ja2102423_si_001.pdf (1.79 MB)
Structural Basis for Telomeric G-Quadruplex Targeting by Naphthalene Diimide Ligands
journal contribution
posted on 2012-02-08, 00:00 authored by Gavin
W. Collie, Rossella Promontorio, Sonja M. Hampel, Marialuisa Micco, Stephen Neidle, Gary N. ParkinsonThe folding of the single-stranded 3′ end of the
human telomere
into G-quadruplex arrangements inhibits the overhang from hybridizing
with the RNA template of telomerase and halts telomere maintenance
in cancer cells. The ability to thermally stabilize human telomeric
DNA as a four-stranded G-quadruplex structure by developing selective
small molecule compounds is a therapeutic path to regulating telomerase
activity and thereby selectively inhibit cancer cell growth. The development
of compounds with the necessary selectivity and affinity to target
parallel-stranded G-quadruplex structures has proved particularly
challenging to date, relying heavily upon limited structural data.
We report here on a structure-based approach to the design of quadruplex-binding
ligands to enhance affinity and selectivity for human telomeric DNA.
Crystal structures have been determined of complexes between a 22-mer
intramolecular human telomeric quadruplex and two potent tetra-substituted
naphthalene diimide compounds, functionalized with positively charged
N-methyl-piperazine side-chains. These compounds promote parallel-stranded
quadruplex topology, binding exclusively to the 3′ surface
of each quadruplex. There are significant differences between the
complexes in terms of ligand mobility and in the interactions with
quadruplex grooves. One of the two ligands is markedly less mobile
in the crystal complex and is more quadruplex-stabilizing, forming
multiple electrostatic/hydrogen bond contacts with quadruplex phosphate
groups. The data presented here provides a structural rationale for
the biophysical (effects on quadruplex thermal stabilization) and
biological data (inhibition of proliferation in cancer cell lines
and evidence of in vivo antitumor activity) on compounds
in this series and, thus, for the concept of telomere targeting with
DNA quadruplex-binding small molecules.