Fudickar Werner, Linker Torsten
Department of Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam, Germany.
Department of Chemistry, University of Potsdam, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam, Germany.
Bioorg Med Chem. 2020 Apr 15;28(8):115432. doi: 10.1016/j.bmc.2020.115432. Epub 2020 Mar 16.
In the search of new DNA groove binding agents a series of substituted 9,10-methylpyridiniumanthracenes have been synthesized and their interactions with DNA have been studied by UV/vis absorption, CD and fluorescence spectroscopy. A minor groove binding mode is confirmed by DNA melting studies, strong CD effects, the dependence of the binding affinity on ionic strength, and the differentiation between AT and GC base pairs. No binding occurs to GC sequences. Binding constants to calf thymus DNA (ct-DNA) and poly(dA:dT) in the range between 1 × 10 and 3 × 10 M have been determined. The binding strength decreases with the size of substituents attached at the anthracene site. Variation of the substitution pattern of the charged groups shows that methyl groups in meta position cause slightly stronger binding than methyl groups in para position. In contrast, with these groups in ortho position, no binding interaction has been observed. The strongest binding is achieved with an expansion of the peripheral heterocycle from pyridine to quinoline. Molecular modeling reveals the pivotal role of the substitution pattern: Anthracenes with para and meta pyridines align along the minor grooves. On the other hand, the ortho derivative adopts no groove-alignment.
在寻找新型DNA沟槽结合剂的过程中，合成了一系列取代的9,10 - 甲基吡啶蒽，并通过紫外/可见吸收光谱、圆二色光谱和荧光光谱研究了它们与DNA的相互作用。DNA熔解研究、强烈的圆二色效应、结合亲和力对离子强度的依赖性以及AT和GC碱基对之间的差异证实了其小沟结合模式。与GC序列不发生结合。已测定了与小牛胸腺DNA（ct - DNA）和聚（dA:dT）的结合常数，范围在1×10至3×10 M之间。结合强度随着蒽位点连接的取代基尺寸增大而降低。带电基团取代模式的变化表明，间位甲基的结合略强于对位甲基。相比之下，邻位有这些基团时，未观察到结合相互作用。将外围杂环从吡啶扩展到喹啉可实现最强结合。分子建模揭示了取代模式的关键作用：对位和间位吡啶的蒽沿着小沟排列。另一方面，邻位衍生物不采用沟内排列。
