Macrocyclization of bis-indole quinolines for selective stabilization of G-quadruplex DNA structures,Chemical Science

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Macrocyclization of bis-indole quinolines for selective stabilization of G-quadruplex DNA structures
Chemical Science ( IF 7.6 ) Pub Date : 2020-09-16 , DOI: 10.1039/d0sc03519j
Rabindra Nath Das ₁ , Måns Andréasson ₁ , Rajendra Kumar ₁ , Erik Chorell ₁

Affiliation

The recognition of G-quadruplex (G4) DNA structures as important regulatory elements in biological mechanisms, and the connection between G4s and the evolvement of different diseases, has sparked interest in developing small organic molecules targeting G4s. However, such compounds often lack drug-like properties and selectivity. Here, we describe the design and synthesis of a novel class of macrocyclic bis-indole quinolines based on their non-macrocyclic lead compounds. The effects of the macrocyclization on the ability to interact with G4 DNA structures were investigated using biophysical assays and molecular dynamic simulations. Overall, this revealed compounds with potent abilities to interact with and stabilize G4 structures and a clear selectivity for both G4 DNA over dsDNA and for parallel/hybrid G4 topologies, which could be attributed to the macrocyclic structure. Moreover, we obtained knowledge about the structure–activity relationship of importance for the macrocyclic design and how structural modifications could be made to construct improved macrocyclic compounds. Thus, the macrocyclization of G4 ligands can serve as a basis for the optimization of research tools to study G4 biology and potential therapeutics targeting G4-related diseases.

中文翻译：

双吲哚喹啉大环化选择性稳定 G-四链体 DNA 结构

人们认识到 G 四链体 (G4) DNA 结构是生物机制中的重要调控元件，以及 G4 与不同疾病进化之间的联系，引发了人们对开发针对 G4 的有机小分子的兴趣。然而，此类化合物通常缺乏药物样特性和选择性。在这里，我们描述了基于非大环先导化合物的一类新型大环双吲哚喹啉的设计和合成。使用生物物理测定和分子动力学模拟研究了大环化对与 G4 DNA 结构相互作用的能力的影响。总体而言，这揭示了化合物具有与 G4 结构相互作用和稳定 G4 结构的强大能力，并且对 G4 DNA 相对于 dsDNA 以及对平行/混合 G4 拓扑具有明显的选择性，这可归因于大环结构。此外，我们还获得了有关大环设计的重要构效关系以及如何进行结构修饰以构建改进的大环化合物的知识。因此，G4配体的大环化可以作为优化研究工具的基础，以研究G4生物学和针对G4相关疾病的潜在疗法。

更新日期：2020-10-07

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