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. 2014 Jan:130:103-11.
doi: 10.1016/j.jinorgbio.2013.10.008. Epub 2013 Oct 14.

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

Kyle T Hufziger  1 , 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
Affiliations

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

Kyle T Hufziger et al. J Inorg Biochem. 2014 Jan.

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 ~0.3Å) 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.

Keywords: Anti-cancer; Light-activated; Polypyridyl; Prodrug; Ruthenium; pH-selective.

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Figures

Figure 1
Figure 1
Proposed mechanism for ligand dissociation upon absorption of light. R = CH3 for Glazer studies and R = OH for studies carried out in this work. * represents the excited state of the complex.
Figure 2
Figure 2
Structures of the protonated and deprotonated forms of the ligands: a) 4,4′-dihydroxy-2,2′-bipyridine (44′bpy(OH)2) and b) 6,6′-dihydroxy-2,2′-bipyridine 66′bpy(OH)2).
Figure 3
Figure 3
Light-induced HeLa cytotoxicity from ruthenium complexes. When HeLa cells were treated with [Ru(bpy)2(66′bpy(OH)2)]2+ or irradiated at 450 nm for 1 hour little cell death occurred. In contrast, when cells were treated with [Ru(bpy)2(66′bpy(OH)2)]2+ and 450 nm irradiation viability dropped to 47%. Controls using [Ru(bpy)2(44′bpy(OH)2)]2+ and [Ru(bpy)3]2+ showed limited cell death, even with irradiation. (−) Indicates no irradiation and (+) indicates irradiation at 450 nm for 1 hour.
Figure 4
Figure 4
Crystal structures of a) [Ru(bpy)2(66′bpy(OH)2)][PF6]2 and b) [Ru(bpy)2(66′bpy(O−)2)]. Counter ions are omitted for clarity.
Figure 5
Figure 5
Cyclic Voltammograms of (black line, top) 1.3 mM [Ru(bpy)2(66′bpy(OH)2)]2+ and (red line, bottom) 1.1 mM [Ru(bpy)2(66′bpy(O−)2)] in acetonitrile with 0.1 M tetrabutylammonium hexafluorophosphate at 25 °C. Tetrabutylammonium hydroxide was used for deprotonation. Scan rates were 200 mV/s. Data reported versus SCE.
Figure 6
Figure 6
UV/Visible spectra of 75 μM [Ru(bpy)2(66′bpy(OH)2)]2+ in aqueous buffers ranging from pH = 1 to pH = 13 at 25 °C. The arrows indicate the directions of absorbance change with increasing pH.
Figure 7
Figure 7
Highest occupied molecular orbitals and relative energies involved in electronic transitions for a) [Ru(bpy)2(66′bpy(OH)2)]2+ and b) [Ru(bpy)2(66′bpy(O−)2)].
Figure 8
Figure 8
UV/Visible spectra of a) protonated 50 μM [Ru(bpy)2(66′bpy(OH)2)]2+ at pH 5 in aqueous media and b) deprotonated 50 μM [Ru(bpy)2(66′bpy(O−)2)] at pH 7.5 in aqueous media irradiated with 450 nm blue light from (red = —) 0 min to (purple = —) 60 min. c) protonated 50 μM [Ru(bpy)2(66′bpy(OH)2)]2+ in acetonitrile irradiated with 450 nm blue light from (red = —) 0 min to (purple = —) 20 min. The vertical arrows indicate the directions of absorbance changes with time. All spectra were collected at 25 °C.
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