Influence of the metal center and linker on the intracellular distribution and biological activity of organometal-peptide conjugates.

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  • Author(s): Hu W;Hu W; Splith K; Neundorf I; Merz K; Schatzschneider U
  • Source:
    Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry [J Biol Inorg Chem] 2012 Feb; Vol. 17 (2), pp. 175-85. Date of Electronic Publication: 2011 Sep 07.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Springer Country of Publication: Germany NLM ID: 9616326 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-1327 (Electronic) Linking ISSN: 09498257 NLM ISO Abbreviation: J Biol Inorg Chem Subsets: MEDLINE
    • Publication Information:
      Original Publication: Berlin : Springer, c1996-
    • Subject Terms:
      Antineoplastic Agents/*chemistry ; Antineoplastic Agents/*pharmacokinetics ; Cell-Penetrating Peptides/*chemistry ; Cell-Penetrating Peptides/*pharmacokinetics ; Organometallic Compounds/*chemistry ; Organometallic Compounds/*pharmacokinetics; Amino Acid Sequence ; Antineoplastic Agents/pharmacology ; Breast Neoplasms/drug therapy ; Cell Line, Tumor ; Cell Membrane Permeability ; Cell-Penetrating Peptides/pharmacology ; Female ; Humans ; Manganese/chemistry ; Manganese/pharmacokinetics ; Manganese/pharmacology ; Models, Molecular ; Molecular Sequence Data ; Organometallic Compounds/pharmacology ; Rhenium/chemistry ; Rhenium/pharmacokinetics ; Rhenium/pharmacology ; Solid-Phase Synthesis Techniques
    • Abstract:
      Organometallic complexes conjugated to cell-penetrating peptides (CPPs) are promising systems for diagnostic imaging and therapeutic applications in human medicine. Recently, we reported on the synthesis of cymantrene(CpMn(CO)(3))-CPP conjugates with biological activity on different cancer cell lines. However, the precise mechanism of cytotoxicity remained elusive in these studies. To investigate the role of the metal center and the linker between the CpM(CO)(3) moiety and the peptide, a number of derivatives with manganese replaced by rhenium and the keto linker originally used substituted by a methylene group were prepared and fully characterized by (1)H NMR spectroscopy, infrared spectroscopy, electrospray ionization mass spectrometry, and elemental analysis as well as X-ray structure determination. The organometal-peptide conjugates as well as carboxyfluorescein-labeled derivatives thereof were prepared by solid-phase peptide synthesis, purified by high-performance liquid chromatography, and analyzed by mass spectrometry. Fluorescence microscopy studies of MCF-7 human breast cancer cells revealed an efficient cellular uptake and pronounced nuclear localization of the bioconjugates with the methylene linker compared with systems with the keto group. In addition, the latter also showed a higher cytotoxicity. In contrast, the variation of the metal center from manganese to rhenium had a negligible effect. The structure-activity relationships determined in the present work will aid in the further tuning of the biological activity of organometal-peptide conjugates.
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    • Accession Number:
      0 (Antineoplastic Agents)
      0 (Cell-Penetrating Peptides)
      0 (Organometallic Compounds)
      42Z2K6ZL8P (Manganese)
      7440-15-5 (Rhenium)
    • Publication Date:
      Date Created: 20110908 Date Completed: 20120521 Latest Revision: 20211020
    • Publication Date:
      20221213
    • Accession Number:
      10.1007/s00775-011-0840-5
    • Accession Number:
      21898043