Science ministry unveils molecular editing method for drug redesign

The science ministry said that an Institute for Basic Science team had developed a method, called N-atom transposition, that repositions nitrogen within pyridine rings and could expand the search for drug candidates.

Pyridine is a six-membered ring of five carbon atoms and one nitrogen atom, widely used in pharmaceuticals and other chemicals. Nitrogen's position relative to attached groups can substantially alter chemical properties and biological activity, and making each positional isomer has generally required a distinct starting material and synthesis route.

Rather than move attached groups, the researchers inserted a new nitrogen atom from an external source and removed the existing one, temporarily expanding the ring from six atoms to seven before it rearranged. The method was applied to pyridines with one attached group, multiple groups and groups with differing chemical properties. Isotope-tracing experiments showed the added nitrogen remained in the ring while the original atom exited as nitrogen gas.

Under optimized conditions, the method produced positional isomers with yields of up to 88 percent and maintained a 74 percent yield using 10 millimoles of reactant. The team used it on vismodegib, abiraterone acetate and etoricoxib, producing candidate molecules that preserved the drugs' complex frameworks but repositioned nitrogen. "It will help directly edit the core framework of completed molecules at the atomic level, explore changes in physical properties and drug efficacy from multiple angles, and greatly widen the scope for identifying drug candidates," Hong Seung-woo, acting head of an IBS research group, said.

Solvent choice changed the proportion of positional isomers formed from the same starting material, with computational chemistry tying the difference to energy barriers under each condition. The researchers said adjusting solvent conditions could selectively synthesize a desired positional isomer. The work was published in Nature on Aug. 18.