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 α-diimine ligands (dppz= dipyridophenazine, np = naphtha[2,3-f][1,ω]phenanthroline, CN-np = naphtho[2,3-f][1,10]phenanthroline-9-carbonitrile, CN_2-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]Cl_2 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 α-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 N^2-cyclopropyldeoxyguanosine (d^(Cp)G). Photoexcited [(dppz)Pt(mes')_2]^(2+) is found to be most efficient in this photooxidation, as well as in the photoreduction of N^4-cyclopropylcytidine (^(Cp)C); these modified nucleosides rapidly decompose in a ring-opening reaction upon oxidation or reduction. Photoexcited [(dppz)Pt(mes')_2]Cl_2, 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, ^(Cp)C and ^(Cp)G. These Pt complexes may therefore offer useful reactive tools to compare and contrast directly reductive and oxidative chemistry in double helical DNA.
© 2005 American Chemical Society. Received July 6, 2005. Publication Date (Web): September 29, 2005. We are grateful to the NIH (GM33309) for financial support, the Distinguished Research Award of Prof. Chi-Ming Che at The University of Hong Kong for a postdoctoral fellowship (W.L.), and the American Cancer Society for a postdoctoral fellowship (D.A.V.). We also thank Lawrence M. Henling at the Caltech X-ray Crystallography Laboratory for help with structure determinations, and Dr. Eylon Yavin for helpful discussions. Scheme depicting the synthesis of the ligands, glassy emission spectra, CIF file, and structural parameters of crystal structure of 2·(DMF)_3·(H2O)_2, additional figures of the UV−vis traces of the Pt(II) complexes upon DNA titration, and HPLC traces for photoreactions with ^(Cp)C, d^(Cp)G, and DNAs.
Supplemental Material - ic051124lsi20050706_045920.pdf
Supplemental Material - ic051124lsi20050706_045941.pdf