title: Protease-activatable organometal-Peptide bioconjugates with enhanced cytotoxicity on cancer cells.
abstract: Over the past years, numerous promising new metalorganic lead structures have been developed exhibiting highly active cytostatic properties. However, the efficiency of such chemotherapeutics in the treatment of tumors is often limited by their low therapeutic index due to their short half-life, lack of tumor selectivity, and associated side effects. Furthermore, the membrane barrier often restricts their cellular uptake by passive diffusion. In this contribution, we describe the synthesis, cellular uptake, and biologic activity of a series of cymantrene-peptide conjugates. Cymantrene CpMn(CO)(3) is a robust organometallic group, which is stable in air and water and easy to functionalize. In this work, some new cymantrene derivatives with different linkers between the half-sandwich complex and the carboxylate group were attached to the cell-penetrating peptide sC18 that should act as a transporter for the metal moiety. All conjugates were characterized for their cytotoxic activity on human breast adenocarcinoma cells (MCF-7) and human colon carcinoma cells (HT-29). We found that bioconjugates bearing two cymantrene groups were more active than the monofunctionalized ones. By the introduction of a cathepsin B cleavage site next to the organometallic group, the biologic activity could be in increased even further. Fluorescence microscopy studies and apoptosis assays gave preliminary hints on the mode of action of these systems.
authors.affiliation: Institut fur Biochemie, Fakultat fur Biowissenschaften, Pharmazie und Psychologie, D-04103 Leipzig, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Splith
authors.forename: Wanning
authors.initials: W
authors.lastname: Hu
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schatzschneider
authors.forename: Ronald
authors.initials: R
authors.lastname: Gust
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
authors.forename: Liliane A
authors.initials: LA
authors.lastname: Onambele
authors.forename: Aram
authors.initials: A
authors.lastname: Prokop
authors.forename: Ines
authors.initials: I
authors.lastname: Neundorf
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008345:Manganese / Q000737:chemistry*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry*; D013054:Spectrophotometry, Atomic; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D010455:Peptides; D008345:Manganese; D010447:Peptide Hydrolases; C044679:manganese cyclopentadienyl tricarbonyl