Synthesis, cytotoxicity, and insight into the mode of action of Re(CO) 3 thymidine complexes

Mark D. Bartholomä, Anthony R. Vortherms, Shawn Hillier, Birgit Ploier, John Joyal, John Babich, Robert Patrick Doyle, Jon A Zubieta

Research output: Contribution to journalArticle

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Abstract

Nucleoside analogues are extensively used in the treatment of cancer and viral diseases. The antiproliferative properties of organorhenium(I) complexes, however, have been scarcely explored to date. Herein we present the syntheses, characterization, and in vitro evaluation of ReI(CO)3 core complexes of thymidine and uridine. For the binding of the Re I(CO)3 core, a tridentate dipicolylamine metal chelate was introduced at positions C5′, C2′, N3, and C5 with spacers of various lengths. The corresponding organometallic thymidine complexes were fully characterized by IR and NMR spectroscopy and mass spectrometry. Their cytotoxicity was assessed against the A549 lung carcinoma cell line. Toxicity is dependent on the site and mode of conjugation as well as on the nature and the length of the tether. Moderate toxicity was observed for conjugates carrying the rhenium moiety at position C5′ or N3 (IC50=124-160 μm). No toxicity was observed for complexes modified at C2′ or C5. Complex 53, with a dodecylene spacer at C5′, exhibits remarkable toxicity and is more potent than cisplatin, with an IC50 value of 6.0 μm. To the best of our knowledge, this is the first report of the antiproliferative properties of [M(CO)3]+1-nucleoside conjugates. In competitive inhibition experiments with A549 cell lysates and purified recombinant human thymidine kinase 1 (hTK-1), enzyme inhibition was observed for complexes modified at either N3 or C5′, but our results suggest that the toxicity cannot be attributed solely to interaction with hTK-1.

Original languageEnglish (US)
Pages (from-to)1513-1529
Number of pages17
JournalChemMedChem
Volume5
Issue number9
DOIs
StatePublished - Sep 3 2010

Fingerprint

Carbon Monoxide
Cytotoxicity
Thymidine
Toxicity
Nucleosides
Inhibitory Concentration 50
Rhenium
Uridine
Virus Diseases
Cisplatin
Mass Spectrometry
Magnetic Resonance Spectroscopy
Enzyme inhibition
Metals
Carcinoma
Organometallics
Cell Line
Lung
Nuclear magnetic resonance spectroscopy
Mass spectrometry

Keywords

  • A549 cells
  • Cytotoxicity
  • Nucleosides
  • Rhenium
  • Thymidine kinase

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Bartholomä, M. D., Vortherms, A. R., Hillier, S., Ploier, B., Joyal, J., Babich, J., ... Zubieta, J. A. (2010). Synthesis, cytotoxicity, and insight into the mode of action of Re(CO) 3 thymidine complexes. ChemMedChem, 5(9), 1513-1529. https://doi.org/10.1002/cmdc.201000196

Synthesis, cytotoxicity, and insight into the mode of action of Re(CO) 3 thymidine complexes. / Bartholomä, Mark D.; Vortherms, Anthony R.; Hillier, Shawn; Ploier, Birgit; Joyal, John; Babich, John; Doyle, Robert Patrick; Zubieta, Jon A.

In: ChemMedChem, Vol. 5, No. 9, 03.09.2010, p. 1513-1529.

Research output: Contribution to journalArticle

Bartholomä, MD, Vortherms, AR, Hillier, S, Ploier, B, Joyal, J, Babich, J, Doyle, RP & Zubieta, JA 2010, 'Synthesis, cytotoxicity, and insight into the mode of action of Re(CO) 3 thymidine complexes', ChemMedChem, vol. 5, no. 9, pp. 1513-1529. https://doi.org/10.1002/cmdc.201000196
Bartholomä MD, Vortherms AR, Hillier S, Ploier B, Joyal J, Babich J et al. Synthesis, cytotoxicity, and insight into the mode of action of Re(CO) 3 thymidine complexes. ChemMedChem. 2010 Sep 3;5(9):1513-1529. https://doi.org/10.1002/cmdc.201000196
Bartholomä, Mark D. ; Vortherms, Anthony R. ; Hillier, Shawn ; Ploier, Birgit ; Joyal, John ; Babich, John ; Doyle, Robert Patrick ; Zubieta, Jon A. / Synthesis, cytotoxicity, and insight into the mode of action of Re(CO) 3 thymidine complexes. In: ChemMedChem. 2010 ; Vol. 5, No. 9. pp. 1513-1529.
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