The interaction of peptide-tethered platinum(II) complexes with DNA

The sequence specificity and intensity of DNA damage induced by six peptide-tethered platinum complexes was compared to cisplatin and Pt(en)Cl-2. DNA damage was investigated in pUC19 plasmid and in intact HeLa cells, and quantitatively analyzed using a Taq DNA polymerase/linear amplification assay. The DNA sequence specificity of the peptide-platinum compounds was found to be very similar to cisplatin and Pt(en)Cl-2. with runs of consecutive guanines being the most intensely damaged sites. The observed reactivity of the peptide-platinum complexes towards plasmid DNA was lower compared to cisplatin and Pt(en)Cl-2, with the glycine-tethered complex 3 and the phenylalanine-tethered complex 4 producing the highest relative damage intensity, followed by (in decreasing order) lysine-tethered (5), arginine-tethered (6), serine-tethered (7) and glutamate-tethered (8). The reactivity of the peptide-platinum complexes towards cellular DNA was also lower compared to cisplatin and Pt(en)Cl-2. For most investigated complexes, the relative damage intensities were found to be similar in cells compared to plasmid DNA, but were greatly reduced for 3 and 4. The lysine-tethered 5 complex produced the highest DNA damage intensity in cells followed by (in decreasing order) 6, 7, 3, 4 and 8. (C) 2003 Elsevier Inc. All rights reserved.