Topology Specific Stabilization of Promoter over Telomeric G-Quadruplex DNAs by Bisbenzimidazole Carboxamide Derivatives
Topology Specific Stabilization of Promoter over Telomeric G-Quadruplex DNAs by Bisbenzimidazole Carboxamide Derivatives
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DOI：
10.1021/cb5008597
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发表时间：
2015-03-01
影响因子：
4
通讯作者：
Pradeepkumar, P. I.
中科院分区：
文献类型：
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作者：
Dhamodharan, V.;Harikrishna, S.;Pradeepkumar, P. I.
基因组中存在的各种潜在的G-四链形成序列提供了一个平台，通过稳定分子来调节它们的功能。尽管G-四链体结构呈现出不同的结构拓扑，但G-四联体作为一种常见的结构元素的存在使得拓扑特定配体的设计成为一项艰巨的任务。为了解决这一问题，可以利用四链结构中存在的环和槽的细微结构变化。为此，我们报道了基于吡啶、1，8-萘啶和1，10-邻菲咯啉的双苯并咪唑甲酰胺类化合物的四链稳定剂的设计和合成。所设计的配体特异性地结合并稳定在任何人类端粒四链拓扑(平行、杂交或反平行)和双链DNA上具有平行拓扑的启动子四链。CD熔融研究表明，与端粒和双链DNA(Delta T-m)相比，配体可以赋予c-myc和c-kit启动子四链更高的稳定性(在TM中最高增加21摄氏度)
Various potential G-quadruplex forming sequences present in the genome offer a platform to modulate their function by means of stabilizing molecules. Though G-quadruplex structures exhibit diverse structural topologies, the presence of G-quartets as a common structural element makes the design of topology specific ligands a daunting task. To address this, the subtle structural variations of loops and grooves present in the quadruplex structures can be exploited. To this end, we report the design and synthesis of quadruplex stabilizing agents based on bisbenzimidazole carboxamide derivatives of pyridine, 1,8-naphthyridine, and 1,10-phenanthroline. The designed ligands specifically bind to and stabilize promoter quadruplexes having parallel topology over any of the human telomeric quadruplex topologies (parallel, hybrid, or antiparallel) and duplex DNAs. CD melting studies indicate that ligands could impart higher stabilization to c-MYC and c-KIT promoter quadruplexes (up to 21 degrees C increment in Tm) than telomeric and duplex DNAs (Delta T-m