Conjugating a groove binder analogue to a styryl-quinolinium scaffold for the light-up detection of duplex and G-Quadruplex DNA with different binding modes

The rational design of novel small molecules, which can target specific DNA sequences or secondary structural DNAs, is one of the most important goals in medicinal chemistry. Also the studies of DNA binding potency which can give fundamental insight into binding mechanisms and specificity are essential. In this paper, a N-methylated quinolinium probe NSQ functionalized with a G-Quadruplex DNA groove binder analogue was designed and synthesized. NSQ was found to express selective and sensitive for "light-up" detection of both G-Quadruplex and duplex DNAs over RNA and other biomolecules. The characteristics of NSQ and its interactions with DNAs were comprehensively evaluated by means of fluorescence, UV-Vis, circular dichroism, FID assay, DFT calculation and molecular docking. NSQ exhibited higher binding affinity to G-Quadruplex than to duplex DNA. Binding mechanism analysis indicated NSQ interacted with G-Quadruplex DNA mainly through end-stacking mode, while bound with duplex DNA into the minor groove of AT-rich regions. Further, NSQ exhibited potent in vitro anti-tumor activity, and to elucidate the cellular applications, confocal cell imaging was carried out and validated its mainly nuclear localization. (c) 2019 Elsevier B.V. All rights reserved.

设计能够靶向特定DNA序列或二级结构DNA的新型小分子是药物化学中最重要的目标之一。对DNA结合效力的研究也至关重要，它能从根本上深入了解结合机制和特异性。在本文中，设计并合成了一种用G - 四链体DNA沟结合剂类似物官能化的N - 甲基化喹啉鎓探针NSQ。发现NSQ对G - 四链体和双链DNA相对于RNA和其他生物分子的“点亮”检测具有选择性和灵敏性。通过荧光、紫外 - 可见光谱、圆二色性、荧光各向异性衰减（FID）测定、密度泛函理论（DFT）计算和分子对接等方法，对NSQ的特性及其与DNA的相互作用进行了综合评估。NSQ对G - 四链体的结合亲和力高于对双链DNA的结合亲和力。结合机制分析表明，NSQ主要通过末端堆积模式与G - 四链体DNA相互作用，而与双链DNA结合在富含AT区域的小沟内。此外，NSQ在体外表现出较强的抗肿瘤活性，为了阐明其细胞应用，进行了共聚焦细胞成像并验证了其主要定位于细胞核。（c）2019爱思唯尔有限公司。保留所有权利。