Enhancing Binding Affinity to CGG/CGG Triad: Optimizing Naphthyridine Carbamate Dimer Derivatives with Varied Linker Lengths

This study examines the binding properties of six naphthyridine carbamate dimer (NCD) derivatives with varying linker lengths to the CGG/CGG triad, a non‐canonical DNA structure linked to repeat expansion disorders. By altering the linker length from 2 to 4 methylene groups, we found changes in thermal stability of the ligand‐bound complexes while maintaining a consistent 2 : 1 binding stoichiometry. Among the derivatives, CC23 showed superior binding affinity compared to the parent molecule CC33 (NCD). Spectroscopic analyses revealed that linker length influences the conformational equilibrium of NCD derivatives. Thermal melting temperature measurements demonstrated CC23′s enhanced thermal stability over CC33. These findings underscore the potential of optimized NCD derivatives, like CC23, as tools to modulate CGG repeat structures, offering insights for therapeutic strategies targeting repeat expansion disorders. The structure of the CGG repeat binding molecule NCD was optimized by changing the linker length connecting two 1,8‐naphthyridine heterocycles. The NCD23, having asymmetric linker length exhibited the highest affinity.