Studies on the binding of 5-N-methylated quindoline derivative to human telomeric G-quadruplex.
Studies on the binding of 5-N-methylated quindoline derivative to human telomeric G-quadruplex.
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DOI：
10.1016/j.bbrc.2011.02.070
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发表时间：
2011-03
影响因子：
3.1
通讯作者：
Wei Xu;Jia-Heng Tan;Shuo-Bin Chen;Jin-Qiang Hou;Ding Li;Zhishu Huang;L. Gu
中科院分区：
文献类型：
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作者：
Wei Xu;Jia-Heng Tan;Shuo-Bin Chen;Jin-Qiang Hou;Ding Li;Zhishu Huang;L. Gu
喹多啉衍生物作为端粒四链体的配体已经显示出良好的抑制端粒酶的生物活性。在本研究中，我们使用光谱和量热方法研究了喹多啉衍生物（5-甲基-11-（2-吗啉基-乙氨基）-10-H-吲哚-[3，2-B]喹啉-5-碘化鎓，化合物1）与人端粒G-四链体之间的相互作用。等温滴定量热法（ITC）的热力学研究表明，它们的结合过程是温度依赖的和熵-熵共同驱动的。由焓变的温度依赖性实验得到了显着的负热容，这与理论计算结果一致，表明疏水性对分子识别过程有重要贡献。根据紫外可见光谱、ITC、稳态荧光和时间分辨荧光的结果，确定它们的结合模式为两个配体分子堆积在四链体两端的四联体上。这些结果为合理设计和开发喹多啉衍生物作为G-四链体结合配体提供了参考。
Quindoline derivatives as telomeric quadruplex ligands have shown good biological activity for telomerase inhibition. In the present study, we used spectroscopic and calorimetric methods to investigate the interactions between a quindoline derivative (5-methyl-11-(2-morpholino-ethylamino)-10-H-indolo-[3,2-b]quinolin-5-ium iodide, compound 1) and human telomeric G-quadruplex. The thermodynamic studies using isothermal titration calorimetry (ITC) indicated that their binding process was temperature-dependent and enthalpy–entropy co-driven. The significant negative heat capacity was obtained experimentally from the temperature dependence of enthalpy changes, which was consistent with that from theoretical calculation, and all suggesting significant hydrophobic contribution to the molecular recognition process. Based on the results from UV–vis, ITC, steady-state and time-resolved fluorescence, their binding mode was determined as two ligand molecules stacking on the quartets on both ends of the quadruplex. These results shed light on rational design and development of quindoline derivatives as G-quadruplex binding ligands.