Mechanistic Investigation into DNA Modification by a RuII ,RhIII Bimetallic Complex.

Despite significant progress in the treatment of cancer, there remains an urgent need for more effective therapies that also have less impact on patient wellbeing. Photodynamic therapy employs targeted light activation of a photosensitizer in selected tissues, thereby reducing off-target toxicity. Our group previously reported a RuII ,RhIII bimetallic architecture that displays multifunctional covalent photomodification of DNA in the therapeutic window in an oxygen-independent manner, features that are essential for treating deep and hypoxic tumors. Herein, we explore the mechanism by which a new analogue, [(phen)2 Ru(dpp)Rh(phen)Cl2 ]3+ , or RuII -RhIII , interacts with DNA. We established that RuII -RhIII exhibits "light switch" behavior in the presence of DNA, undergoing strong electrostatic interactions that might involve groove binding. Furthermore, these noncovalent interactions play a major role in the covalent photobinding and photocleavage of DNA, which occur according to an oxygen-independent mechanism. Polymerase chain reaction (PCR) revealed that covalent modification of DNA by RuII -RhIII , especially photobinding, is critical to inhibiting amplification, thus suggesting that the complex could exert its toxic activity by interfering with DNA replication in cells. This new structural motif, with phenanthroline at all three terminal ligand positions, has a number of properties that are promising for the continued refinement of photodynamic-therapy strategies.

Tetra- and Heptametallic Ru(II),Rh(III) Supramolecular Hydrogen Production Photocatalysts.

Supramolecular mixed metal complexes combining the trimetallic chromophore [{(bpy)2Ru(dpp)}2Ru(dpp)]6+ (Ru3) with [Rh(bpy)Cl2]+ or [RhCl2]+ catalytic fragments to form [{(bpy)2Ru(dpp)}2Ru(dpp)RhCl2(bpy)](PF6)7 (Ru3Rh) or [{(bpy)2Ru(dpp)}2Ru(dpp)]2RhCl2(PF6)13 (Ru3RhRu3) (bpy = 2,2'-bipyridine and dpp = 2,3-bis(2-pyridyl)pyrazine) catalyze the photochemical reduction of protons to H2. This first example of a heptametallic Ru,Rh photocatalyst produces over 300 turnovers of H2 upon photolysis of a solution of acetonitrile, water, triflic acid, and N,N-dimethylaniline as an electron donor. In contrast, the tetrametallic Ru3Rh produces only 40 turnovers of H2 due to differences in the excited state properties and nature of the catalysts upon reduction as ascertained from electrochemical data, transient absorption spectroscopy, and flash-quench experiments. While the lowest unoccupied molecular orbital of Ru3Rh is localized on a bridging ligand, it is Rh-centered in Ru3RhRu3 facilitating electron collection at Rh in the excited state and reductively quenched state. The Ru → Rh charge separated state of Ru3RhRu3 is endergonic with respect to the emissive Ru → dpp 3MLCT excited and cannot be formed by static electron transfer quenching of the 3MLCT state. Instead, a mechanism of subnanosecond charge separation from high lying states is proposed. Multiple reductions of Ru3 and Ru3Rh using sodium amalgam were carried out to compare UV-vis absorption spectra of reduced species and to evaluate the stability of highly reduced complexes. The Ru3 and Ru3Rh can be reduced by 10 and 13 electrons, respectively, to final states with all bridging ligands doubly reduced and all bpy ligands singly reduced.

Probing Co-Assembly of Supramolecular Photocatalysts and Polyelectrolytes Using Isothermal Titration Calorimetry.

The creation of renewable fuels to replace dwindling fossil energy resources is one of the greatest challenges facing the scientific community. Generating H2 fuel from water is a carbon-neutral strategy that demonstrates great promise. Photocatalysts of the molecular architecture [{(TL)2Ru(BL)}2RhX2]5+ (BL = bridging ligand, TL = terminal ligand, X = halide) catalyze the formation of H2 in deoxygenated organic solvents but are limited by poor performance in air-saturated aqueous solutions. Addition of the water-soluble polyelectrolyte poly(sodium 4-styrenesulfonate) (PSS) was recently shown as being a promising new strategy to increase efficiency and stability of H2 evolving photocatalysts in air-saturated aqueous solutions. Herein we investigate intermolecular interactions between Ru,Rh,Ru photocatalysts and water-soluble polyelectrolytes using isothermal titration calorimetry (ITC). ITC studies provide insight into the thermodynamic forces that drive assembly of PSS-photocatalyst aggregates and give new evidence for the intermolecular forces that lead to increased photocatalytic efficiency.

Exploring the activity of a polyazine bridged Ru(ii)-Pt(ii) supramolecule in F98 rat malignant glioma cells.

The mixed-metal supramolecular complex, [(Ph2phen)2Ru(dpp)PtCl2]2+, displays significant DNA modification, cell growth inhibition, and toxicity towards F98 malignant glioma cells following visible light irradiation. The design of this complex affords superior cellular uptake and antiproliferative activity compared to the classic chemotherapeutic agent, cisplatin.

A new hydrophilic supramolecular photocatalyst for the production of H2 in aerobic aqueous solutions.

Addition of sulfonated terminal ligands into a Ru,Rh,Ru photocatalyst has a significant impact on the excited-state properties of the complex. The hydrophilic photocatalyst demonstrates increased solubility and H2 production in aqueous solutions. H2 production is observed under aerobic conditions for the new complex, a stark contrast to the hydrophobic analog in organic solvents.

A new class of Ru(II) polyazine agents with potential for photodynamic therapy.

Appending anthracene units to [(bpy)2Ru(dpp)](2+) results in Ru(II) agents that exhibit dynamic photoreactivity towards DNA and protein. [(Anthbpy)(bpy)Ru(dpp)](2+) and [(Anthbpy)2Ru(dpp)](2+) are the first metal-organic Ru(II) agent with dpp ligands shown to photomodify DNA in the presence or absence of oxygen, while also binding protein in an oxygen-dependent manner.

Enhancement of Solar Fuel Production Schemes by Using a Ru,Rh,Ru Supramolecular Photocatalyst Containing Hydroxide Labile Ligands.

Polyazine-bridged Ru(II)Rh(III)Ru(II) complexes with two halide ligands, Cl(-) or Br(-), bound to the catalytically active Rh center are efficient single-component photocatalysts for H2O reduction to H2 fuel, with the coordination environment on Rh impacting photocatalysis. Herein reported is a new, halide-free Ru(II)Rh(III)Ru(II) photocatalyst with OH(-) ligands bound to Rh, further enhancing the photocatalytic reactivity of the structural motif. H2 production experiments using the photocatalyst bearing OH(-) ligands at Rh relative to the analogues bearing halides at Rh in solvents of varying polarity (DMF, CH3CN, and H2O) suggest that ion pairing with halides deactivates photocatalyst function, representing an exciting phenomenon to exploit in the development of catalysts for solar H2 production schemes.

Increased Water Reduction Efficiency of Polyelectrolyte-Bound Trimetallic [Ru,Rh,Ru] Photocatalysts in Air-Saturated Aqueous Solutions.

The groundbreaking use of polyelectrolytes to increase the efficiency of supramolecular photocatalysts in solar H2 production schemes under aqueous aerobic conditions is reported. Supramolecular photocatalysts of the architecture [{(TL)2 Ru(BL)}2 RhX2 ](5+) (BL=bridging ligand, TL=terminal ligand, X=halide) demonstrate high efficiencies in deoxygenated organic solvents but do not function in air-saturated aqueous solution because of the quenching of the metal-to-ligand charge-transfer (MLCT) excited state under these conditions. The new photocatalytic system incorporates poly(4-styrenesulfonate) (PSS) into aqueous solutions containing [{(bpy)2 Ru(dpp)}2 RhCl2 ](5+) (bpy=2,2'-bipyridine, dpp=2,3-bis(2-pyridyl)pyrazine). PSS has a profound impact on the photocatalyst efficiency, increasing H2 production over three times that of deoxygenated aqueous solutions alone. H2 photocatalysis proceeds even under aerobic conditions for PSS-containing solutions, an exciting consequence for solar hydrogen-production research.

A new Ru,Ru,Pt supramolecular architecture for photocatalytic H2 production.

A new polyazine-bridged RuRuPt trimetallic supramolecular architecture emulates the photophysical properties of the previously reported Ru2RuPt tetrametallic architecture that exhibits photoinduced charge separation. The RuRuPt complexes are more robust H2O reduction photocatalysts with enhanced stability compared to the Ru2RuPt tetrametallic analogues.

Electrocatalytic H2 Evolution by Supramolecular Ru(II)-Rh(III)-Ru(II) Complexes: Importance of Ligands as Electron Reservoirs and Speciation upon Reduction.

The supramolecular water reduction photocatalysts [{(Ph2phen)2Ru(dpp)}2RhX2](PF6)5 (Ph2phen = 4,7-diphenyl-1,10-phenanthroline, dpp =2,3-bis(2-pyridyl)pyrazine X = Cl, Br) are efficient electrocatalysts for the reduction of CF3SO3H, CF3CO2H, and CH3CO2H to H2 in DMF or DMF/H2O mixtures. The onset of catalytic current occurs at -0.82 V versus Ag/AgCl for CF3SO3H, -0.90 V for CF3CO2H, and -1.1 V for CH3CO2H with overpotentials of 0.61, 0.45, and 0.10 V, respectively. In each case, catalysis is triggered by the first dpp ligand reduction implicating the dpp as an electron reservoir in catalysis. A new species with Epc ∼ -0.75 V was observed in the presence of stoichiometric amounts of strong acid, and its identity is proposed as the Rh(H)(III/II) redox couple. H2 was produced in 72-85% Faradaic yields and 95-116 turnovers after 2 h and 435 turnovers after 10 h of bulk electrolysis. The identities of Rh(I) species upon reduction have been studied. In contrast to the expected dissociation of halides in the Rh(I) state, the halide loss depends on solvent and water content. In dry CH3CN, in which Cl(-) is poorly solvated, a [Ru] complex dissociates and [(Ph2phen)2Ru(dpp)Rh(I)Cl2](+) and [(Ph2phen)2Ru(dpp)](2+) are formed. In contrast, for X = Br(-), the major product of reduction is the intact trimetallic Rh(I) complex [{(Ph2phen)2Ru(dpp)}2Rh(I)](5+). Chloride loss in CH3CN is facilitated by addition of 3 M H2O. In DMF, the reduced species is [{(Ph2phen)2Ru(dpp)}2Rh(I)](5+) regardless of X = Cl(-) or Br(-).

A new Ru(II)Rh(III) bimetallic with a single Rh-Cl bond as a supramolecular photocatalyst for proton reduction.

A new Ru(II)Rh(III) structural motif [(bpy)2Ru(dpp)RhCl(tpy)](4+) with one halide on the Rh(III) center demonstrates light-driven proton reduction ability, establishing that two halide ligands are not mandatory despite all prior systems containing a cis-RhCl2 catalytic site. This new design provides a novel approach to modulate Rh(III) redox behavior and catalytic activity with insight into catalytic intermediates.

Tuning the Photophysical Properties of Ru(II) Monometallic and Ru(II),Rh(III) Bimetallic Supramolecular Complexes by Selective Ligand Deuteration.

A series of three new complexes of the design [(TL)2Ru(BL)](2+), two new complexes of the design [(TL)2Ru(BL)Ru(TL)2](4+), and three new complexes of the design [(TL)2Ru(BL)RhCl2(TL)](3+) (TL = bpy or d8-bpy; BL = dpp or d10-dpp; TL = terminal ligand; BL = bridging ligand; bpy = 2,2'-bipyridine; dpp = 2,3-bis(2-pyridyl)pyrazine) were synthesized and the (1)H NMR spectroscopy, electrochemistry, electronic absorbance spectroscopy, and photophysical properties studied. Incorporation of deuterated ligands into the molecular architecture simplifies the (1)H NMR spectra, allowing for complete (1)H assignment of [(d8-bpy)2Ru(dpp)](PF6)2 and partial assignment of [(bpy)2Ru(d10-dpp)](PF6)2. The electrochemistry for the deuterated and nondeuterated species showed nearly identical redox properties. Electronic absorption spectroscopy of the deuterated and nondeuterated complexes are superimposable with the lowest energy transition being Ru(dπ) → BL(π*) charge transfer in nature (BL = dpp or d10-dpp). Ligand deuteration impacts the excited-state properties with an observed increase in the quantum yield of emission (Φ(em)) and excited-state lifetime (τ) of the Ru(dπ) → d10-dpp(π*) triplet metal-to-ligand charge transfer ((3)MLCT) excited state when dpp is deuterated, and a decrease in the rate constant for nonradiative decay (knr). Choice of ligand deuteration between bpy and dpp strongly impacts the observed photophysical properties with BL = d10-dpp complexes showing an enhanced Φ(em) and τ, providing further support that the lowest electronic excited state populated via UV or visible excitation is the photoactive Ru(dπ) → dpp(π*) CT excited state. The Ru(II),Rh(III) complex incorporating the deuterated BL shows increased hydrogen production compared to the variants incorporating the protiated BL, while demonstrating identical dynamic quenching behaviors in the presence of sacrificial electron donor.

Nonchromophoric halide ligand variation in polyazine-bridged Ru(II),Rh(III) bimetallic supramolecules offering new insight into photocatalytic hydrogen production from water.

The new bimetallic complex [(Ph2phen)2Ru(dpp)RhBr2(Ph2phen)](PF6)3 (1) (Ph2phen = 4,7-diphenyl-1,10-phenanthroline; dpp = 2,3-bis(2-pyridyl)pyrazine) was synthesized and characterized to compare with the Cl(-) analogue [(Ph2phen)2Ru(dpp)RhCl2(Ph2phen)](PF6)3 (2) in an effort to better understand the role of halide coordination at the Rh metal center in solar H2 production schemes. Electrochemical properties of complex 1 display a reversible Ru(II/III) oxidation, and cathodic scans indicate multiple electrochemical mechanisms exist to reduce Rh(III) by two electrons to Rh(I) followed by a quasi-reversible dpp(0/-) ligand reduction. The weaker σ-donating ability of Br(-) vs Cl(-) impacts the cathodic electrochemistry and provides insight into photocatalytic function by these bimetallic supramolecules. Complexes 1 and 2 exhibit identical light-absorbing properties with UV absorption dominated by intraligand (IL) π → π* transitions and visible absorption by metal-to-ligand charge transfer (MLCT) transitions to include a lowest energy Ru(dπ) → dpp(π*) (1)MLCT transition (λ(abs) = 514 nm; ε = 16 000 M(-1) cm(-1)). The relatively short-lived, weakly emissive Ru(dπ) → dpp(π*) (3)MLCT excited state (τ = 46 ns) for both bimetallic complexes is attributed to intramolecular electron transfer from the (3)MLCT excited state to populate a low-energy Ru(dπ) → Rh(dσ*) triplet metal-to-metal charge transfer ((3)MMCT) excited state that allows photoinitiated electron collection. Complex 1 outperforms the related Cl(-) bimetallic analogue 2 as a H2 photocatalyst despite identical light-absorbing and excited-state properties. Additional H2 experiments with added halide suggest ion pairing plays a role in catalyst deactivation and provides new insight into observed differences in H2 production upon halide variation in Ru(II),Rh(III) supramolecular architectures.

Mechanistic insight into the electronic influences imposed by substituent variation in polyazine-bridged ruthenium(II)/rhodium(III) supramolecules.

Unusual and unprecedented multipathway electrochemical mechanisms for a new class of supramolecular Ru/Rh bimetallic photocatalysts have been uncovered. The near isoenergetic Rh(dσ*) and bridging ligand(π*) molecular orbitals and a rate of halide loss that occurs on the cyclic voltammetry timescale provide a series of closely related complexes which display four different electrochemical mechanisms. A single complex displays two concurrent electrochemical pathways in marked contrast to all previously studied cis-[Rh(NN)(2)X(2)] motifs.

New supramolecular structural motif coupling a ruthenium(II) polyazine light absorber to a rhodium(I) center.

Two new complexes, [(bpy)2Ru(dpp)Rh(I)(COD)](PF6)3 and [(Me2bpy)2Ru(dpp)Rh(I)(COD)](PF6)2(BF4) (bpy = 2,2'-bipyridine, Me2bpy = 4,4'-dimethyl-2,2'-bipyridine, dpp = 2,3-bis(2-pyridyl)pyrazine, and COD = 1,5-cyclooctadiene), representing a new Ru(II),Rh(I) structural motif, have been prepared and characterized by mass spectrometry, (1)H NMR spectroscopy, electrochemistry, electronic absorption spectroscopy, and emission spectroscopy. These two complexes represent a new type of supramolecular complex with a [(TL)2Ru(dpp)](2+) (TL = terminal ligand) light absorber (LA) coupled to a Rh(I) center and are models for Ru(II),Rh(I) intermediates in the photochemical reduction of water using dpp-bridged Ru(II),Rh(III) photocatalysts. Electrochemical study reveals overlapping reversible Ru(II/III) and irreversible Rh(I/II/III) oxidations and a quasi-reversible dpp(0/-) reduction, demonstrating that the lowest unoccupied molecular orbital (LUMO) is dpp(π*) based. The COD ligand is sterically bulky, displaying steric repulsions between hydrogen atoms on the alkene of COD and dpp about the square planar Rh(I) center. An interesting reactivity occurs in coordinating solvents such as CH3CN, where Rh(I) substitution leads to an equilibrium between the Ru(II),Rh(I) bimetallic and [(TL)2Ru(dpp)](2+) and [Rh(I)(COD)(solvent)2](+) monometallic species. The electronic absorption spectra of both complexes feature transitions at ca. 500 nm attributed to a Ru(dπ) → dpp(π*) metal-to-ligand charge transfer (MLCT) transition that is slightly red-shifted from the Ru synthon upon Rh(I) complexation. The methylation of TL on the Ru impacts the electrochemical and optical properties in a minor but predictable manner. The photophysical studies, by comparison with the model complex [{Ru(bpy)2}2(dpp)](PF6)4 and related Rh(III) complex [(bpy)2Ru(dpp)Rh(III)Cl2(phen)](PF6)3, reveal the expected absence of a Ru(dπ) → Rh(dσ*) (3)MMCT state (metal-to-metal charge transfer) in the title complexes, which is present in Rh(III) systems. The absence of this (3)MMCT state in Ru(II),Rh(I) complexes results in a longer lifetime and higher emission quantum yield for the Ru(dπ) → dpp(π*) (3)MLCT state than [(bpy)2Ru(dpp)Rh(III)Cl2(phen)](PF6)3. Both complexes display photocatalytic hydrogen production activity in the presence of water and a sacrificial electron donor, with the [(bpy)2Ru(dpp)Rh(I)(COD)](PF6)3 possessing a higher catalytic activity than the methyl analogue. Both display low activities, hypothesized to occur due to steric crowding about the Rh(I) site.

Subunit variation to uncover properties of polyazine-bridged Ru(II), Pt(II) supramolecules with low lying charge separated states providing insight into the functioning as H2O reduction photocatalysts to produce H2.

Two new structurally diverse polyazine-bridged Ru(II),Pt(II) tetrametallic complexes, [{(Ph2phen)2Ru(dpp)}2Ru(dpp)PtCl2](PF6)6 (1a) and [{(Ph2phen)2Ru(dpp)}2Ru(dpq)PtCl2](PF6)6 (2a) (Ph2phen = 4,7-diphenyl-1,10-phenanthroline, dpp = 2,3-bis(2-pyridyl)pyrazine, dpq = 2,3-bis(2-pyridyl)quinoxaline), as well as their trimetallic precursors have been synthesized to provide a comparison for detailed analysis to elucidate component effects in the previously reported photocatalyst [{(phen)2Ru(dpp)}2Ru(dpq)PtCl2](PF6)6 (4a) (phen = 1,10-phenanthroline). Electrochemistry shows terminal Ru based highest occupied molecular orbitals (HOMOs) with remote BL' (BL' = bridging ligand coupling central Ru and cis-PtCl2 moiety) based lowest unoccupied molecular orbitals (LUMOs). Population of a lowest-lying charge separated ((3)CS) excited state with oxidized terminal Ru and reduced remote BL' via intramolecular electron transfer is predicted by electrochemical analysis and is observed through steady-state and time-resolved emission studies as well as emission excitation profiles which display unusual nonunity population of the lowest lying emissive Ru→dpp (3)MLCT (metal-to-ligand charge transfer) state. Each tetrametallic complex is an active photocatalyst for H2 production from H2O with 2a showing the highest activity (94 TON (turnover number) in 10 h, where TON = mol H2/mol catalyst). The nature of the bridging ligand coupling the trimetallic light absorber to the cis-PtCl2 moiety has a significant impact on the catalyst activity, correlated to the degree of population of the (3)CS excited state. The choice of terminal ligand affects visible light absorption and has a minor influence on photocatalytic H2 production from H2O. Evidence that an intact supramolecule functions as the photocatalyst includes a strong dependence of the photocatalysis on the identity of BL', an insensitivity to Hg(l), no detectable H2 production from the systems with the trimetallic synthons and cis-[PtCl2(DMSO)2] as well as spectroscopic analysis of the photocatalytic system.

A new, bioactive structural motif: Visible light induced DNA photobinding and oxygen independent photocleavage by RuII, RhIII bimetallics.

The Ru,Rh bimetallic complexes, [(bpy)(2)Ru(dpp)RhCl(2)(phen)](3+) and [(bpy)(2)Ru(bpm)RhCl(2)(phen)](3+) (bpy=2,2'-bipyridine, dpp=2,3-bis(2-pyridyl)pyrazine, phen=1,10-phenanthroline, and bpm=2,2'-bipyrimidine), couple one ruthenium polyazine light absorber to a cis-Rh(III)Cl(2) center through a dpp or bpm bridging ligand in contrast to the previously studied Ru,Rh,Ru trimetallics. This motif provides a sterically accessible Rh reactive site. These bimetallics are efficient visible light absorbers possessing many advantages compared to the previously reported trimetallics: lower cationic charges, reduced stereoisomerization, and independent variation of terminal ligands at each metal center to modulate properties. The bimetallic systems display efficient visible light induced bioreactivities with DNA. In addition to the known DNA photocleavage in related Ru,Rh,Ru trimetallics, these Ru,Rh bimetallic systems display visible light induced DNA binding. Low lying triplet metal to metal charge transfer ((3)MMCT) excited states provide oxygen independent photoreactivity. This previously unexplored structural motif for DNA modification holds promises in photodynamic therapy and DNA modification schemes.

Metal to ligand charge transfer induced DNA photobinding in a Ru(II)-Pt(II) supramolecule using red light in the therapeutic window: a new mechanism for DNA modification.

The Ru(II)-Pt(II) supramolecular complex, [(Ph(2)phen)(2)Ru(dpp)PtCl(2)](2+), displays a new mechanism for DNA modification: photobinding through a (3)MLCT excited state. Gel shift analysis, selective DNA precipitation, and DNA melting point experiments support efficient covalent DNA binding following visible light excitation.