NEW ANTITUMOR PLATINUM COMPOUNDS LINKED TO AMINO PHOSPHONIC-ACIDS WHICH LOSE THE PHOSPHONATE AND TERTIARY AMINE LIGAND UPON BINDING TO NUCLEIC-ACIDS

The interaction of the antitumor active platinum phosphonato complexes [cis-Pt(NH3)2(ntmp)] and [Pt(R,S-dach)(ntmp)] (ntmp = nitrilotris(methylenephosphonic acid), dach = diaminocyclohexane) with (oligo)nucleotides has been investigated using H-1 NMR and P-31 NMR spectroscopy. For both complexes the formation of GN7,GN7 chelates is observed, together with the release of ntmp. First, the platinum-phosphonate bond is broken, probably by direct attack of the first G-base. The coordination of the second base is accompanied by breakage of the bond between the Pt(II) ion and the tertiary amine ligand, a very unusual observation, as N-donor ligands generally act as nonleaving groups in platinum antitumor chemistry. For this type of platinum antitumor complexes of which the strucural formula seems to violate the classical structure-activity relationships, both pH and nonleaving amine group do influence the rate of the reaction with (oligo)nucleotides significantly.