Department of Chemistry, Georgia State University, 50 Decatur St., Atlanta, GA 30303, USA.
Molecules. 2013 Nov 4;18(11):13588-607. doi: 10.3390/molecules181113588.
A variety of cyanines provide versatile and sensitive agents acting as DNA stains and sensors and have been structurally modified to bind in the DNA minor groove in a sequence dependent manner. Similarly, we are developing a new set of cyanines that have been designed to achieve highly selective binding to DNA G-quadruplexes with much weaker binding to DNA duplexes. A systematic set of structurally analogous trimethine cyanines has been synthesized and evaluated for quadruplex targeting. The results reveal that elevated quadruplex binding and specificity are highly sensitive to the polymethine chain length, heterocyclic structure and intrinsic charge of the compound. Biophysical experiments show that the compounds display significant selectivity for quadruplex binding with a higher preference for parallel stranded quadruplexes, such as cMYC. NMR studies revealed the primary binding through an end-stacking mode and SPR studies showed the strongest compounds have primary KD values below 100 nM that are nearly 100-fold weaker for duplexes. The high selectivity of these newly designed trimethine cyanines for quadruplexes as well as their ability to discriminate between different quadruplexes are extremely promising features to develop them as novel probes for targeting quadruplexes in vivo.
各种花菁染料提供了多功能和敏感的试剂，可作为 DNA 染料和传感器，其结构已被修饰以序列依赖性方式结合到 DNA 小沟中。同样，我们正在开发一组新的花菁染料，旨在实现与 DNA G-四链体的高度选择性结合，与 DNA 双链的结合则弱得多。已经合成并评估了一套结构类似的三甲川花菁染料，以用于四链体靶向。结果表明，四链体结合的增强和特异性对聚甲川链长、杂环结构和化合物的固有电荷高度敏感。生物物理实验表明，这些化合物对四链体结合具有显著的选择性，对平行链的四链体（如 cMYC）具有更高的偏好。NMR 研究表明主要通过末端堆积模式结合，SPR 研究表明最强的化合物的 KD 值低于 100 nM，而与双链体的结合则弱近 100 倍。这些新设计的三甲川花菁染料对四链体的高选择性以及它们区分不同四链体的能力是将它们开发为体内靶向四链体的新型探针的极具前景的特征。
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