Use of neomycin as a structured amino‐containing side chain motif for phenanthroline‐based G‐quadruplex ligands and telomerase inhibitors
Use of neomycin as a structured amino‐containing side chain motif for phenanthroline‐based G‐quadruplex ligands and telomerase inhibitors
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DOI：
10.1111/cbdd.13741
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发表时间：
2020-06
影响因子：
3
通讯作者：
Mandeep Singh;Siwen Wang;Hyun Joo;Zhihan Ye;K. Christison;Ryan M. Hekman;C. Vierra;L. Xue
中科院分区：
文献类型：
--
作者：
Mandeep Singh;Siwen Wang;Hyun Joo;Zhihan Ye;K. Christison;Ryan M. Hekman;C. Vierra;L. Xue
本文报道了邻菲咯啉-新霉素偶联物（7）的合成。化合物7与人端粒G-四链体（G1）的结合亲和力高于其母体化合物（菲咯啉和新霉素），这是通过几项生物物理学研究确定的。化合物7显示出对G-四链体（G4）DNA优于双链体DNA的良好选择性。7与G1的结合主要是焓驱动的，并且7与G1的结合化学计量是如通过ESI质谱测定的紧密结合事件的化学计量。一种合理的结合模式是末端堆积和沟相互作用的协同效应，如对接研究所示。化合物7可以在低微摩尔浓度下抑制人端粒酶活性，这比先前报道的5-取代菲咯啉衍生物更有效。
In this paper, we report the synthesis of a phenanthroline and neomycin conjugate (7). Compound 7 binds to a human telomeric G‐quadruplex (G1) with a higher affinity compared with its parent compounds (phenanthroline and neomycin), which is determined by several biophysical studies. Compound 7 shows good selectivity for G‐quadruplex (G4) DNA over duplex DNA. The binding of 7 with G1 is predominantly enthalpy‐driven, and the binding stoichiometry of 7 with G1 is one for the tight‐binding event as determined by ESI mass spectrometry. A plausible binding mode is a synergistic effect of end‐stacking and groove interactions, as indicated by docking studies. Compound 7 can inhibit human telomerase activity at low micromolar concentrations, which is more potent than previously reported 5‐substituted phenanthroline derivatives.