Mixed-metal ruthenium-platinum polyazine supermolecules: Synthesis, characterization and exploration of DNA binding

The goal of this research was to design, prepare and study a new class of supermolecules coupling ruthenium and platinum, which would display covalent binding to DNA. These supermolecules were modular in design, facilitating the use of coordination chemistry to vary individual components within the design. Drawing upon the well-established efficacy of cis-diamminedichloroplatinum(II) (cisplatin) and the DNA-binding properties of select ruthenium polyazine complexes, the approach was to bind the cis-PtIICl 2 active site of cisplatin to ruthenium light absorbers using the dpq and dpb bridging ligands (where dpq = 2,3-bis(2-pyridyl)quinoxaline, dpb = 2,3-bis(2-pyridyl)benzoquinoxaline). These complexes are potentially bifunctional, capable of DNA intercalation through the bridging ligand and covalent binding to DNA through the cis-PtCl2 site. The use of the ruthenium(II) center allows these complexes to be cationic and provides for enhanced water-solubility relative to the neutral cisplatin. These ruthenium centers function as chromophores leading to efficient light absorption by the Ru-Pt systems throughout the ultraviolet & visible region of the electromagnetic spectrum.; Synthetic methods were developed to prepare the mixed-metal, bimetallic complexes [(bpy)2Ru(BL)PtCl2](CF3SO 3)2 and [(phen)2Ru(BL)PtCl2](CF 3SO3)2 (where bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline) in high purity and good overall yields. These new systems were characterized using electronic absorption spectroscopy, electrochemistry, and FAB-MS. The DNA-binding ability of these complexes was probed by reaction with linearized plasmid DNA and subsequent analysis by native and denaturing gel electrophoresis. The known DNA binders, cisplatin and trans-{lcub}[PtCl(NH 3)2]2(mu-H2N(CH2) 6NH2){rcub}2+ (1,1/t,t), were examined under equivalent conditions and used as positive controls. Native gel electrophoresis was used to show that these complexes strongly bind DNA, retarding the migration of DNA through the gel in a fashion inversely proportional to the ratio of DNA base pairs (bp) to metal complex (mc). Equivalent studies using the ruthenium monometallic synthons, [(bpy)2Ru(BL)](CF3SO3) 2 and [(phen)2Ru(BL)](CF3SO3) 2, had no effect on DNA migration, suggesting that the Ru-Pt complexes bind to DNA through the PtCl2 site. Analysis by denaturing gel electrophoresis determined that the Ru-Pt complexes bind to DNA in a fashion similar to cisplatin, forming primarily intrastrand adducts. However, these systems also appear to form interstrand adducts at a 10-fold lower metal concentration than cisplatin. (Abstract shortened by UMI.)...