Impacts of amino acid-linked platinum(II) complexes on DNA structure.

Abstract

The discovery of cisplatin (cisPt) as an effective anticancer agent was a milestone in the health industry. Despite its success, undesired side effects and acquired resistance still limit the therapeutic usefulness of cisPt. Intrastrand adduct formation at consecutive purines and structural modifications of DNA caused by platinum(II) complexes are important factors for antitumor efficacy. In this study, we examined amino acid-linked platinum(II) complexes, collectively referred to as AAPt, for antiproliferative activity and ability to induce DNA bending. The antiproliferative activity of one AAPt complex tested against a prostate cancer cell line was comparable to that of cisPt, whereas only activity of the AAPt complex was lower in a normal human prostate cell line. Various AAPt analogues were examined for impact on the structures of DNAs with four different purine dinucleotide target sites (GG, AG, GA, and AA) and compared to the parent cisPt. The roles of side-chain identity, chirality, and coordination type (e.g., (N,O) vs. (N,N)) of AAPt complexes are discussed with respect to DNA adduct formation and ability to induce DNA bending. Although the AAPt complexes display different nucleotide preferences (A for AAPt vs. G for cisPt), DNAs containing GG-platinum adducts display a greater degree of bending compared to DNAs with AA-platinum adducts.