Water soluble, hydrolytically stable derivatives of the antitumor drug titanocene dichloride and binding studies with nucleotides

The rate of hydrolysis of the aromatic rings of Cp₂TiX₂ and the dimethylsubstituted derivatives (MeCp)₂TiX₂ [X=Cl, O₂CCH₂NH₃Cl], in aqueous solutions at pH 2-8 have been studied by ¹H-NMR spectroscopy. Rapid hydrolysis of both the halide and cyclopentadienyl ligands in Cp₂TiX₂ [X=Cl, O₂CCH₂NH₃Cl] occurs to give predominantly insoluble precipitates at pH 7. In contrast, under the same experimental conditions, the predominant species present in aqueous solutions of (MeCp)₂TiX₂ [X=Cl, O₂CCH₂NH₃Cl] at pH 2-8 contains both methycyclopentadienyl rings metal bound. At pH<5, Cp₂TiX₂ and (MeCp)₂TiX₂ form similar complex(es) with purine nucleotides. However, at pH〉5, while stable adducts between nucleotides and Cp₂TiX₂ are not formed, in the presence of 1 equiv. of 5′-dAMP or 5′-dGMP, (MeCp)₂TiX₂ formed complex(es) which were stable for 24 h. These results suggest that formation of stable chelates between (MeCp)₂TiX₂ and nucleic acid constituents in vivo is possible.