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

• Published in: Inorganic chemistry 2006-09, Vol.45 (18), p.7144-7159
• Main Authors: Li, Lei, Murthy, Narasimha N, Telser, Joshua, Zakharov, Lev. N, Yap, Glenn P. A, Rheingold, Arnold L, Karlin, Kenneth D, Rokita, Steven E
• Format: Article
• Language: English
• Subjects: 3-Mercaptopropionic Acid - chemistry; Copper - chemistry; Crystallography, X-Ray; DNA - chemistry; DNA, Single-Stranded - chemistry; Electrochemistry; Electron Spin Resonance Spectroscopy; Free Radical Scavengers - chemistry; Guanine - chemistry; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Oxidation-Reduction; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/ic0605930

A dinuclear copper(II) complex [CuII 2(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 [ZnII 2(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 [CuII 2(PD‘O-)(G)]3+ complex (8) and dizinc analogue [ZnII 2(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.