Targeted Guanine Oxidation by a Dinuclear Copper(II) Complex at Single Stranded/Double Stranded DNA Junctions

A dinuclear copper(II) complex [CuII2(PD‘O-)(H2O)2](ClO4)3 (5) with terminal Cu(II)−H2O moieties and a Cu···Cu
distance of 4.13 Å (X-ray structure) has been synthesized and characterized by EPR spectroscopy (ferromagnetic
coupling observed) and cyclic voltammetry. Dizinc(II) and mononuclear copper(II) analogues [ZnII2(PD‘O-)(H2O)2]3+
(7) and [CuII(mPD‘OH)(H2O)]2+ (6), respectively, have also been synthesized and structurally characterized. Reacting
5/MPA/O2 (MPA = 3-mercaptopropionic acid) with DNA leads to a highly specific oxidation of guanine (G) at a
junction between single- and double-stranded DNA. Mass spectrometric analysis of the major products indicates
a gain of +18 and +34 amu relative to initial DNA strands. The most efficient reaction requires G at the first and
second unpaired positions of each strand extending from the junction. Less reaction is observed for analogous
targets in which the G cluster is farther from the junction or contains less than four Gs. Consistent with our previous
systems, the multinuclear copper center is required for selective reaction; mononuclear complex 6 is not effective.
Hydrogen peroxide as a substitute for MPA/O2 also does not lead to activity. Structural analysis of a [CuII2(PD‘O-)(G)]3+
complex (8) and dizinc analogue [ZnII2(PD‘O-)(G)](ClO4)3 (9) (G = guanosine) reveals coordination of the G O6
and N7 atoms with the two copper (or zinc) centers and suggests that copper−G coordination likely plays a role
in recognition of the DNA target. The Cu2−O2 intermediate responsible for guanine oxidation appears to be different
from that responsible for direct-strand scission induced by other multinuclear copper complexes; the likely course
of reaction is discussed.