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.
Robillard
Marc S
MS
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.
Davies
Neil P
NP
van der Marel
Gijs A
GA
van Boom
Jacques H
JH
Reedijk
Jan
J
Murray
Vincent
V
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D018736:DNA Adducts / Q000737:chemistry; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010957:Plasmids / Q000187:drug effects; D010984:Platinum / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D018736:DNA Adducts; D009942:Organometallic Compounds; D010455:Peptides; D010984:Platinum