Ruthenium dihydroxybipyridine complexes are tumor activated prodrugs due to low pH and blue light induced ligand release

Kyle T. Hufziger, Fathima Shazna Thowfeik, David J. Charboneau, Ismael Nieto, William G. Dougherty, W. Scott Kassel, Timothy J. Dudley, Edward J. Merino, Elizabeth T. Papish, Jared J. Paul

    Research output: Contribution to journalArticlepeer-review

    32 Scopus citations

    Abstract

    Ruthenium drugs are potent anti-cancer agents, but inducing drug selectivity and enhancing their modest activity remain challenging. Slow Ru ligand loss limits the formation of free sites and subsequent binding to DNA base pairs. Herein, we designed a ligand that rapidly dissociates upon irradiation at low pH. Activation at low pH can lead to cancer selectivity, since many cancer cells have higher metabolism (and thus lower pH) than non-cancerous cells. We have used the pH sensitive ligand, 6,6′-dihydroxy- 2,2′-bipyridine (66′bpy(OH)2), to generate [Ru(bpy) 2(66′(bpy(OH)2)]2+, which contains two acidic hydroxyl groups with pKa1 = 5.26 and pKa2 = 7.27. Irradiation when protonated leads to photo-dissociation of the 66′bpy(OH)2 ligand. An in-depth study of the structural and electronic properties of the complex was carried out using X-ray crystallography, electrochemistry, UV/visible spectroscopy, and computational techniques. Notably, RuN bond lengths in the 66′bpy(OH)2 complex are longer (by ~ 0.3 Å) than in polypyridyl complexes that lack 6 and 6′ substitution. Thus, the longer bond length predisposes the complex for photo-dissociation and leads to the anti-cancer activity. When the complex is deprotonated, the 66′bpy(O-)2 ligand molecular orbitals mix heavily with the ruthenium orbitals, making new mixed metal-ligand orbitals that lead to a higher bond order. We investigated the anti-cancer activities of [Ru(bpy)2(66′(bpy(OH)2)]2+, [Ru(bpy)2(44′(bpy(OH)2)]2+, and [Ru(bpy)3]2+ (44′(bpy(OH)2 = 4,4′-dihydroxy-2,2′-bipyridine) in HeLa cells, which have a relatively low pH. It is found that [Ru(bpy)2(66′(bpy(OH) 2)]2+ is more cytotoxic than the other ruthenium complexes studied. Thus, we have identified a pH sensitive ruthenium scaffold that can be exploited for photo-induced anti-cancer activity.

    Original languageEnglish (US)
    Pages (from-to)103-111
    Number of pages9
    JournalJournal of Inorganic Biochemistry
    Volume130
    Issue number1
    DOIs
    StatePublished - 2014

    Bibliographical note

    Funding Information:
    We would like to thank Nicholas Piro for help with Fig. 4 . JJP thanks the Donors of the American Chemical Society Petroleum Research Fund for partial support of this research and support from the College of Liberal Arts and Sciences at Villanova University is gratefully acknowledged. ETP thanks NSF CAREER for generous financial support. EJM thanks the UC Technology Accelerator for funding as well as an Institutional Clinical and Translational Science Award, NIH/NCR R Grant Number 1UL1RR026314-01 . This article is dedicated to Michael Paul, who lost his battle with cancer early this year. This article is also dedicated to Jessica Bongiovanni, a former undergraduate student in the Papish group, whose diagnosis and death from cancer in 2012 helped inspire this project.

    Keywords

    • Anti-cancer
    • Light-activated
    • Polypyridyl
    • Prodrug
    • Ruthenium
    • pH-selective

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