Molecular Basis of Structure–Activity
Relationships between Salphen Metal Complexes and Human Telomeric
DNA Quadruplexes
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Abstract
The first X-ray crystal structures of nickel(II) and
copper(II)
salphen metal complexes bound to a quadruplex DNA are presented. Two
structures have been determined and show that these salphen–metal
complexes bind to human telomeric quadruplexes by end-stacking, with
the metal in each case almost in line with the potassium ion channel.
Quadruplex and duplex DNA binding is presented for these two and other
related salphen complexes, all with side-chains terminating in pyrrolidino
end-groups and differing patterns of substitution on the salphen core.
The crystal structures are able to provide rationalizations for the
structure–activity data, and in particular for the superior
quadruplex-binding of the nickel complexes compared to that of the
copper-containing ones. The complexes show significant antiproliferative
activity for the compounds in a panel of cancer cell lines. They also
show telomerase inhibitory activity in the telomerase TRAP-LIG assay