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)(2)TiX2 [X = Cl, O2CCH2NH3Cl], in aqueous solutions at pH 2-8 have been studied by H-1-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)(2)TiX2 [X = Cl, O2CCH2NH3Cl] at pH 2-8 contains both methycyclopentadienyl rings metal bound. At pH < 5, Cp2TiX2 and (MeCp)(2)TiX2 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)(2)TiX2 formed complex(es) which were stable for 24 h. These results suggest that formation of stable chelates between (MeCp)(2)TiX2 and nucleic acid constituents in vivo is possible. (C) 1998 Elsevier Science S.A. All rights reserved.