Department of Regulatory Bioorganic Chemistry, SANKEN (The Institute of Scientific and Industrial Research), Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan.
Department of Life and Environmental Sciences, Faculty of Engineering, Chiba Institute of Technology, Chiba 275-0016, Japan.
J Org Chem. 2022 Jan 7;87(1):340-350. doi: 10.1021/acs.joc.1c02383. Epub 2021 Dec 22.
Small molecules targeting DNA regions with structural fluctuation are an important class of molecule as chemical probes for studying the role of these structures in biological systems and the development of neurological disorders. The molecule we described here, where a three-atom linker connects two 2-amino-1,8-naphthyridines at the C7 position, was found to form stacked structure with protonation of naphthyridine at low pH, and bound to the internal loop consisting of C/CC and T/CC in double-stranded DNA with affinities of 4.8 and 34.4 nM, respectively. Mass spectrometry and isothermal titration calorimetry analyses determined the stoichiometry for the binding as 1:1, and chemical footprinting with permanganate and NMR structural analysis revealed that the T in the T/CC was forced to flip out toward an extrahelical position upon binding. Protonated stacked interacted with two adjacent cytosines through hydrogen bonding and occupied the position in the duplex by flipping out the C or T opposite CC. Finally, this study demonstrated the potential of for binding to the sequences of biological significance with the TG(T/C)CC repeat of the promoter and the telomere repeat CCCTAA.
小分子靶向具有结构波动的 DNA 区域是一类重要的分子，可作为化学探针用于研究这些结构在生物系统中的作用以及神经紊乱的发展。我们在这里描述的分子，其中三个原子的连接体将两个 2-氨基-1,8-萘啶在 C7 位置连接，被发现与萘啶质子化在低 pH 下形成堆积结构，并与双链 DNA 中的 C/CC 和 T/CC 组成的内环结合，亲和力分别为 4.8 和 34.4 nM。质谱和等温热滴定法分析确定结合的化学计量比为 1:1，而高锰酸盐化学足迹和 NMR 结构分析表明，T/CC 中的 T 在外环位置被迫翻转。质子化的堆积结构通过氢键与两个相邻的胞嘧啶相互作用，并通过翻转 CC 对面的 C 或 T 来占据双链中的位置。最后，这项研究证明了 与具有生物学意义的序列结合的潜力，包括 启动子的 TG(T/C)CC 重复序列和端粒重复 CCCTAA。
