Does Ligand Symmetry Play a Role in the Stabilization of DNA G-Quadruplex Host-Guest Complexes?
Anna Maria Almerico.
In efforts to find agents with improved biological activity against cancer cells, recent years have seen an increased
interest in the study of small molecules able to bind the deoxyribonucleic acid (DNA) when it assumes secondary
structures known as G-quadruplexes (G4s) preferring them over the B form. Currently, several compounds reported in literature
have already shown to be good candidates as G4s DNA stabilizers. Even though some specific features for the G4s
affinity are known, such as a π-delocalized system able to stack at the top/end of a G-tetrad and positively charged substituents
able to interact with the grooves, it is not clear yet what kind of structural features affect more the G4 arrangement.
This is mainly due to the structure heterogeneity of both the G4 stabilizer compounds and the DNA G4s isoforms.
In this review, we aim to classify some known G4 binders by analyzing them from a new perspective surprisingly never
approached up to date: the symmetry features. Molecular symmetry could be responsible for the specific binding mode to
the G4- DNA but could also be crucial in determining different isoform affinity. We propose to classify the G4s stabilizers
in five main point group symmetry classes. This classification could be useful to design new ligands able to stabilize a
specific G-quadruplex isoform, in order to increase the selectivity of new potential anticancer G-quadruplex targeting
drugs, a goal yet highly sought by researchers.
Keywords: Anticancer drugs, DNA G-quadruplex, host-guest complexes, ligand symmetry, point group symmetry.
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