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Functionalization of osmium arene anticancer complexes with (poly)arginine : effect on cellular uptake, internalization, and cytotoxicity
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Rijt, Sabine H. van, Kostrhunova, Hana, Brabec, V. (Viktor) and Sadler, P. J. (2011) Functionalization of osmium arene anticancer complexes with (poly)arginine : effect on cellular uptake, internalization, and cytotoxicity. Bioconjugate Chemistry, Vol.22 (No.2). pp. 218-226. doi:10.1021/bc100369p ISSN 1043-1802.
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WRAP_vanRijt_459_bc-2010-00369pScript_RevFinal3.pdf - Accepted Version Download (1199Kb) | Preview |
Official URL: http://dx.doi.org/10.1021/bc100369p
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 OsII anticancer complex [(η6-biphenyl)Os(picolinate)Cl] with different arginine (Arg) chain lengths. Complexes conjugated to Arg5 or Arg8 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 Arg8 compared to the Arg1 conjugate. The Arg5 and Arg8 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 Arg8 complex was cytotoxic (IC50 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 Arg5 and Arg8 conjugates. These studies demonstrate the potential for use of cell- and nucleus-penetrating peptides in targeting organometallic arene anticancer complexes.
| Item Type: | Journal Article | ||||
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| Subjects: | Q Science > QD Chemistry R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RS Pharmacy and materia medica |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||
| Library of Congress Subject Headings (LCSH): | Antineoplastic agents -- Design, Osmium, Arginine, Organometallic compounds, Peptide drugs, Peptides -- Synthesis, Cell-mediated cytotoxicity | ||||
| Journal or Publication Title: | Bioconjugate Chemistry | ||||
| Publisher: | American Chemical Society | ||||
| ISSN: | 1043-1802 | ||||
| Official Date: | 2011 | ||||
| Dates: |
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| Volume: | Vol.22 | ||||
| Number: | No.2 | ||||
| Page Range: | pp. 218-226 | ||||
| DOI: | 10.1021/bc100369p | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Restricted or Subscription Access | ||||
| Date of first compliant deposit: | 17 December 2015 | ||||
| Date of first compliant Open Access: | 17 December 2015 | ||||
| Funder: | Engineering and Physical Sciences Research Council (EPSRC), European Research Council (ERC), European Regional Development Fund (ERDF), Advantage West Midlands (AWM), Czech Science Foundation (CSF), Akademie věd České republiky [Academy of Sciences of the Czech Republic] (ASCR) | ||||
| Grant number: | EP/H500308/1 (EPSRC), 247450 (ERC), P301/10/0598 (CSF), M200040901 (ASCR) |
Data sourced from Thomson Reuters' Web of Knowledge
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