Department of Chemistry, Umeå University, 90187, Umeå, Sweden.
AstraZeneca, Pepparedsleden 1, 431 50, Mölndal, Gothenburg, Sweden.
Chemistry. 2022 Nov 21;28(65):e202202020. doi: 10.1002/chem.202202020. Epub 2022 Sep 19.
This study aims to deepen the knowledge of the current state of rational G4-ligand design through the design and synthesis of a novel set of compounds based on indoles, quinolines, and benzofurans and their comparisons with well-known G4-ligands. This resulted in novel synthetic methods and G4-ligands that bind and stabilize G4 DNA with high selectivity. Furthermore, the study corroborates previous studies on the design of G4-ligands and adds deeper explanations to why a) macrocycles offer advantages in terms of G4-binding and -selectivity, b) molecular pre-organization is of key importance in the development of strong novel binders, c) an electron-deficient aromatic core is essential to engage in strong arene-arene interactions with the G4-surface, and d) aliphatic amines can strengthen interactions indirectly through changing the arene electrostatic nature of the compound. Finally, fundamental physicochemical properties of selected G4-binders are evaluated, underscoring the complexity of aligning the properties required for efficient G4 binding and stabilization with feasible pharmacokinetic properties.
本研究旨在通过设计和合成一系列基于吲哚、喹啉和苯并呋喃的新型化合物，并将其与知名的 G4 配体进行比较，深入了解当前合理 G4-配体设计的现状。这导致了新型的合成方法和 G4 配体的出现，它们能够高度选择性地结合和稳定 G4 DNA。此外，该研究证实了之前关于 G4 配体设计的研究，并对以下原因进行了更深入的解释：a）大环在 G4 结合和选择性方面具有优势；b）分子预组织在开发强新型结合物方面至关重要；c）缺电子芳环核对于与 G4 表面进行强芳环-芳环相互作用至关重要；d）脂肪胺可以通过改变化合物的芳环静电性质间接地增强相互作用。最后，评估了所选 G4 结合物的基本物理化学性质，强调了与可行的药代动力学性质相协调以实现有效 G4 结合和稳定所需的性质的复杂性。
