Rhoden Smith Amy, Iverson Brent L
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, USA.
J Am Chem Soc. 2013 Aug 28;135(34):12783-9. doi: 10.1021/ja4057344. Epub 2013 Aug 20.
The development of small molecules that bind DNA sequence specifically has the potential to modulate gene expression in a general way. One mode of DNA binding is intercalation, or the insertion of molecules between DNA base pairs. We have developed a modular polyintercalation system in which intercalating naphthalene diimide (NDI) units are connected by flexible linkers that alternate between the minor and major grooves of DNA when bound. We recently reported a threading tetraintercalator with a dissociation half-life of 16 days, the longest reported to date, from its preferred 14 bp binding site. Herein, three new tetraintercalator derivatives were synthesized with one, two, and three additional methylene units in the central major groove-binding linker. These molecules displayed dissociation half-lives of 57, 27, and 18 days, respectively, from the 14 bp site. The optimal major groove-binding linker was used in the design of an NDI hexaintercalator that was analyzed by gel-shift assays, DNase I footprinting, and UV-vis spectroscopy. The hexaintercalator bound its entire 22 bp binding site, the longest reported specific binding site for a synthetic, non-nucleic acid-based DNA binding molecule, but with a significantly faster dissociation rate compared to the tetraintercalators.
特异性结合DNA序列的小分子的开发具有以一般方式调节基因表达的潜力。一种DNA结合模式是嵌入，即分子插入DNA碱基对之间。我们开发了一种模块化多嵌入系统，其中嵌入的萘二亚胺（NDI）单元通过柔性接头连接，当结合时，这些接头在DNA的小沟和大沟之间交替。我们最近报道了一种穿线四嵌入剂，从其优选的14 bp结合位点解离的半衰期为16天，这是迄今为止报道的最长半衰期。在此，合成了三种新的四嵌入剂衍生物，在中央大沟结合接头中分别带有一个、两个和三个额外的亚甲基单元。这些分子从14 bp位点解离的半衰期分别为57天、27天和18天。最佳的大沟结合接头用于设计一种NDI六嵌入剂，通过凝胶迁移分析、DNase I足迹分析和紫外可见光谱对其进行了分析。该六嵌入剂结合其整个22 bp结合位点，这是报道的基于合成非核酸的DNA结合分子的最长特异性结合位点，但与四嵌入剂相比，其解离速率明显更快。
