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Synthesis and DNA Interaction of Platinum Complex/Peptide Chimera as Potential Drug Candidates

Damian, Mariana S.; Hedman, Hanna LU ; Elmroth, Sofi LU and Diederichsen, Ulf (2010) In European Journal of Organic Chemistry p.6161-6170
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
DNA structures, Antitumor agents, Peptides, Cisplatin, Platinum, DNA, damage
in
European Journal of Organic Chemistry
issue
32
pages
6161 - 6170
publisher
John Wiley & Sons
external identifiers
  • wos:000285041500006
  • scopus:78249268216
ISSN
1434-193X
DOI
10.1002/ejoc.201000677
language
English
LU publication?
yes
id
ea495c2e-9f25-43d1-9cad-5549d9947c73 (old id 1773493)
date added to LUP
2011-02-01 15:49:54
date last changed
2018-05-29 10:21:19
@article{ea495c2e-9f25-43d1-9cad-5549d9947c73,
  abstract     = {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.},
  author       = {Damian, Mariana S. and Hedman, Hanna and Elmroth, Sofi and Diederichsen, Ulf},
  issn         = {1434-193X},
  keyword      = {DNA structures,Antitumor agents,Peptides,Cisplatin,Platinum,DNA,damage},
  language     = {eng},
  number       = {32},
  pages        = {6161--6170},
  publisher    = {John Wiley & Sons},
  series       = {European Journal of Organic Chemistry},
  title        = {Synthesis and DNA Interaction of Platinum Complex/Peptide Chimera as Potential Drug Candidates},
  url          = {http://dx.doi.org/10.1002/ejoc.201000677},
  year         = {2010},
}