Interaction of Polycationic Ni(II)-Salophen Complexes with G‑Quadruplex DNA

A series
of nine Ni­(II) salophen complexes involving one, two,
or three alkyl-imidazolium side-chains was prepared. The lengths of
the side-chains were varied from one to three carbons. The crystal
structure of one complex revealed a square planar geometry of the
nickel ion. Fluorescence resonance energy transfer melting of G-quadruplex
structures in the presence of salophen complex were performed. The
G-quadruplex DNA structures were stabilized in the presence of the
complexes, but a duplex DNA was not. The binding constants of the
complexes for parallel and antiparallel G-quadruplex DNA, as well
as hairpin DNA, were measured by surface plasmon resonance. The compounds
were selective for G-quadruplex DNA, as reflected by equilibrium dissociation
constant KD values in the region 0.1–1
μM for G-quadruplexes and greater than 2 μM for duplex
DNA. Complexes with more and shorter side-chains had the highest binding
constants. The structural basis for the interaction of the complexes
with the human telomeric G-quadruplex DNA was investigated by computational
studies: the aromatic core of the complex stacked over the last tetrad
of the G-quadruplex with peripherical cationic side chains inserted
into opposite grooves. Biochemical studies (telomeric repeat amplification
protocol assays) indicated that the complexes significantly inhibited
telomerase activity with IC50 values as low as 700 nM;
the complexes did not significantly inhibit polymerase activity.