Targeting DNA G‐Quadruplexes with Helical Small Molecules

Abstract

We previously identified quinoline-based oligoamide helical foldamers and a trimeric macrocycle as selective ligands of DNA quadruplexes. Their helical structure may permit the targeting of the backbone loops and grooves of G-quadruplexes instead of the G-tetrads. Given the vast array of morphologies G-quadruplex structures can adopt, this may be a way to elicit sequence selective binding. Herein, we describe the design and synthesis of molecules based on macrocyclic and helically folded oligoamides. We tested their ability to interact with the human telomeric G-quadruplex and an array of promoter G-quadruplexes using Förster Resonance Energy Transfer (FRET) melting assay and single molecule FRET. Our results show that they constitute very potent ligands, comparable to the best reported in the literature. Their mode of interaction differs from that of traditional tetrad binders, opening avenues for the development of molecules specific for certain G-quadruplex conformations.

An overview of peptide and peptoid foldamers in medicinal chemistry

“…DNA G-quadruplexes have been attacked with aromatic oligoamides [138]. Considerable interactions were observed between the foldamers and the DNA.…”

Downregulation of oncogenic RAS and c-Myc expression in MOLT-4 leukaemia cells by a salicylaldehyde semicarbazone copper(II) complex

“…However, they have a higher incidence in promoters of oncogenes and telomeres2122. Thus, many studies exploited these G-quadruplexes as rational targets for anticancer therapy23242526. Since complex 1 has been shown to bind selectively to the telomeric quadruplex, we decided to investigate its binding affinity to G-quadruplex forming sequences in selected well-established oncogene promoters and cancer-related genes using Fluorescence Intercalator Displacement (FID) titrations.…”

Single-Molecule Studies of Telomeres and Telomerase

“…These techniques include single-molecule Förster resonance energy transfer (smFRET) (48, 57–59, 64, 74, 77, 80, 81, 110, 124), optical tweezers (26, 27, 54, 98), magnetic tweezers (125, 126), combined smFRET–magnetic tweezers (63), atomic force microscopy (AFM) (66), tethered particle motion assays (18, 62), and protein nanopores (4–6, 102, 119). Each approach comes with its own advantages and drawbacks; however, the most widely employed experiments to date have used smFRET or optical/magnetic tweezers.…”

“…As such, it has remained a major challenge to develop GQ-binding ligands with the high affinity and specificity required for therapeutic applications. Excitingly, a recent smFRET study reported the binding behavior of a novel class of small helical compounds that bind telomere GQ structure through a series of spatially specific backbone interactions, resulting in binding affinities on par with the best GQ-binding ligands to date (74). …”