Interactions with DNA Models of the Oxaliplatin Analog ( cis -1,3-DACH)PtCl 2 .
Alessandra BarbanenteParide PapadiaAnna Maria Di CosolaConcetta PacificoGiovanni NatileJames D HoescheleNicola MargiottaPublished in: International journal of molecular sciences (2024)
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.