Mitoxantrone and Analogues Bind and Stabilize i-Motif Forming DNA Sequences

Abstract

There are hundreds of ligands which can interact with G-quadruplex DNA, yet very few which target i-motif. To appreciate an understanding between the dynamics between these structures and how they can be affected by intervention with small molecule ligands, more i-motif binding compounds are required. Herein we describe how the drug mitoxantrone can bind, induce folding of and stabilise i-motif forming DNA sequences, even at physiological pH. Additionally, mitoxantrone was found to bind i-motif forming sequences preferentially over double helical DNA. We also describe the stabilisation properties of analogues of mitoxantrone. This offers a new family of ligands with potential for use in experiments into the structure and function of i-motif forming DNA sequences.

i-Motif DNA: structural features and significance to cell biology

“…Several small molecule ligands have been investigated in an attempt to expand the i-motif-specific ligand library such as the type 2 topoisomerase inhibitor mitoxantrone ( 86 ), the para -isomer of the peptidomimetic ligand PBP1 ( 87 ), which leads to the upregulation of BCL2 gene expression, and thiazole orange ( 88 ). Recently, Shu et al.…”

Preferential targeting of i-motifs and G-quadruplexes by small molecules

“… 12 – 17 Although i-motifs are hypothesized to play important roles in gene transcription, 18 – 21 only a few ligands are known to selectively target i-motifs in biological systems. 18 – 22 Furthermore, i-motifs and G-quadruplexes are highly dynamic and they can exist in equilibrium with unfolded DNA under physiological conditions. 12 , 18 – 20 However, little is known about how small molecules can regulate the relative populations of these two dynamic secondary structures.…”

i-Motif-Binding Ligands and Their Effects on the Structure and Biological Functions of i-Motif

“…Electrospray mass spectroscopy confirmed that two molecules of 14 are involved in this interaction, and these molecules bind cooperatively to the i-motif structure. 63) 3.2. Ligands Other than G4-Inspired Interacting Agents 3.2.1.…”