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Bimolecular excited-state proton-coupled electron transfer (PCET*) was observed for reaction of the triplet MLCT state of [(dpab)₂Ru(4,4′-dhbpy)]²⁺ (dpab = 4,4′-di(n-propyl)amido-2,2′-bipyridine, 4,4′-dhbpy = 4,4′-dihydroxy-2,2′-bipyridine) with N-methyl-4,4′-bipyridinium (MQ⁺) and N-benzyl-4,4′-bipyridinium (BMQ⁺) in dry acetonitrile solutions. The PCET* reaction products, the oxidized and deprotonated Ru complex, and the reduced protonated MQ+ can be distinguished from the excited state electron transfer (ET*) and the excited state proton transfer (PT*) products by the difference in the visible absorption spectrum of the species emerging from the encounter complex. The observed behavior differs from that of reaction of the MLCT state of [(bpy)₂Ru(4,4′-dhbpy)]²⁺ (bpy = 2,2′-bipyridine) with MQ⁺, where initial ET* is followed by diffusion-limited proton transfer from the coordinated 4,4′-dhbpy to MQ⁰. The difference in observed behavior can be rationalized based on changes in the free energies of ET* and PT*. Substitution of bpy with dpab results in the ET* process becoming significantly more endergonic and the PT* reaction becoming somewhat less endergonic.

Cancer cells utilize high basal levels of reactive oxygen species (ROS) to create conditions that facilitate rapid cell proliferation. This creates an Achilles heel, making cancer cells more susceptible than normal cells to cell death caused by a bolus dose of ROS. The common food preservative, tert-butylhydroquinone (tBHQ), generates ROS intracellularly via redox cycling. Herein, we tested the effect of combining tBHQ with a manganese porphyrin, compounds originally designed as super oxide dismutase mimetics which can also generate ROS intracellularly in cancer cells and have radioprotective effects under clinical investigation. We find that the combination treatment of tBHQ and the commercially available Mn(III) tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP) is much more toxic to leukemic Jurkat lymphocytes than either compound alone, e.g., lowering the LC50 of tBHQ by two orders of magnitude to 1.0 μM. MnTMPyP acts as a catalyst to oxidize tBHQ, shown by UV-Vis spectroscopy. Flow cytometry analysis revealed that while 5 μM tBHQ decreases cell viability by less than 10% in 4 hours, the combination of 5 μM tBHQ and 12 μM MnTMPyP decreases viability by 60%, primarily by apoptosis. A clinically tested manganese porphyrin, Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin (Mn2BuOE), was as effective and more potent than MnTMPyP. We evaluated the cancer-targeting effect of tBHQ and Mn2BuOE in both Jurkats and a matched primary CD4 T cell line. The combination treatment induced significantly more cell death in cancerous Jurkats than in the normal CD4 cells. With the promise Mn2BuOE shows in pre-clinical studies and early clinical trials as adjunctive to radiotherapy, and the wide use of tBHQ in prepared food, the results shown here in CD4 cells suggest their combination may be an effective therapy to target cancer cells. Citation Format: Joseph P. LaMorte, Sandra Tamarin, Margueritte Lalo, David J. Sokoloski, Jared J. Paul, Aimee L. Eggler. The cancer targeting synergy of tertbutylhydroquinone and a manganese porphyrin. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4787.

The development of metal complexes with pH dependent ligands could lead to useful design principles in altering catalysis. We have synthesized the complex [Ru(bpy)(bpy(OH)2)2]2+ (bpy=2,2′-bipyridine, bpy(OH)2=4,4′-dihydroxy-2,2′-bipyridine) to better understand how the hydroxyl groups influence the electronic and structural properties of the complex as a function of protonation state. Both experimental and computational methods were utilized to study the complex in the protonated and deprotonated state. The most notable difference observed by X-ray diffraction studies, as well as by computational structural analysis, is the shortening of the modified ligand’s C–O bond length upon deprotonation due to increasing double bond character by resonance. Cyclic voltammetry studies of the complex revealed a 0.96V decrease in RuIII/II potential upon deprotonation. Only one ligand redox wave is observed when deprotonated, assigned to the unmodified bpy ligand. The absorption spectrum of protonated [Ru(bpy)(bpy(OH)2)2]2+ is similar to that of [Ru(bpy)3]2+ with typical metal to ligand charge transfer bands at approximately 460nm. Upon deprotonation, the absorption spectrum shifts dramatically, exhibiting a 4504cm−1 red shift from λmax=468nm to λmax=593nm in acetonitrile. Computational studies indicate that the bpy(O−)2 ligand’s orbitals heavily mix with the Ru d-orbitals, leading to mixed metal–ligand to ligand charge transfer transitions. Luminescence studies reveal absolute quenching of the excited state upon deprotonation in accordance with the energy gap law. These studies alongside results from the previously studied [Ru(bpy)2(bpy(OH)2)]2+ and [Ru(bpy(OH)2)3]2+ complexes, provide useful insight into the impact of increasing electron donation to the metal center.

The development of metal complexes with pH dependent ligands could lead to useful design principles in altering catalysis. We have synthesized the complex [Ru(bpy)(bpy(OH)2)2]2+ (bpy = 2,2′-bipyridine, bpy(OH)2 = 4,4′-dihydroxy-2,2′-bipyridine) to better understand how the hydroxyl groups influence the electronic and structural properties of the complex as a function of protonation state. Both experimental and computational methods were utilized to study the complex in the protonated and deprotonated state. The most notable difference observed by X-ray diffraction studies, as well as by computational structural analysis, is the shortening of the modified ligand’s C–O bond length upon deprotonation due to increasing double bond character by resonance. Cyclic voltammetry studies of the complex revealed a 0.96 V decrease in RuIII/II potential upon deprotonation. Only one ligand redox wave is observed when deprotonated, assigned to the unmodified bpy ligand. The absorption spectrum of protonated [Ru(bpy)(bpy(OH)2)2]2+ is similar to that of [Ru(bpy)3]2+ with typical metal to ligand charge transfer bands at approximately 460 nm. Upon deprotonation, the absorption spectrum shifts dramatically, exhibiting a 4504 cm−1 red shift from λmax = 468 nm to λmax = 593 nm in acetonitrile. Computational studies indicate that the bpy(O−)2 ligand’s orbitals heavily mix with the Ru d-orbitals, leading to mixed metal–ligand to ligand charge transfer transitions. Luminescence studies reveal absolute quenching of the excited state upon deprotonation in accordance with the energy gap law. These studies alongside results from the previously studied [Ru(bpy)2(bpy(OH)2)]2+ and [Ru(bpy(OH)2)3]2+ complexes, provide useful insight into the impact of increasing electron donation to the metal center.

The particle acidity of secondary organic aerosol (SOA) created from ozonolysis of α-pinene in the presence of acidic inorganic seed aerosols was investigated using an indoor Teflon film chamber. Colorimetry integrated with a reflectance UV-Visible spectrometer was used for the first time to dynamically measure the aerosol acidity over time. An external calibration curve was produced based on the correlation between the proton mass (ng) collected on the filter, which was impregnated with metanil yellow, and the absorbance of the reflectance UV-Visible spectra for the protonated and the unprotonated metanil yellow on the filter. Using this calibration curve, the particle acidity of the submicron acidic sulfate aerosol coated with SOA was measured from the reflectance UV-Visible spectra of filter samples. The colorimetric analysis requires a short sampling time (less than 2 m) for SOA studies using the laboratory Teflon film chamber and eliminates extraction of the filter sample with water. Results show tha...

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.

Excited-state proton-transfer dynamics between 7-hydroxy-4-(trifluoromethyl)coumarin and 1-methylimidazole base in toluene were studied using ultrafast pump–probe and time-resolved emission methods. Charge-transfer excitation of the hydroxycoumarin shifts electron density from the hydroxyl group to the carbonyl, resulting in an excited state where proton transfer to the base is highly favored. In addition to its the photoacid characteristics, the shift in the hydroxycoumarin electronic distribution gives it characteristics of a photobase as well. The result is a tautomerization process occurring on the picosecond time scale in which the 1-methylimidazole base acts as a proton-transfer shuttle from the hydroxyl group to the carbonyl.