Pyrophosphate-bridged complexes with picomolar toxicity

Oluwatayo F. Ikotun, Elizabeth M. Higbee, Wayne Ouellette, Robert P. Doyle

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Recently, we have observed the emergence of a new series of pyrophosphate-bridged coordination complexes. Such complexes have been prepared by overcoming the ready hydrolysis of the pyrophosphate moiety. To date, no exploration has been conducted on the cytotoxicity of such complexes. Three pyrophosphate-bridged complexes, namely {[Ni(phen)2]2(μ-P2O7)}·27H2O, {[Cu(phen)(H2O)]2(μ-P2O7)}·8H2O and {[Co(phen)2]2(μ-P2O7)}·6MeOH, (where phen is 1,10′-phenanthroline) were chosen for their comparative structural similarities and suitable aqueous solubility. Cytotoxicity studies in the adriamycin-resistant ovarian cancer cell line A2780/AD demonstrated highly significant efficacy, with values as low as 160 pM for the cobalt complex at 72 h. The underlying mechanism for such exceptional toxicity is investigated focusing on DNA interactions, topoisomerase I enzyme inhibition and oxidative stress (followed by intracellular glutathione levels). The role of hydrolysis in uptake and toxicity is also explored (followed by electronic absorption spectroscopy, 31P NMR, and confocal microscopy) and the complexes are compared to cisplatin controls. Overall a clear picture of the extraordinary toxicity emerged. The results demonstrate a new class of prodrugs with significant potential for future development for the treatment of drug-resistant cancer cell lines.

Original languageEnglish (US)
Pages (from-to)1254-1264
Number of pages11
JournalJournal of Inorganic Biochemistry
Volume103
Issue number9
DOIs
StatePublished - Sep 1 2009

Keywords

  • Co complexes
  • Confocal microscopy
  • Cu complexes
  • Cytotoxicity
  • DNA interactions
  • Ni complexes
  • Oxidative stress
  • Pyrophosphate

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

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