Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy.
Department of Pharmaceutical Sciences, University of Piemonte Orientale, Largo Donegani 2/3, 28100 Novara, Italy.
Int J Mol Sci. 2021 Nov 4;22(21):11959. doi: 10.3390/ijms222111959.
Besides the well-known double-helical conformation, DNA is capable of folding into various noncanonical arrangements, such as G-quadruplexes (G4s) and i-motifs (iMs), whose occurrence in gene promoters, replication origins, and telomeres highlights the breadth of biological processes that they might regulate. Particularly, previous studies have reported that G4 and iM structures may play different roles in controlling gene transcription. Anyway, molecular tools able to simultaneously stabilize/destabilize those structures are still needed to shed light on what happens at the biological level. Herein, a multicomponent reaction and a click chemistry functionalization were combined to generate a set of 31 bis-triazolyl-pyridine derivatives which were initially screened by circular dichroism for their ability to interact with different G4 and/or iM DNAs and to affect the thermal stability of these structures. All the compounds were then clustered through multivariate data analysis, based on such capability. The most promising compounds were subjected to a further biophysical and biological characterization, leading to the identification of two molecules simultaneously able to stabilize G4s and destabilize iMs, both in vitro and in living cells.
除了众所周知的双螺旋构象外，DNA 还能够折叠成各种非典型构象，如 G-四链体（G4s）和 i- 基序（iMs），它们在基因启动子、复制起点和端粒中的存在突出了它们可能调节的广泛生物过程。特别是，先前的研究报告称，G4 和 iM 结构可能在控制基因转录中发挥不同的作用。无论如何，仍然需要能够同时稳定/去稳定这些结构的分子工具，以揭示在生物学水平上发生的情况。在此，将多组分反应和点击化学功能化相结合，生成了一组 31 个双三唑基吡啶衍生物，最初通过圆二色性筛选这些化合物与不同的 G4 和/或 iM DNA 相互作用的能力，并影响这些结构的热稳定性。然后，根据这种能力，通过多元数据分析对所有化合物进行聚类。最有前途的化合物进一步进行了生物物理和生物学特性分析，确定了两种能够同时稳定 G4s 和去稳定 iMs 的分子，无论是在体外还是在活细胞中。
