Design and Synthesis of Heterocyclic Cations for Specific DNA Recognition: From AT-Rich to Mixed-Base-Pair DNA Sequences

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• 作者：Yun Chai ; Ananya Paul ; Michael Rettig ; W. David Wilson ; David W. Boykin
• 刊名：Journal of Organic Chemistry
• 出版年：2014
• 出版时间：February 7, 2014
• 年：2014
• 卷：79
• 期：3
• 页码：852-866
• 全文大小：866K
• ISSN：1520-6904

文摘

The compounds synthesized in this research were designed with the goal of establishing a new paradigm for mixed-base-pair DNA sequence-specific recognition. The design scheme starts with a cell-permeable heterocyclic cation that binds to AT base pair sites in the DNA minor groove. Modifications were introduced in the original compound to include an H-bond accepting group to specifically recognize the G-NH that projects into the minor groove. Therefore, a series of heterocyclic cations substituted with an azabenzimidazole ring has been designed and synthesized for mixed-base-pair DNA recognition. The most successful compound, 12a, had an azabenzimidazole to recognize G and additional modifications for general minor groove interactions. It binds to the DNA site 鈭扐AAGTTT鈥?more strongly than the 鈭扐AATTT鈥?site without GC and indicates the design success. Structural modifications of 12a generally weakened binding. The interactions of the new compound with a variety of DNA sequences with and without GC base pairs were evaluated by thermal melting analysis, circular dichroism, fluorescence emission spectroscopy, surface plasmon resonance, and molecular modeling.