title: Influence of the metal center and linker on the intracellular distribution and biological activity of organometal-peptide conjugates.
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.
authors: Institut für Anorganische Chemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.
authors: Wanning
authors: W
authors: Hu
authors: Katrin
authors: K
authors: Splith
authors: Ines
authors: I
authors: Neundorf
authors: Klaus
authors: K
authors: Merz
authors: Ulrich
authors: U
authors: Schatzschneider
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability; D057846:Cell-Penetrating Peptides / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D006801:Humans; D008345:Manganese / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009942:Organometallic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D012211:Rhenium / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D060327:Solid-Phase Synthesis Techniques
chemical_list: D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D009942:Organometallic Compounds; D008345:Manganese; D012211:Rhenium