Steric Determinants of Pt/DNA Interactions and Anticancer Activity
Trevor W. Hambley,1Susan J. Berners-Price,2Murray S. Davies,1Connie I. Diakos,1Hui Meng Er,1Ronald R. Fenton,1Edwina C. H. Ling,1and Evonne M. Rezler1
Received30 Jun 1998
Accepted14 Jul 1998
Abstract
Studies directed at establishing the structural features that control Pt/DNA interactions and
the anticancer activity of Pt drugs are described. [H1,N15]-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.