Interactions with DNA Models of the Oxaliplatin Analog ( cis -1,3-DACH)PtCl 2 .

It is generally accepted that adjacent guanine residues in DNA are the primary target for platinum antitumor drugs and that differences in the conformations of the Pt-DNA adducts can play a role in their antitumor activity. In this study, we investigated the effect of the carrier ligand cis -1,3-diaminocyclohexane ( cis -1,3-DACH) upon formation, stability, and stereochemistry of the ( cis -1,3-DACH)PtG ₂ and ( cis -1,3-DACH)Pt(d(GpG)) adducts (G = 9-EthlyGuanine, guanosine, 5'- and 3'-guanosine monophosphate; d(GpG) = deoxyguanosil(3'-5')deoxyguanosine). A peculiar feature of the cis -1,3-DACH carrier ligand is the steric bulk of the diamine, which is asymmetric with respect to the Pt-coordination plane. The ( cis -1,3-DACH)Pt(5'GMP) ₂ and ( cis -1,3-DACH)Pt(3'GMP) ₂ adducts show preference for the ΛHT and ∆HT conformations, respectively (HT stands for Head-to-Tail). Moreover, the increased intensity of the circular dichroism signals in the cis -1,3-DACH derivatives with respect to the analogous cis -(NH ₃ ) ₂ species could be a consequence of the greater bite angle of the cis -1,3-DACH carrier ligand with respect to cis -(NH ₃ ) ₂ . Finally, the ( cis -1,3-DACH)Pt(d(GpG)) adduct is present in two isomeric forms, each one giving a pair of H8 resonances linked by a NOE cross peak. The two isomers were formed in comparable amounts and had a dominance of the HH conformer but with some contribution of the ΔHT conformer which is related to the HH conformer by having the 3'-G base flipped with respect to the 5'-G residue.