Reductive and Oxidative DNA Damage by Photoactive Platinum(II) Intercalators

Several photoactive platinum R-diimine intercalators have been prepared to develop new probes of DNA oxidation and reduction chemistry. Five water-soluble bis(mes′)Pt(II) complexes (mes′ ) N,N,N,3,5-pentamethylaniline) with various aromatic R-diimine ligands (dppz ) dipyridophenazine, np ) naphtha[2,3-f][1,ω]phenanthroline, CN-np ) naphtho[2,3-f][1,10]phenanthroline-9-carbonitrile, CN2-np ) naphtho[2,3-f][1,10]phenanthroline-9,14-dicarbonitrile, and bp ) benzo-[f][1,10]phenanthroline) were synthesized. The complex [(np)Pt(mes′)2]Cl2 was also characterized by X-ray crystallography, and the crystal structure shows that the ortho-methyl groups of the mes′ ligands conveniently block substitution at the vacant sites of platinum without overlapping with the intercalating R-diimine ligand. The Pt(II) complexes were found to have excited-state oxidation and reduction potentials of −0.6 to −1.0 and 1.0 to 1.5 V versus NHE, respectively, making them potent photoreductants as well as photooxidants. Many of the complexes are found to promote the photooxidation of N2-cyclopropyldeoxyguanosine (dCpG). Photoexcited [(dppz)Pt(mes′)2]2+ is found to be most efficient in this photooxidation, as well as in the photoreduction of N4-cyclopropylcytidine (CpC); these modified nucleosides rapidly decompose in a ring-opening reaction upon oxidation or reduction. Photoexcited [(dppz)Pt(mes′)2]Cl2, upon intercalation into the DNA π stack, is found, in addition, to promote reductive and oxidative damage within the DNA duplex, as is also probed using the kinetically fast electron and hole traps, CpC and CpG. These Pt complexes may therefore offer useful reactive tools to compare and contrast directly reductive and oxidative chemistry in double helical DNA.