Coordination of hydroxyquinolines to a ruthenium bis-dimethyl-phenanthroline scaffold radically improves potency for potential as antineoplastic agents

David K. Heidary, Brock S. Howerton, Edith C. Glazer

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

A series of ruthenium coordination complexes containing hydroxyquinoline ligands were synthesized that exhibited radically improved potencies up to 86-fold greater than clioquinol, a known cytotoxic compound. The complexes were also >100-fold more potent than clioquinol in a tumor spheroid model, with values similar to currently used chemotherapeutics for the treatment of solid tumors. Cytotoxicity occurs through rapid processes that induce apoptosis but appear to be mediated by cell-cycle independent mechanisms. The ruthenium complexes do not inhibit the proteasome at concentrations relevant for cell death, and contrary to previous reports, clioquinol and other hydroxyquinoline compounds do not act as direct proteasome inhibitors to induce cell death.

Original languageEnglish
Pages (from-to)8936-8946
Number of pages11
JournalJournal of Medicinal Chemistry
Volume57
Issue number21
DOIs
StatePublished - Nov 13 2014

Bibliographical note

Publisher Copyright:
© 2014 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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