Modification and optimization of the anticancer drug cisplatin is of interest with respect to selective cell targeting and DNA binding efficiency. Attractive approaches contain both, modification of the platinum coordination sphere and design of hybrid molecules of the cisplatin binding moiety including peptide motifs. Peptides with cell penetrating, directing or recognizing properties can be implemented. In this study, positively charged peptide sequences were investigated with the potential of inducing DNA structural distortions caused by charge neutralization of the dsDNA helix. Association of charged peptides is likely to increase the flexibility of the DNA thereby facilitating platinum binding. The synthesis and DNA interaction of five new cisplatin–peptide hybrids with enhanced solubility and potential antitumor activity is presented. Propylenediamine or bisimidazole units were used as bisdentate platinum ligands and were coupled to a peptide sequence in the final elongation step of the solid‐phase peptide synthesis (SPPS). Agarose and polyacrylamide gel electrophoresis, fluorescence intercalation, and thermal UV melting studies, all support the presence of covalently formed platinum DNA adducts in a reaction mediated by the positively charged peptide.

Abstract. Thermodynamic parameters are presented here illustrating the effects caused by the two anticancer active metal complexes cisplatin and oxaliplatin after introduction into four closely related RNA and DNA duplexes. The duplexes used are blunt end, fully complementary 15-mer duplexes with a centrally located either GG-or GNG (here: N = T or U) binding site. For all duplexes, a common trend of reduced melting temperature was observed after platination. Analysis of the thermodynamic parameters for the duplex dissociation reactions showed good correlation between variations in melting temperatures (T m ) and ground state enthalpies (ΔH) in both DNA-and RNA du-

Conjugation of metal complexes with peptide scaffolds possessing high DNA binding affinity has shown to modulate their biological activities and to enhance their interaction with DNA. In this work, a platinum complex/peptide chimera was synthesized based on a model of the Integration Host Factor (IHF), an architectural protein possessing sequence specific DNA binding and bending abilities through its interaction with a minor groove. The model peptide consists of a cyclic unit resembling the minor grove binding subdomain of IHF, a positively charged lysine dendrimer for electrostatic interactions with the DNA phosphate backbone and a flexible glycine linker tethering the two units. A norvaline derived artificial amino acid was designed to contain a dimethylethylenediamine as a bidentate platinum chelating unit, and introduced into the IHF mimicking peptides. The interaction of the chimeric peptides with various DNA sequences was studied by utilizing the following experiments: thermal melting studies, agarose gel electrophoresis for plasmid DNA unwinding experiments, and native and denaturing gel electrophoresis to visualize non-covalent and covalent peptide-DNA adducts, respectively. By incorporation of the platinum metal center within the model peptide mimicking IHF we have attempted to improve its specificity and DNA targeting ability, particularly towards those sequences containing adjacent guanine residues.

The cover picture shows the covalent DNA binding of cisplatin‐like complexes. These molecules were designed as hybrids between the platinum coordination site and positively charged peptides, which involves the covalent binding of one or two nucleobases by cisplatin‐analogous platinum complexes and the bending of double‐stranded DNA initiated by the peptide chain. An optimization of cisplatin‐like anticancer drugs is intended. Binding of cisplatin analogs is facilitated by simultaneous DNA bending. Details are discussed in the article by U. Diederichsen et al. on p. 6161 ff.