Department of Regulatory Bioorganic Chemistry, SANKEN, The University of Osaka, 8-1 Mihogaoka, Ibaraki, 567-0047, Japan.
ChemMedChem. 2024 Oct 1;19(19):e202400351. doi: 10.1002/cmdc.202400351. Epub 2024 Aug 21.
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.
本研究考察了六种带有不同连接基团的萘啶基氨基甲酸酯二聚体（NCD）衍生物与 CGG/CGG 三核苷酸的结合特性，CGG/CGG 三核苷酸是与重复扩展疾病相关的非典型 DNA 结构。通过将连接基团的长度从 2 个亚甲基改变为 4 个亚甲基，我们发现配体结合复合物的热稳定性发生了变化，同时保持了一致的 2:1 结合比例。在这些衍生物中，CC23 与母体分子 CC33（NCD）相比表现出更好的结合亲和力。光谱分析表明，连接基团的长度影响 NCD 衍生物的构象平衡。热融温度测量表明 CC23 的热稳定性优于 CC33。这些发现强调了优化后的 NCD 衍生物（如 CC23）作为调节 CGG 重复结构的工具的潜力，为针对重复扩展疾病的治疗策略提供了新的见解。
