Karen J. Brewer

Designing Red-Light-Activated Multifunctional Agents for the Photodynamic Therapy†

The quest to find a cure for cancer has led to the development of a variety of therapies. At issue is the need to selectively destroy cancer cells while not killing so many normal cells that it results in patient death. Typical treatments for cancer include surgery, chemotherapy, and radiation therapy. One means to overcome the limitations of systemic treatment with chemotherapy is the use of photodynamic therapy (PDT). In PDT, an inactive form of the drug is delivered to the patient and light energy is used to generate the active drug only at the site of the tumor. 3] PDT allows localized versus systemic delivery and therefore application of highly toxic drugs. Ideal PDT agents need to absorb light in the therapeutic window, 600–1000 nm, where biological tissue does not absorb, be nontoxic in the inactive form, be highly toxic in the active form, and ideally function in tumor tissues that are often oxygen-depleted. An early-generation PDT agent still in use is Photofrin (1; Scheme 1), which is a mixture of substituted porphyrin oligomers. The state diagram (Figure 1) displays the lightactivated dynamics observed for typical type II oxygendependent PDTagents where excitation is followed by energy transfer to molecular oxygen in tissue, which generates singlet oxygen, O2, a reactive oxygen species (ROS). The ROS are highly damaging to a variety of biomolecules, have very short diffusion distances, and lead to cell death. The development of metal complexes as potential PDT agents is an exciting field where the organic framework as well as the metal incorporated can be varied to tune properties often providing multifunctional activity. Multifunctional activity describes systems that have two modes of action with the biological target, for example binding to and photocleaving of DNA. Metal complexes often allow for the direct optical population of triplet states because of enhanced spin–orbit coupling. The requirement to absorb lower-energy light in the therapeutic window often leads to metal complexes with shortened excited-state lifetimes as predicted by the energy gap law. This has made the development of systems that provide for red-light excitation elusive. Recent approaches to provide for new potential drugs have been successful, including enhanced red-light absorptivity by spin–orbit coupling which allows direct singlet-totriplet excitation, implementation of targeting agents to deliver the drugs, use of atypical excited states, and the development of type II O2 independent systems. However, the development of totally new drug motifs through initial in vitro methods can lead to unexpected issues in vivo such as metal toxicity if a toxic level of metal ions is released from the ligand set. The Fe complex 2 (Scheme 1) is unique in many aspects. The use of Fe in PDT is not typical, but may lead to lower metal toxicity as the complex is cleared from the system following treatment. The low stability of bidentate coordinated complexes in vivo often limits their application. Complex 2 absorbs light in the red using an unusual ligand-tometal charge transfer (LMCT) excitation shifted into the red at 805 nm by the catechol ligand with a molar extinction coefficient, e, of 2400m 1 cm . The catechol ligand provides for higher-energy donor orbitals moving the excitation into Figure 1. State diagram illustrating the mechanisms of action for drugs displaying oxygen-dependent photodynamic action with k’s (rate constants) for f (fluorescence), p (phosphorescence), r (radiative), nr (nonradiative), ic (internal conversion), isc (intersystem crossing), en (energy transfer), and rxn (reaction). The electronic state Dg is observed at 1270 nm or 0.97 V, Sg is estimated at 1.6–1.8 V but is short-lived.

Solar energy conversion using photochemical molecular devices: photocatalytic hydrogen production from water using mixed-metal supramolecular complexes

Photocatalytic generation of hydrogen from water is an integral part of the next generation clean fuel technologies. The conversion of solar energy into useful chemical energy is of great interest in contemporary investigations. The splitting of water is a multi-electron process involving the breaking and making of chemical bonds which requires multi-component photocatalytic systems. Supramolecular complexes [{(TL)2Ru(BL)}2RhX2](Y)5 (where TL = terminal ligand, BL = bridging ligand, X = Cl− or Br−, and Y = PF6− or Br−) have been synthesized and studied for their light absorbing, electrochemical and photocatalytic properties. The supramolecular complexes in this investigation are multi-component systems comprised of two ruthenium based light absorbers connected through bridging ligands to a central rhodium, which acts as an electron collecting center upon excitation. These complexes absorb light throughout the ultraviolet and visible regions of the solar spectrum. The supramolecular complexes possess ruthenium based highest occupied molecular orbitals (HOMO) and a rhodium based lowest unoccupied molecular orbital (LUMO). These molecular devices have been investigated and shown to function as photoinitiated electron collectors at the reactive rhodium metal center, and explored as photocatalysts to generate hydrogen from water in an aqueous solution in the presence of an electron donor.

Redox, spectroscopic, and photophysical properties of Ru-Pt mixed-metal complexes incorporating 4,7-diphenyl-1,10-phenanthroline as efficient DNA binding and photocleaving agents.

The redox, spectroscopic, and photophysical properties as well as DNA interactions of the new bimetallic complexes [(Ph2phen)2Ru(BL)PtCl2](2+) (Ph2phen = 4,7-diphenyl-1,10-phenanthroline, and BL (bridging ligand) = dpp = 2,3-bis(2-pyridyl)pyrazine, or dpq = 2,3-bis(2-pyridyl)quinoxaline) were investigated. These Ru-polyazine chromophores with Ph2phen TLs (terminal ligands) and polyazine BLs are efficient light absorbers. The [(Ph2phen)2Ru(BL)PtCl2](2+) complexes display reversible Ru(II/III) oxidations at 1.57 (dpp) and 1.58 (dpq) V vs SCE (saturated calomel electrode) with an irreversible Pt(II/IV) oxidation occurring prior at 1.47 V vs SCE. Four, reversible ligand reductions occur at -0.50 dpp(0/-), -1.06 dpp(-/2-), -1.37 Ph2phen(0/-), and -1.56 V vs SCE Ph2phen(0/-). For the [(Ph2phen)2Ru(dpq)PtCl2](2+) complex, the first two reductions shift to more positive potentials at -0.23 and -0.96 V vs SCE. The electronic absorption spectroscopy is dominated in the UV region by π → π* ligand transitions and in the visible region by metal-to-ligand charge transfer (MLCT) transitions at 517 nm for [(Ph2phen)2Ru(dpp)PtCl2](2+) and 600 nm for [(Ph2phen)2Ru(dpq)PtCl2](2+). Emission spectroscopy shows that upon attaching Pt to the Ru monometallic precursor the λmax(em) shifts from 664 nm for [(Ph2phen)2Ru(dpp)](2+) to 740 nm for [(Ph2phen)2Ru(dpp)PtCl2](2+). The cis-Pt(II)Cl2 bioactive site offers the potential of targeting DNA by covalently binding the mixed-metal complex to DNA bases. The multifunctional interactions with DNA were assayed using both linear and circular plasmid pUC18 DNA gel shift assays. Both title complexes can bind to and photocleave DNA with dramatically enhanced efficiency relative to previously reported systems. The impact of the Ph2phen TL on photophysics and bioreactivity is somewhat surprising given the Ru → BL charge transfer (CT) nature of the photoreactive state in the complexes.

Utilization of substituted polyazine bridging ligands to tune the spectroscopic and electrochemical properties of bimetallic ruthenium complexes

Abstract The polyazine bridging ligands Cl 2 dpq and Me 2 dpq (where Cl 2 dpq=6,7-dichloro-2,3-bis(2′-pyridyl)quinoxaline and Me 2 dpq=6,7-dimethyl-2,3-bis(2′-pyridyl)quinoxaline) have been synthesized and their electrochemical and spectroscopic properties studied. Cl 2 dpq is easier to reduce than the unsubstituted dpq (dpq=2,3-bis(2′-pyridyl)quinoxaline) ligand by 250 mV, while Me 2 dpq is harder to reduce than dpq by 180 mV. These two substituted dpq ligands, along with dpp, dpq and dpb (dpp=2,3-bis(2′-pyridyl)pyrazine and dpb=2,3-bis(2′-pyridyl)benzoquinoxaline), give a series of five polyazine bridging ligands which provide a similar coordination environment to metals. In addition, this series of ligands makes possible the systematic variation of the energy of the lowest unoccupied molecular orbital (LUMO), the bridging ligand based π*. The relative energy of the π* orbitals is dpp>Me 2 dpq>dpq>Cl 2 dpq>dpb. The new monometallic and bimetallic systems of the form [(bpy) 2 Ru(BL)] 2+ and [(bpy) 2 Ru]2(BL) 4+ (where BLMe 2 dpq and Cl 2 dpq) have been synthesized and their spectroscopic and electrochemical properties studied. In addition, the previously studied systems with dpp, dpq and dpb as the bridging ligand have been prepared and their properties are reported herein for comparison. The metal complexes become easier to reduce as a function of bridging ligand with E 1/2 (reduction) for dpp 2 dpq 2 dpq E abs or E em for dpp>Me 2 dpq>dpq>Cl 2 dpq>dpb. These results indicate that it is possible to tune the spectroscopic and electrochemical properties of multimetallic complexes through the incorporation of substituent groups on polyazine bridging ligands.

A new Os,Rh bimetallic with O2 independent DNA cleavage and DNA photobinding with red therapeutic light excitation

Many Ru and Os systems display photoactive (3)MLCT states. Systems activated by therapeutic window light in the absence of O(2) remain elusive. [(bpy)(2)Os(dpp)RhCl(2)(phen)](3+) photobinds and photocleaves DNA under red light in an oxygen independent manner, due to molecular design involving one Os chromophore coupled to a photoactive cis-Rh(III)Cl(2) moiety.

Mixed-metal polymetallic platinum complexes designed to interact with DNA

Abstract Complexes of the general form [(bpy) 2 M(dpb)PtCl 2 ]Cl 2 (where MRu II or Os II , bpy = 2.2′-bipyridine and dpb = 2,3-bis(2-pyridyl)benzoquinoxaline) have been designed by our group to form the basis of a new type of structural motif for metal-based complexes which bind to DNA. These systems are of interest in that they couple a light absorbing ruthenium or osmium site to a reactive platinum site. The platinum site contains the cis -dichloride platinum moiety thought to be responsible for the anticancer activity of cisplatin, cis -[Pt(NH 3 ) 2 Cl 2 ]. The bridging ligand used, dpb, has an extended π system. Complexes of similar structures containing polyazine ligands with extended π systems have been shown to undergo binding to DNA, often in an intercalative fashion. The design of our complexes was to couple a light absorber to a cis -dichloride platinum moiety using a ligand, which is capable of intercalative binding to DNA. This provides a system with two potential modes of binding to DNA, intercalative and covalent. This study explores the nature of the covalent interaction of our two heterobimetallic complexes with DNA. Our study utilizes a 2958 bp linearized plasmid DNA and denaturing gel electrophoresis to probe the nature of this interaction. Comparisons are given to cisplatin, which forms primarily intrastrand crosslinks, and [( trans -PtCl(NH 3 ) 2 ) 2 -(μ-H 2 N(CH 3 ) 4 NH 2 )]Cl 2 (1.1/t,t), which forms primarily interstrand crosslinks. Our results indicate that our [(bpy) 2 M(dpb)PtCl 2 ]Cl 2 complexes, like cisplatin, form primarily intrastrand crosslinks. It is also evident that our systems form a higher percentage of interstrand crosslinks than cisplatin. Details of these studies are presented herein.

Photochemical properties of mixed-metal supramolecular complexes

Abstract We have prepared a series of mixed-metal trimetallic complexes of the form {[(bpy) 2 Ru(BL)] 2 MCl 2 } n + (bpy  2,2′-bipyridine; BL  2,3-bis(2-pyridyl)pyrazine (dpp), 2,3-bis(2-pyridyl)quinoxaline (dpq) or 2,3-bis(2-pyridyl)-benzoquinozaline (dpb); M  Ir(III), Rh(III) or Os(II). This new class of trimetallic complexes can be prepared with a good yield, often as high as 95%, using our building block strategy. The central rhodium and iridium fragments of these trimetallic, namely [M(BL) 2 Cl 2 ] + , have been shown in our laboratory to be capable of delivering multiple electrons, “stored” on the bridging ligand π* orbitals, to a substrate as they functioned as electrocatalysts for the reduction of carbon dioxide to formate. The two terminal ruthenium metals are good light absorbers designed to give rise to photochemical activity. These bichromophoric systems should be capable of absorbing two photons of light, each giving rise to a desired photochemical reaction, namely excited-state electron transfer. Thus these systems form the basis of a molecular device for photoinitiated electron collection. The properties of these supramolecular complexes have been tuned by variation in the central metal and bridging ligand. Comparison of this array of nine complexes is described herein.

Tuning the spectroscopic and electrochemical properties of polypyridyl bridged mixed-metal trimetallic ruthenium(II), iridium(III) complexes: a spectroelectrochemical study

Abstract A series of polypyridyl bridged trimetallic complexes of the type {[(bpy) 2 Ru(BL)] 2 IrCl 2 } 5+ (where BL = 2,3-bis-2′-pyridylpyrazine (dpp), 2,3-bis-2′-pyridylquinoxaline (dpq) or 2,3-bis-2′-pyridylbenzoquinoxaline (dpb); bpy = 2,2′-bipyridine) have been prepared and their synthesis, characterization and spectroelectrochemical analysis are reported within. These complexes are of interest in that they contain two visible light absorbing centers covalently coupled to a known catalytically active central metal site. The trimetallic complexes show absorbances throughout the visible region of the spectrum and exhibit many electrochemical processes within the acetonitrile solvent window. All the systems studied possess a ruthenium based oxidative process as well as four bridging ligand based reductions, followed by iridium and bipyridine based reductive processes. The relative energy of the ruthenium based dπ highest-occupied molecular orbital (HOMO) remains constant for this series of trimetallic complexes. The energy of the lowest lying bridging ligand based π* orbital, the lowest-unoccupied molecular orbital (LUMO), however, shifts to more positive potentials when dpq or dpb are substituted for dpp. This gives rise to a lowest energy absorption, Ru(dπ) → BL(π*) metal-to-ligand charge transfer (MLCT) transition, which can be tuned to lower energy as a function of bridging ligand from dpp to dpq to dpb. Through the synthetic variation of bridging ligand orbital energy and the use of spectroelectrochemical studies, it has been possible to elucidate the nature of the complex spectroscopy and electrochemistry of these supramolecular complexes. The dpp and dpq bridged systems emit in fluid solution at room temperature and their emission energies and lifetimes have been determined.

Comparing the spectroscopic and electrochemical properties of ruthenium and osmium complexes of the tridentate polyazine ligands 2,2′:6′,2″-terpyridine and 2,3,5,6-tetrakis(2-pyridyl)pyrazine

Abstract A number of osmium and ruthenium complexes of the tridentate ligands 2,2′:6′,2″-terpyridine (tpy) and 2,3,5,6-tetrakis(2-pyridyl)pyrazine (tpp) have been prepared and characterized by our laboratory. All these complexes possess metal based oxidations and ligand based reductions localized on each polyazine ligand. Polymetallic complexes bridged by the tpp ligand exhibit two sequential tpp based reductions prior to the reduction of other polyazine ligands in these complexes. The spectroscopy of these complexes is dominated by ligand based π-π ∗ transitions in the ultraviolet and MLCT (metal-to-ligand charge transfer) bands terminating on each polyzine ligand in the visible. For the complexes reported herein the lowest lying optical transitionis a M → BL CT band. For most of the complexes reported, occupation of this excited state gives rise to an observable emission at room temperature. For ruthenium complexes of these tridentate ligands, the presence of a low-lying LF state shortens the excited state lifetimes of these chromophores. This gives rise to ruthenium complexes that display shorter excited state lifetimes than the analogous osmium based systems. Incorporation of tpp based chromophores into polymetallic frameworks leads to the production of bimetallic species with long-lived excited states, ∼ 100 ns at room temperature. This makes these chromophores good candidates for the development of stereochemically defined supramolecular complexes. It is possible to measure an electrochemical HOMO-LUMO energy gap and a correlation between this electrochemically measured energy gap and the spectroscopic energy associated with this HOMO→LUMO transition are reported herein (HOMO== highest occupied molecular orbital, LUMO = lowest unoccupied molecular orbital).

A Structurally Diverse RuII,PtII Tetrametallic Motif for Photoinitiated Electron Collection and Photocatalytic Hydrogen Production

Coupling a reactive metal to light absorbers affords molecular devices for photoinitiated electron collection and photocatalytic conversion of substrates to fuels. A new Ru(II),Pt(II) tetrametallic supramolecule, [{(phen)(2)Ru(dpp)}(2)Ru(dpq)PtCl(2)](PF(6))(6), and the trimetallic precursors, [{(phen)(2)Ru(dpp)}(2)RuCl(2)](PF(6))(4) and [{(phen)(2)Ru(dpp)}(2)Ru(dpq)](PF(6))(6), have been synthesized, and their redox, spectroscopic, spectroelectrochemical, photophysical and photocatalytic properties studied. They efficiently absorb UV and visible light. The electrochemistry of [{(phen)(2)Ru(dpp)}(2)Ru(dpq)PtCl(2)](PF(6))(6) suggests a lowest-lying terminal Ru→dpq charge-separated state that quenches the emission of the parent complex with non-unity population of the emissive (3)MLCT excited state. Photolysis of [{(phen)(2)Ru(dpp)}(2)Ru(dpq)PtCl(2)](6+) at 470 nm with DMA gives multielectron reduction, storing electrons in a new manner on the central (dpp)(2)Ru(II)(dpq) moiety. Addition of H(2)O to the photolysis system produces 21 μmol of H(2) in 5 h, with 115 turnovers of the tetrametallic photocatalyst.