ORGANOMETALLIC ANTICANCER AGENTS - THE EFFECT OF THE CENTRAL METAL AND HALIDE LIGANDS ON THE INTERACTION OF METALLOCENE DIHALIDES CP(2)MX(2) WITH NUCLEIC-ACID CONSTITUENTS

The interactions of the metallocene dihalides Cp(2)MX(2) (M = Ti, Mo, Zr, Hf) and Cp(2)TiX(2) (X = F, Cl, Br, I) and the nucleic acid building blocks D-ribose-5'-phosphate, nucleobases, nucleosides, and nucleotides have been studied by H-1 and P-31 NMR spectroscopy. In the series Cp(2)TiX(2) (X = F, Cl, Pr, I), similar H-1 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 Cp(2)Ti((aq))(2+), 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 Cp(2)MCl(2) and DNA subunits. Immediate complexation occurs between nucleotides and the antitumor active metallocenes Cp(2)MX(2) (M = Ti and Mo, 0.25-1.00 equiv). In contrast, fomation of discrete complexes between nucleotides and the biologically inactive metallocenes Cp(2)MCl(2) (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.