A new synthetic method that allows the structure of pyridine compounds — the most widely used building blocks in pharmaceuticals — to be readily rearranged has been developed by a Korean research team. By altering only the position of the nitrogen atom while leaving the complex framework of a finished drug intact, the approach is seen as opening a path to rapidly screen a wide range of new drug candidates.
 [코리안투데이] A conceptual diagram of positional isomerization achieved by relocating the nitrogen in pyridine © 장형임 기자 |
The Ministry of Science and ICT (Deputy Prime Minister and Minister of Science and ICT Bae Kyung-hoon) announced that a research team led by Hong Seung-woo, acting director of the Center for Catalytic Hydrocarbon Functionalizations at the Institute for Basic Science (IBS, President Chang Suk-bok) and a professor of chemistry at KAIST, has developed an ‘N-atom transposition’ synthetic method that moves the nitrogen within a pyridine structure to a desired position. The research was carried out under the Ministry’s IBS research center support program and was published in the world-renowned journal Nature at midnight on August 18 (Korean time).
Pyridine is a hexagonal ring structure made up of five carbon atoms and one nitrogen atom, and it serves as the basic framework of countless pharmaceuticals and chemicals. Even when the same substituent is attached, the physicochemical properties — such as solubility, absorption, permeability and binding — as well as the drug efficacy vary greatly depending on the relative position of the nitrogen and the substituent. For this reason, drug development requires the essential task of creating several positional isomers that differ only slightly in the location of the nitrogen and comparing their functions.
Until now, the substituents attached to a pyridine ring have been regarded as fixed elements that are difficult to relocate. To obtain an isomer with the desired arrangement, a separate starting material and synthetic route had to be designed from scratch for each one. There had been attempts to move only the substituents on a completed molecule, but because the reaction conditions differ for each type of substituent, such approaches were practically impossible to apply to complex molecules bearing multiple substituents.
Instead of moving the substituents one by one, the team solved the problem with a reverse approach: shifting the position of the nitrogen, which serves as the reference point. By keeping the substituents in place and moving the nitrogen instead, they changed the positional relationships of the various substituents relative to the nitrogen all at once. To do this, they devised a method that inserts a new nitrogen from an external nitrogen source into the ring and then removes the existing nitrogen. In this process, the existing six-membered ring temporarily expands into a seven-membered ring and then rearranges, producing a new pyridine with the nitrogen in a different position. Isotope-tracing experiments confirmed that the newly introduced nitrogen remains in the ring, while the original nitrogen is released as nitrogen gas (N2).
The new synthetic method was applied broadly, from simple structures with a single substituent to complex structures with two or more, and even to structures bearing several substituents with differing properties. When the reaction conditions were optimized, the yield of the isomer synthesis reached 88 percent, and even in an experiment that greatly increased the amount of reactant to 10 millimoles, a high yield of 74 percent was maintained — demonstrating the potential for mass production and practical use.
In particular, the team applied the technique to the commercially available anticancer drugs vismodegib and abiraterone acetate, as well as the anti-inflammatory painkiller etoricoxib, creating new candidate molecules that kept the complex drug framework intact while differing only in the position of the nitrogen. They also found that even with the same starting material, the ratio of positional isomers changes depending on the solvent used. Computational chemistry analysis showed this is because the height of the ‘energy barrier’ — the minimum energy required for the chemical reaction — varies with the solvent, demonstrating that the desired isomer can be selectively synthesized simply by adjusting the solvent conditions.
This achievement draws attention because it could change the very way candidate substances are obtained in drug development. Rather than preparing different starting materials and synthesizing each one separately from the beginning, researchers can now use a single already-made molecule as a starting point to directly explore a variety of positional isomers. Because it becomes possible to systematically examine how minute structural changes affect a drug’s properties and efficacy, the likelihood of quickly finding safer and more effective drugs increases accordingly.
Hong Seung-woo, acting director at IBS, said, ‘This research began with a shift in thinking — moving away from conventional methods to change the very position of the atoms within the core framework.’ He added, ‘By directly editing the core framework of a completed molecule at the atomic level, we can explore changes in properties and efficacy from multiple angles, and this will contribute to dramatically broadening the scope of new drug candidate discovery.’ Kim Sung-soo, director-general for research and development policy at the Ministry of Science and ICT, said, ‘This study is a representative achievement showing that creativity can open new paths to research innovation,’ adding, ‘We will continue to provide support so that researchers can boldly take on the creation of new concepts and the pioneering of unknown territory beyond existing frameworks.’
The team plans to extend the ring-editing strategy secured through this work to a variety of nitrogen-containing heteroaromatic rings beyond pyridine. Through this, they expect to rapidly build the libraries of positional isomers needed for drug development without separate total synthesis, and to accelerate structure-activity relationship (SAR) research.
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