Department of Food, Environmental and Nutritional Sciences (DeFENS), University of Milan, Via Celoria 2, 20133 Milan, Italy.
Department of Chemistry, University of Milan, 20133 Milan, Italy.
Molecules. 2022 Apr 27;27(9):2791. doi: 10.3390/molecules27092791.
G-quadruplexes are secondary structures originating from nucleic acid regions rich in guanines, which are well known for their involvement in gene transcription and regulation and DNA damage repair. In recent studies from our group, kynurenic acid (KYNA) derivative was synthesized and found to share the structural features typical of G-quadruplex binders. Herein, structural modifications were conducted on this scaffold in order to assist the binding with a G-quadruplex, by introducing charged hydrophilic groups. The antiproliferative activity of the new analogues was evaluated on an IGROV-1 human ovarian cancer cell line, and the most active compound, compound was analyzed with NMR spectrometry in order to investigate its binding mode with DNA. The results indicated that a weak, non-specific interaction was set with duplex nucleotides; on the other hand, titration in the presence of a G-quadruplex from human telomere d(TTAGGGT) showed a stable, although not strong, interaction at the 3'-end of the nucleotidic sequence, efficiently assisted by salt bridges between the quaternary nitrogen and the external phosphate groups. Overall, this work can be considered a platform for the development of a new class of potential G-quadruplex stabilizing molecules, confirming the crucial role of a planar system and the ability of charged nitrogen-containing groups to facilitate the binding to G-quadruplex grooves and loops.
四链体是一种二级结构，起源于富含鸟嘌呤的核酸区域，其已知功能包括参与基因转录和调控以及 DNA 损伤修复。在我们小组最近的研究中，合成了色氨酸酮酸（KYNA）衍生物，并发现其具有与 G-四链体结合剂相似的结构特征。在此基础上，对该支架进行了结构修饰，通过引入带电荷的亲水性基团来辅助与 G-四链体的结合。对新类似物在 IGROV-1 人卵巢癌细胞系中的抗增殖活性进行了评价，并通过 NMR 光谱对最活跃的化合物进行了分析，以研究其与 DNA 的结合模式。结果表明，与双链核苷酸之间存在弱的、非特异性相互作用；另一方面，在存在来自人端粒 d（TTAGGG）的 G-四链体的情况下进行滴定，显示在核苷酸序列的 3'-末端存在稳定的（尽管不是强的）相互作用，这是由季铵氮和外部磷酸基团之间的盐桥有效地辅助的。总的来说，这项工作可以被认为是开发一类新型潜在 G-四链体稳定分子的平台，证实了平面系统的关键作用以及含氮带电荷基团促进与 G-四链体沟槽和环结合的能力。
