Ruthenium dihydroxybipyridine complexes are tumor activated prodrugs due to low pH and blue light induced ligand release
| Autor: | Fathima Shazna Thowfeik, Timothy J. Dudley, Kyle T. Hufziger, David J. Charboneau, Ismael Nieto, W. Scott Kassel, Edward J. Merino, Jared J. Paul, William G. Dougherty, Elizabeth T. Papish |
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| Rok vydání: | 2013 |
| Předmět: |
Light
Organomercury Compounds Stereochemistry chemistry.chemical_element Protonation Antineoplastic Agents Crystallography X-Ray Ligands Biochemistry Medicinal chemistry Ruthenium Article Inorganic Chemistry Bipyridine chemistry.chemical_compound Deprotonation Electrochemistry Humans Molecular orbital Prodrugs Molecular Structure Chemistry Ligand Hydrogen-Ion Concentration Bond order humanities Selectivity HeLa Cells |
| Zdroj: | Journal of inorganic biochemistry. 130 |
| ISSN: | 1873-3344 |
| Popis: | 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 ~0.3A) 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. |
| Databáze: | OpenAIRE |
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