Steric Determinants of Pt/DNA Interactions and Anticancer Activity

Studies directed at establishing the structural features that control Pt/DNA interactions and the anticancer activity of Pt drugs are described. [1H, 15N]-HSQC 2D NMR spectroscopic studies of the reactions of cisplatin with oligonucleotides containing ApG and GpA binding sites reveal dramatic differences in the rates of formation of monofunctional adducts at the two sites. When the reactant is cis-[Pt(NH3)2(OH2)2]2+ no such differences are observed suggesting that outer-sphere interactions between the reactant and the oligonucleotide may play a substantial role in determining the rates. Rates of closure to the bifunctional adducts are similar to those observed for cisplatin. Studies of the adduct profiles formed by sterically bulky and/or optically active complexes reveal that steric interactions play a major role in mediating the binding of Pt(ll) to DNA but that hydrogen bonds play less of a role. In vitro cytotoxic activities for these complexes do not always follow the trends that would be expected on the basis of the adduct profiles

Combined NMR and molecular mechanics study of the isomers formed in the reaction of dichloro(1,4-diazacycloheptane)platinum(II) with the dinucleotide d(GpG)

The two isomeric products that arise from the reaction of [Pt(1,4-diazacycloheptane)Cl₂] with d(GpG) have been separated by HPLC. Using a combination of 2D NMR and molecular mechanics modeling the isomers were found to differ in the orientation of the two and three carbon chains of the hpip ligand with respect to the heads (H8 protons) of the guanine bases.6 page(s