Synthesis and Investigation of the G-Quadruplex Binding Properties of Kynurenic Acid Derivatives with a Dihydroimidazoquinoline-3,5-dione Core

G-quadruplexes are secondary structures originating from nucleic acid regions rich in
guanines, which are well known for their involvement in gene transcription and regulation and
DNA damage repair. In recent studies from our group, kynurenic acid (KYNA) derivative 1 was
synthesized and found to share the structural features typical of G-quadruplex binders. Herein,
structural modifications were conducted on this scaffold in order to assist the binding with a G
quadruplex, by introducing charged hydrophilic groups. The antiproliferative activity of the new
analogues was evaluated on an IGROV-1 human ovarian cancer cell line, and the most active
compound, compound 9, was analyzed with NMR spectrometry in order to investigate its binding
mode with DNA. The results indicated that a weak, non-specific interaction was set with duplex
nucleotides; on the other hand, titration in the presence of a G-quadruplex from human telomere
d(TTAGGGT)4 showed a stable, although not strong, interaction at the 3-end of the nucleotidic 4
sequence, efficiently assisted by salt bridges between the quaternary nitrogen and the external
phosphate groups. Overall, this work can be considered a platform for the development of a new
class of potential G-quadruplex stabilizing molecules, confirming the crucial role of a planar system
and the ability of charged nitrogen-containing groups to facilitate the binding to G-quadruplex
grooves and loops.