Organometallic anticancer agents: the effect of the central metal and halide ligands on the interaction of metallocene dihalides Cp2MX2 with nucleic acid constituents.

The interactions of the metallocene dihalides Cp2MX2 (M = Ti, Mo, Zr, Hf) and Cp2TiX2 (X = F, Cl, Br, I) and the nucleic acid building blocks D-ribose-5'-phosphate, nucleobases, nucleosides, and nucleotides have been studied by 1H and 31P NMR spectroscopy. In the series Cp2TiX2 (X = F, Cl, Br, I), similar 1H NMR spectra were obtained in titrations of each metallocene with the four nucleotides. The spectra are consistent with dissociation of the halide ligands to give Cp2-Ti2+(aq), which coordinates to nucleobase (N) and phosphate (O) binding sites. The metal center (Ti, Mo, Zr, Hf) strongly influences the nature and extent of interactions between metallocene dichlorides Cp2MCl2 and DNA subunits. Immediate complexation occurs between nucleotides and the antitumor active metallocenes Cp2MX2 (M = Ti and Mo, 0.25-1.0 equiv). In contrast, formation of discrete complexes between nucleotides and the biologically inactive metallocenes Cp2MCl2 (M = Hf, Zr, 0.25-1.00) is not observed, and instead hydrolysis of the Cp rings to give free cyclopentadiene is the major reaction pathway. The complexes formed between titanocene dihalides and nucleotides are stable for hours at pH 2-5; at higher pH the binding is significantly weakened. These results are in agreement with the observed antitumor properties of the metallocene dihalides and provide support for the hypothesis that DNA-metallocene interactions are a major determinant in the antitumor properties of this class of compounds.