Threading Polyintercalators with Extremely Slow Dissociation Rates and Extended DNA Binding Sites

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• 作者：Amy Rhoden Smith ; Brent L. Iverson
• 刊名：Journal of the American Chemical Society
• 出版年：2013
• 出版时间：August 28, 2013
• 年：2013
• 卷：135
• 期：34
• 页码：12783-12789
• 全文大小：373K
• 年卷期：v.135,no.34(August 28, 2013)
• ISSN：1520-5126

文摘

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鈥搗is 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.