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

Abstract

Macrocyclization improves the selectivity, affinity, and ability to stabilize G4 DNA structures.

Quadruplex DNA-guided ligand selection from dynamic combinatorial libraries of acylhydrazones

“…42 Performed at a constant temperature, this method is suitable to characterise of strong binders with K d values down to few nM, and is gaining increasing popularity in Please do not adjust margins Please do not adjust margins characterizing ligand-G4 interactions. 13,43 The results of titrations, performed with four fluorophore-labelled G4-DNA oligonucleotides belonging to different folding topology groups (Pu24T and myc22: parallel, 25TAG: hybrid, 22CTA: antiparallel, sequences: cf. Table S1 †), confirmed the G4binding properties of novel derivatives (Table 1, titration curves: Fig.…”

Using Macrocyclic G‐Quadruplex Ligands to Decipher the Interactions Between Small Molecules and G‐Quadruplex DNA

“…To overcome some of the challenges associated with targeting G4 DNA, macrocyclic compounds can offer a beneficial starting point in terms of ligand design [30] . Macrocycles have been shown to enable design of compounds with good oral pharmacokinetic (PK) properties when operating in the challenging chemical space termed “beyond rule of 5” [31] .…”

“…In our previous work, we have shown that macrocyclization can indeed be a powerful tool to generate compounds that strongly bind and stabilise G4 structures while still showing complete selectivity towards G4 DNA over double‐stranded DNA [30] . Here, we have further explored this approach and used it as an example in combination with well‐known ligands to delineate key properties for efficient G4 ligand design.…”

“…[14,29] To overcome some of the challenges associated with targeting G4 DNA, macrocyclic compounds can offer a beneficial starting point in terms of ligand design. [30] Macrocycles have been shown to enable design of compounds with good oral pharmacokinetic (PK) properties when operating in the challenging chemical space termed "beyond rule of 5". [31] In other words, they allow for properties such as a molecular weight > 500 Da, the number of rotatable bonds > 10, a polar surface area (PSA) > 140 Å [2] , and still retain a good bioavailability in contrary to classical drug-like molecules.…”

Preferential Recognition of Human Telomeric G-Quadruplex DNA by a Red-Emissive Molecular Rotor

“…Human telomeres are single-stranded overhangs of a hexanucleotide (TTAGGG) repeat unit, which are known to adopt antiparallel G-quadruplex conformation in solution . This structure is polymorphic, and subtle changes in the base composition, position, salt type, ionic strength, and hydration are known to modulate its conformational ensembles. − Many efforts have been made over the past two decades to discover G-quadruplex targeting ligands of both synthetic and natural origins. − A general picture that has emerged from these studies indicates that G-quadruplex binding molecules usually contain extended π-conjugation over a well-spread flat surface, such as those found in fused aromatic rings or macrocyclic systems − containing additional interaction centers to enhance binding.…”