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Macrocyclization of Bis-Indole Quinolines for Selective Stabilization of G-quadruplex DNA Structures

Abstract

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 the interest to develop 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 design. 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 for the study of G4 biology and as potential therapeutics targeting G4-related diseases.

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Supplementary files

Article information


Submitted
25 Jun 2020
Accepted
15 Sep 2020
First published
16 Sep 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020, Accepted Manuscript
Article type
Edge Article

Macrocyclization of Bis-Indole Quinolines for Selective Stabilization of G-quadruplex DNA Structures

R. Das, M. Andréasson, R. Kumar and E. Chorell, Chem. Sci., 2020, Accepted Manuscript , DOI: 10.1039/D0SC03519J

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