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

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 -1,3-diaminocyclohexane (-1,3-DACH) upon formation, stability, and stereochemistry of the (-1,3-DACH)PtG and (-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 -1,3-DACH carrier ligand is the steric bulk of the diamine, which is asymmetric with respect to the Pt-coordination plane. The (-1,3-DACH)Pt(5'GMP) and (-1,3-DACH)Pt(3'GMP) 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 -1,3-DACH derivatives with respect to the analogous -(NH) species could be a consequence of the greater bite angle of the -1,3-DACH carrier ligand with respect to -(NH). Finally, the (-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.