-woo, acting director of the Center for Molecular-Level Control of Chemical Reactions and a chemistry professor at KAIST, has developed a new synthetic method that freely repositions nitrogen atoms within pyridine structures.

The findings were published in the international journal Nature.

Pyridine is a hexagonal ring structure composed of five carbon atoms and one nitrogen atom, widely used as the basic framework for pharmaceuticals and a broad range of chemical compounds. Even when substituents remain the same, shifting the relative positions of the nitrogen atom and those substituents can significantly alter solubility, absorption, permeability, molecular binding affinity and pharmacological efficacy.

In drug development, synthesizing a variety of "positional isomers" — molecules that differ only in where the nitrogen or substituents are located — is essential for comparing their functional properties.

Conventional synthetic methods, however, made it difficult to change only the position of a specific atom in a completed pyridine molecule. Producing a desired positional isomer required designing entirely new starting materials and synthetic routes for each variant. The process becomes even more demanding when applied to complex pharmaceutical compounds carrying multiple substituents.

The research team solved this problem by inverting the conventional approach: rather than moving substituents one by one, they repositioned the nitrogen atom itself — the reference point of the ring. By keeping the substituents fixed and shifting the nitrogen, they changed the positional relationships of all substituents relative to the nitrogen in a single step.

To achieve this, the team devised a method of inserting a new nitrogen atom from an external nitrogen source into the ring, then removing the original nitrogen. During this process, the existing six-membered ring temporarily expanded into a seven-membered ring before rearranging back, forming a new pyridine with the nitrogen in a different position. Isotope-tracing experiments confirmed that the newly introduced nitrogen remained in the ring while the original nitrogen was expelled as nitrogen gas (N2).

The new synthetic method was applied not only to simple pyridines but also to complex structures bearing a variety of substituents.

Hong Seung-woo, acting director of the IBS Center for Molecular-Level Control of Chemical Reactions. [Provided by IBS]
Hong Seung-woo, acting director of the IBS Center for Molecular-Level Control of Chemical Reactions. [Provided by IBS]

The team successfully repositioned nitrogen atoms in molecules ranging from simple pyridines with a single substituent to complex pyridines bearing two or more. Under optimized conditions, the synthesis yield for positional isomers reached as high as 88 percent, and a yield of 74 percent was maintained even when the reaction scale was expanded to 10 millimoles (mmol).

The technology was also applied to drugs already on the market. Using the anticancer drugs vismodegib and abiraterone acetate, as well as the anti-inflammatory analgesic etoricoxib, the team synthesized new candidate molecules that retained the complex core frameworks of the existing drugs while altering only the nitrogen position within the pyridine ring.

The researchers also found that even when starting from the same material, the ratio of different positional isomers produced varied depending on the solvent used. Computational chemistry analysis revealed that the solvent affects the energy barriers required at different stages of the reaction.

"This research started from a shift in thinking — instead of working within existing methods, we asked whether we could directly change the positions of atoms within the core framework itself," Hong said. "By editing the core framework of a completed molecule at the atomic level, this work will contribute to exploring changes in physical properties and pharmacological efficacy from multiple angles, and to dramatically expanding the range of drug candidates that can be discovered."


nbgkoo@heraldcorp.com