title: Functionalization of osmium arene anticancer complexes with (poly)arginine: effect on cellular uptake, internalization, and cytotoxicity.
abstract: Attaching peptides to metallodrugs may result in improved biological properties of the complexes. The potential use of cell penetrating peptides (CPPs) as cell delivery vectors is attractive, since directed cell uptake of (metallo)drugs remains a major challenge in anticancer drug design. In this work, we report the synthesis of peptide conjugates of the organometallic Os(II) anticancer complex [(η(6)-biphenyl)Os(picolinate)Cl] with different arginine (Arg) chain lengths. Complexes conjugated to Arg(5) or Arg(8) at the 5-position of the picoline ring increase Os uptake into A2780 human ovarian cancer cells by ca. 2× and 10×, respectively, whereas a single Arg had no effect. Furthermore, a 15-fold increase in binding of Os to DNA, a potential target for these complexes, was observed for Arg(8) compared to the Arg(1) conjugate. The Arg(5) and Arg(8) conjugates exhibited fast kinetics of binding to calf thymus DNA and an ability to precipitate DNA at very low concentrations. In serum-free medium, the Arg(8) complex was cytotoxic (IC(50) 33 μM) and appears to be a rare example of a bioactive organometallic peptide conjugate. Experiments on CHO cells deficient in DNA repair suggested that unrepaired DNA damage contributes to the cytotoxicity of the Arg(5) and Arg(8) conjugates. These studies demonstrate the potential for use of cell- and nucleus-penetrating peptides in targeting organometallic arene anticancer complexes.
authors.affiliation: Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, United Kingdom.
authors.forename: Sabine H van
authors.initials: SH
authors.lastname: Rijt
authors.forename: Hana
authors.initials: H
authors.lastname: Kostrhunova
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009992:Osmium / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D010455:Peptides; C015462:polyarginine; D009992:Osmium; D004247:DNA; C427203:calf thymus DNA