This paper is published as part of a Dalton Transactions themed issue on


Metal Anticancer Compounds
Guest Editor Peter Sadler University of Warwick, UK

Published in issue 48, 2009 of Dalton Transactions

Image reproduced with permission of Chi-Ming Che Articles published in this issue include: PERSPECTIVES: Non-traditional platinum compounds for improved accumulation, oral bioavailability, and tumor targeting Katherine S. Lovejoy and Stephen J. Lippard, Dalton Trans., 2009, DOI: 10.1039/b913896j Metal complexes as photochemical nitric oxide precursors: Potential applications in the treatment of tumors Alexis D. Ostrowski and Peter C. Ford, Dalton Trans., 2009, DOI: 10.1039/b912898k Novel and emerging approaches for the delivery of metallo-drugs Carlos Sanchez-Cano and Michael J. Hannon, Dalton Trans., 2009, DOI: 10.1039/b912708a HOT ARTICLE: Iron(III) complexes of fluorescent hydroxamate ligands: preparation, properties, and cellular processing Antonia J. Clarke, Natsuho Yamamoto, Paul Jensen and Trevor W. Hambley, Dalton Trans., 2009, DOI: 10.1039/b914368h Visit the Dalton Transactions website for more cutting-edge inorganic and bioinorganic research

After a period in industry.7 Here. Gobetto. Fax: +44 (0)24 7652 4112. Luca Salassa received his undergraduate degree (2001) in Italy at the University of Turin.rsc. he was awarded an Intraeuropean Marie Curie Fellowship to study Luca Salassa photoactivatable ruthenium complexes for anticancer applications in Prof. Re.J.1 Photoactivated chemotherapy (PACT) provides the opportunity for control over when and where a drug is activated. and the potential of PACT for cancer treatment shown by metal complexes. Nanoparticles (Ag.1039/b917753a The fields of phototherapy and of inorganic chemotherapy both have long histories. Nicola Farrer Canada). There are excellent reviews concerning the photophysical properties of metal complexes3. Cr. particularly DNA. This journal is © The Royal Society of Chemistry 2009 10690 | Dalton Trans. We discuss the features which need to be considered when developing a metal-based anticancer drug. is also well-documented. V.4 and the potential of photoactive metals for medicinal applications. CV4 7AL.8 We consider the photophysical and photochemical properties which are desirable. R. such as triplet oxygen. multinuclear NMR spectroscopy and chemical applications of photonic crystal fibers. where he also completed his PhD (2004) on fluorescent metal complexes under the supervision of Prof. a number of different decay pathways (both photophysical and photochemical) are available to a metal complex. 2003) and subsequently her PhD (2007) from Cambridge University.. University of Warwick. The use of an inactive precursor or “prodrug” is an important strategy in drug Department of Chemistry. Sadler* Received 28th August 2009. We then provide a comprehensive overview of PACT developments for complexes of the different d-block metals for the treatment of cancer.2 In this perspective. Accepted 27th October 2009 First published as an Advance Article on the web 11th November 2009 DOI: 10.and two-photon photoactivatable metal complexes. Coventry. Ru. Mn. Rh. Pt. Inorganic photoactivated chemotherapy (PACT) offers both temporal and spatial control over drug activation and has remarkable potential for the treatment of cancer. detailing the more established areas concerning Ti. and was supervised by Prof. UK. Os. Gibbet Hill Road. We also discuss the potential held in particular by mixed-metal systems and Ru complexes. Au) and quantum dots (Cd) are also discussed for their photothermal destructive potential. 2009. He later joined the University of Montana (USA) as a post-doctoral fellow and studied protein dynamics using long-lived fluorescent probes. phosphine ligands with a view to detecting catalytic intermediates by electrospray mass spectrometry.PERSPECTIVE www. loss of ligands or transfer of energy to another species. These pathways can result in radiative energy release.5 The effect of light on metal complexes and the subsequent effects on biomolecules. Scott McIndoe (University of Victoria. Brian Johnson (Cambridge). UK. and Cu and also highlighting areas where there is potential for greater exploration. a few examples of which we recently | Dalton Transactions Photoactivated chemotherapy (PACT): the potential of excited-state d-block metals in medicine Nicola J. resulting in a greater specificity of drug action.Sadler@warwick. His research interests are focussed on the photophysics and photochemistry of metal complexes and the use of computational (DFT) and spectroscopic methods for the study of such systems. Introduction Transition metal complexes have proven success as anticancer agents. 10690–10701 . Luca Salassa and Peter J. and the common mechanisms by which the current complexes are believed to operate. with the bulk of the synthetic work undertaken in the lab of Dr.6. Co. Her doctoral work involved developing readily E-mail: P. She returned to the UK to join the Sadler group as a post-doctoral fellow where her research interests include one. Fe. we discuss the photophysical and photochemical processes which can occur following photoexcitation of a metal complex. we focus specifically on inorganic PACT anticancer agents. Following photoexcitation. Tel: +44 (0)24 7652 3653 targeting. Nicola Farrer received her degree (Natural Sciences. Sadler’s group at the University of Warwick (2008).

Once these excited states are generated they can undergo a series of physical radiationless processes which ultimately lead to the ground-state electronic structure: intersystem crossing (ISC). MA and DPhil at the University of Oxford and then spent two years as a Medical Research Council Research Fellow in Molecular Pharmacology at the University of Cambridge and the National Institute for Medical Research. and the chemistry that is associated with their generation. imaging. much shorter than that of classical organic compounds (ms). discuss the activation pathways available. and Peter Sadler Professor of Chemistry. as depicted in Fig. 2009. due to the favourable photophysical properties and the relative non-lability of complexes with these configurations.e.1a Bold + underlined = photochemical + anticancer activity. Radiative processes such as fluorescence (singlet– singlet) and phosphorescence (triplet–singlet) result in a return to the ground state. In particular. but also to the energy and nature of Dalton Trans. 10690–10701 | 10691 . Such classification is a simplification in some cases. DNA footprinting. 1). In 1996 he was appointed to the Crum Brown Chair of Chemistry at the University of Edinburgh. nor will the use of metal photochemistry for diagnostic (e. and summarise the PACT potential shown by the d-block metals (see Fig. 2. internal conversion (IC) vibrational relaxation. however. coloured to demonstrate the PACT potential of each metal.7 The nature of the excited states of metal complexes has been increasingly studied in recent years and several applications have been developed exploiting their photophysics and photochemistry.3 Underlined = well-documented anticancer activity. with emission of light of longer wavelength than was used for the excitation. in the form of light or heat. and in June 2007 took up a Chair in Chemistry at the University of Warwick where he is also Head of Department.g. Photomedicinal applications of the lanthanides (largely radioimmunotherapy and photodynamic therapy)9 and the anticancer activity of the main group metals10 are both welldocumented elsewhere3 and will not be discussed. The transitions to the excited electronic states are formally classified according to the character of the orbitals involved in the electronic transition. furthermore. His research interests are centred on the chemistry of metals in medicine and the design of novel therapeutic agents. and their emission quantum yield is relatively high. photoaffinity labelling) rather than therapeutic purposes. phosphorescence dominates). orbitals may have mixed metal/ligand character depending on the nature of the metal–ligand bond and. He is a Fellow of the Royal Society of Edinburgh (FRSE) and the Royal Society of London (FRS).Fig.and vibrationally-excited states with the same multiplicity as the ground state.) can occur at any stage during the decay back to the ground state. Photochemical reactions from a photophysically excited metal complex (ligand dissociation. as the molecule returns to the ground state. where he subsequently became Reader in Biological Inorganic Chemistry. The excited state which is generated is typically short-lived. d6 transition metal complexes can be used to exemplify the diversity of excited states that can be generated by light excitation. Bold = well-documented photochemical activity. University of London. the energy can be dissipated in a wide variety of ways. redox processes etc. intramolecular vibrational redistribution and solvation dynamics (reorganisation of solvent shells). a chemical modification of the structure or transferral of energy Peter Sadler obtained his BA.. their emissive properties differ significantly from those observed in organic chromophores. In contrast to organic species. The nature of the particular photochemical process is intimately related not only to the nature of the excited state reached by the molecule upon excitation. What do metals offer for PACT? Light can be used to alter the electronic structure of molecules. electronic transitions may involve more than two orbitals at a time. Due to the efficient intersystem crossing promoted by the metal ion. This journal is © The Royal Society of Chemistry 2009 to another species. 1 Table of d-block metals. metals have excited states that are often easily accessible by irradiation with visible and UVA light. the lifetime of such triplet states is typically on the 50 ns–1 ms timescale. In 1973 he was appointed as a Lecturer in Chemistry at Birkbeck College. inducing changes in both physical and chemical properties. based on recent literature. metal complexes generally emit from triplet states (i. Although.11 Excitation leads to electronically. Transition metal complexes with d3 and d6 electronic configurations are particularly promising.

These are orbitally (Laporte)-forbidden. while in the triplet state they are spin-up ( closely-lying states and to the availability of the dynamic processes just described. such as those metal complexes which photorelease a bioactive molecule (e. Ultrafast (fs) time-resolved techniques and computational methods show that more complex scenarios are possible and photochemistry (e. Since MC transitions typically populate antibonding orbitals. ∑ Ligand-centred (LC) transitions (or interligand (IL) transitions). ligand-to-metal (LMCT) or to-solvent (TS)}. Consequently. In the ). These generally involve only ligand-centered orbitals and are often seen in large delocalised systems. reducing the metal centre and generating radicals. solvent) and also result in homolytic bond cleavage.01–500 ¥ 103 M-1 cm-1 ) and can lead to redox reactions (of both the complex and molecules in the local environment e. 2 Simplified orbital and excited-state diagram for a d6 metal complex with octahedral coordination (strong crystal field is assumed). 3) is a reasonable model for most long-lived (ns or longer) inorganic systems.Fig.. DNA). 2009.g. from both singlet and triplet states which are accessible through This journal is © The Royal Society of Chemistry 2009 10692 | Dalton Trans. which can determine the population and depopulation of reactive states. 10690–10701 .13 the excited states generated often lead to bond lengthening and favour ligand substitution.g.g.g. In this way the excited state reactivity of metal complexes can be summarized as follows: Fig. Production of radicals under biological conditions is a wellestablished mechanism for causing damage to cellular components (e. 3 Jabłonski energy diagram. Steady-state and nanosecond spectroscopic characterisation methods can determine the nature of excited states when electronic state evolution is complete and aid identification of the transitions involved following irradiation. ∑ Charge-transfer (CT) transitions {metal-to-ligand (MLCT). Each black arrow (↑↓) represents an electron with its associated spin. These give rise to more intense transitions (typically e ~ 0.14 NO15 ). Associating the photochemical behaviour of a d6 -metal complex with the nature of the lowest lying triplet state (T1 . radiationless) and solid ( . ).e. Fig. radiative) lines. All possible physical processes triggered by light excitation of a d6 metal complex are represented by dashed (---. d-d or ligand-field (LF) transitions}. formally allowed charge-transfer transitions. bond breaking) can occur when electronic-state evolution is not complete. they give rise to weak absorptions (e ~ 1–20 ¥ 103 M-1 cm-1 ) which can be masked by stronger. Coloured arrows ( singlet state electrons are spin-down ( ) represent the electron involved in each electronic transition. and can also be spin-forbidden if the spin state changes. CO. Photochemical lability is commonly a feature of complexes in which a MC excited state is lowest in energy.12 ∑ Metal-centred (MC) transitions {i.

Group 5 Chakravarty et al. of PDT agents (which require O2 ).22. it is capable of initiating free radical reactions in cells. Group 3 The elements of group 3. Tumours exhibit varying levels of oxygenation. which may also reduce drug efficacy.21 Apart from the potential of the metal complex for photobleaching. This range has the maximum depth penetration into mammalian tissue. particularly in photocatalysis. highlighting that several photoactive metals have been scarcely investigated for PACT applications and as such.g. reactive species. exist predominantly in the 3+ oxidation state.20 Different oxidation states often exhibit different ligand binding kinetics. (2) Photosensitisation: Excited triplet states of metal complexes may be deactivated by reaction with ground-state triplet oxygen. Y and La.26 Crucially.30 the heavier elements Zr and Hf have been little studied in this regard. The mechanisms of action fall into three broad categories: (1) Photodissociation and/or redox changes: causing direct reaction of the metal with a biological agent e.24 Generation of a secondary ∑ destructive species (e. forming highly reactive singlet oxygen (1 Dg ) (known as a typeII process). HO ) in this way is known as photosensitisation.2-d:2¢.9b.g. Sc. Mechanisms of anticancer action Although often complex. with little dark toxicity. selective irradiation can often control the type of photoreaction: for example for CoIII .excitation or radiationless processes. (3) Photothermal reaction: Conversion of excited state energy to thermal energy (e. cell uptake and stability in biological media are common considerations for any potential drug. quantum dots). 10690–10701 | 10693 . or photorelease of a bioactive agent e.28 Sadler et al. For activation of photochemotherapeutic compounds. achieving photoactivation at ~800 nm (current PDT agents absorb ~630 nm). CO. The term ‘photocisplatin’ reagents was coined for rhodium (and related) metal complexes which are thermally inert.7. When developing photoactivatable metal anticancer agents additional key features which should be considered include the following. has been studied extensively for its photochemical properties. rational improvement is only possible if the mechanism of action is at least partly understood. in the form TiO2 . PtII ).g. photoreduction of PtIV to PtII generates a much more labile.18 Multiphoton excitation is an effective way to extend the wavelength of excitation of a metal complex. nanoparticles. ∑ The quantum yield or efficiency of the photochemical process. have shown that a mononuclear citrate TiIV complex is able to undergo photoreduction (with UVA) to TiIII . CdII ) configurations usually have moderate to high values of UD as do complexes of some of the heavier elements (PdII . Consequently the excitation volume is much smaller than that for one-photon excitation since two photons need to be absorbed by the molecule simultaneously. photoelectrochemical solar energy conversion and selfcleaning/sterilizing applications. which then destroys the tumour.17 highly pigmented tissue can rapidly attenuate light. protein destruction. whereas irradiation into a MC (d-d) irradiation causes photosubstitution/aquation.23.29 Although Ti is undergoing a renaissance as an anticancer agent. Ti.27. Group 4 Of Group 4.g. 2009.21. d0 (MgII . and cell lysis. irradiation into a LMCT band typically produces photoreduction giving rise to CoII and oxidised ligands. destroying the tumour. e. may be more appropriate.. In order for this to be possible. For multimetal complexes.5 ∑ The dependence of the PACT mechanism on O2 . are developing V-based PDT agents. For current clinical applications the use of red light (~630 nm) is routine although for superficial tumours shorter wavelengths e. For complexes in which the CT absorption band is wellseparated from the MC band. Suitability of the wavelength of light for irradiation (kirr ) As highlighted above. blue (420 nm). It depends on both the wavelength and the tissue type. and the light source needs to have a high photon density (e.25 For PDT applications. Where possible in this overview we highlight the mechanism proposed. AlIII ) or d10 (ZnII . The potential of d-block metals as photoactive anticancer complexes Several excellent reviews have focussed on the handful of welldeveloped PACT metal complexes. the wavelength of irradiation (l irr ) depends on the properties of the photochemical agent and the size of the tumour (and in practice. the singlet oxygen quantum yield UD of a given complex is the crucial parameter which determines the efficacy of the system. following photoexcitation the energy is released as heat. TiO2 can kill cancer cells when irradiated with UVA light.g.g. this can be considered catalytic. 1 O2 . the depth of penetration of light into tissue is important.19 It imposes constraints on the structure of the compound. and for some photoactive complexes different pathways are favoured in the presence or absence of oxygen. as TiIII is a strong reductant. The PACT potential of Group 3 elements has not yet been investigated. a femtosecond laser). and the medical application is photodynamic therapy (PDT).3¢-f ]quinoxaline) Dalton Trans.7 Desirable features of photoactivated metal-based drugs Aspects such as aqueous solubility.21 Subsequent reactions of singlet oxygen in biological systems result in DNA damage. since this is the excitation energy of singlet oxygen (1 O2 ). OxovanadiumIV complexes containing the heterocyclic bases dpq (dipyrido[3.g. but which form coordination bonds with DNA upon irradiation with UV This journal is © The Royal Society of Chemistry 2009 or visible light. NO.g. Pt binding to DNA or protein. the availability of light sources). ∑ The wavelength of activation should ideally lie within a phototherapeutic window of 620–850 nm.16 low levels can reduce drug efficacy e. there is the possibility of additional metal–metal transfers. the energy of the excited state triplet of the metal complex must be ≥ 94 kJ mol-1 compared to the ground state.20 here we discuss the general potential shown by d-block elements for PACT. ∑ A large difference between cytotoxicity in the presence and absence of irradiation is desirable in order to limit unwanted sideeffects. are worthy of pursuit. Due to the absence of radiative (emissive) decay.

but operates through a superoxide O2 ∑ . the complex also exhibits considerable dark toxicity.tetraazacyclotetradecane) releases NO (which sensitises hypoxic tissue to g-radiation59 ) upon irradiation (l irr = 360 nm). 0. RuIII complexes are reasonably inert to ligand substitution and can be activated by reduction to RuII .43 However. they do not possess the drawbacks of dark toxicity exhibited by the CuII complexes.2-d:2¢. guanine (G).45 Anticancer applications exploiting the photochemical activity of Tc are scarce (presumably because all Tc isotopes are radioactive. caused by in vivo reduction to CuI since the VIV complexes may not be so readily reduced in a biological medium. 10690–10701 phototoxic enhancement in HeLa cells. Os complexes possess low energy MLCT bands55 and the design aspects of DNA cleaving complexes involving Os have been considered.47 and recently Prasad et al.040 (650 nm).31 Although VIV (d1 ) complexes show similarities to CuII (d9 ) complexes in terms of possessing low-energy visible bands. Ford and coworkers have developed several CrIII NO complexes which release NO upon light irradiation. Thermal (e. Two-photon excitation (2PE) leading to NO release has been explored in depth for Fe nitrosyls.and bifunctional adducts of DNA.055 (500 nm).3. The triazine radical thus generated is capable of cleaving plasmid DNA by an oxygen-independent pathway. again.g. but the final product is also more robust to degradation.9.39 In particular. have studied the DNA binding properties of photoactive CrIII diimine complexes such as [Cr(phen)Cl2 ].5-di-tert-butyl-2-hydroxybenzyl)aminoacetic acid ligand (which stabilizes the +3 state) causes DNA nicking following irradiation (l irr ≤ 647 nm). making them more hazardous to work with than Re). Thermal or photochemical reduction to the more kinetically labile CoII can induce selective ligand release.g.and HO 1 radical mechanism rather than by O2 generation. releasing a fluorescent marker (indan) and creating a highly reactive Ru species capable of forming both mono. with only the HO∑ radical mechanism operating when irradiated with near-IR light. paving the way for development of PACT applications.51 The photophysics and photochemistry of Ru has been extensively studied.38 which can photorelease a coordinated ligand (e..g. and undergo photochemical substitution of an axial CO ligand when irradiated with UV or visible light. The mechanism involves reductive quenching of the excited state by bases e.3¢-c]phenazine) have been shown to exhibit DNA cleavage mechanisms involving both singlet oxygen and hydroxyl radicals when activated at 365 nm. For X = Cl. the medical applications of Ta are limited to metal implants34 and the poor stability of Nb compounds in aqueous solutions below pH 10 may explain its limited exploration to date. the application of these Mo and W systems to PACT has yet to be demonstrated.32 Others have also reported the photochemical cleavage of DNA by V complexes.8. controlled CO release can be an efficient and advantageous way of promoting cell death. and subsequently decomposes to give N2.5. DNA binders and complexes able to photorelease bioactive ligands.35 Group 6 The photochemistry of Cr has been extensively investigated.14 Radioactive isotopes of both Re and Tc are used in imaging and radiotherapy. W and for a-diimines such as bpy) have well-characterised photochemical properties. Promisingly.4. Related work has shown that oxo-bridged diiron complexes of dpq which are capable of photocleaving bovine serum albumin (l irr = 365 nm).5.11. a combination which shows excellent anticancer activity.62 Stereospecific photocleavage of DNA using chiral This journal is © The Royal Society of Chemistry 2009 . The high thermal stability of OsII complexes can make syntheses challenging.and dppz (dipyrido[3. The dinuclear complex [{(h6 -indan)RuCl}2 (m-2. which can then react either thermally or photochemically with DNA. water-soluble Fe (NO) release agents which show dark toxicity but which exhibit a slight 10694 | Dalton Trans.3a [M(CO)4 (a-diimine)] complexes (where M = Cr.61 McFadyen et al.4. have reported two-photon excitable. 650 nm) since absorption at these longer wavelengths is useful for photoactivation in tissues. the quantum yields (U) for the homolytic bond cleavage and photochemical release of ∑ Cl from the porphycene complex are 0. intercalators. due to the generation of a chargeseparated excited state. charge-separated excited state (Fe2+ ligand radical).4. Group 7 MnIII porphyrins show promise for PDT44 and the photorelease of CO from Mn centres has also been demonstrated. for example.52 The use of p-acceptor ligands such as TAP (1.48 Irradiation of a FeIII triazine complex (72 h. the new generation complexes with antenna ligands have improved absorption properties (l max ca.50 The mechanism of cleavage is oxygen∑ dependent.33 Currently. generating a highly oxidising.3-dpp)](PF6 )2 undergoes arene loss via an oxygen-independent pathway when irradiated (l irr = 365 nm).53 Os offers both a rich photochemistry3b and promise in the anticancer field54 but most PACT investigations using Os have been in mixed-metal systems (see Highlights section). l irr ≥ 455 nm) creates a LMCT excitation. Both RuIII and RuII show potential. hypoxia-activated)57 release is exemplified by a CoIII complex of the matrix metalloproteinase inhibitor Marimastat. WIV polyoxometalates show promise in photoactivatable antibacterial applications.37 Morrison et al.60 Photoreduction is also seen for CoIII and several complexes have been shown to photocleave DNA. Cl). 49 An FeIII complex of dpq (selected for its DNA binding properties) and the tetradentate 2. 2009.045 (600 nm) and 0.36 Although such studies have not yet targeted medical applications.8-tetraazaphenanthrene) and HAT (1.12hexaazatriphenylene) in RuII complexes shows much photochemical potential and is discussed in the Highlights section. again. cis-[CoL(NO2 )(ONO)]+ (L = 6-(anthracen-9-ylmethyl)-1. via the HO∑ radical pathway. have shown that [CoIII (en)2 (dppz)]3+ photocleaves DNA (l irr = 350–400 nm).2-bis(3. Although phototoxicity has been demonstrated in cellulo.46 Group 8 This group offers examples of photosensitizers. Mo.8.56 Group 9 CoIII complexes are usually substitution-inert. producing a radical cation G∑ + which eventually results in cleavage of the DNA backbone.58 Photochemical release has also been used to deliver a therapeutic agent.40 Both porphyrin41 and porphycene42 complexes of [O=MoV –X] show visible light induced dissociation of the axial ligand (X) and reduction to MoIV . although Re has been more extensively investigated.

resulting in photosubstitution. The complex cis[Rh(phen)2 Cl2 ]+ illustrates the dependence of the photochemistry on the presence of various species. a methylated cis-[Rh(phen)2 Cl2 ]Cl derivative which shows phototoxicity towards tumour cells (lirr > 500 nm). [Ni(bpy)2 (benzo[1. Morrison et al. In bis-chelated (polypyridyl) RhIII complexes this is typically a 3 MC state. with formation of singlet oxygen—but the quantum efficiency for photoaquation is increased by the presence of deoxyguanosine (dG). However. 4) increases 34 times upon irradiation.8]naphthyridinone-2-ol)](PF6 )2 binds to DNA in the absence of irradiation. most photobiological applications focus on the luminescent properties70 and the PACT potential of Ir complexes remains relatively unexplored. (l irr > 500 nm) due to the direct population of weakly absorbing 3 MC states by photoexcitation from the ground state. possibly due to reductive quenching. due to long-lived excited states76 while the photochemistry of PtIV complexes is dominated by dissociative/reductive Fig. but may undergo efficient photosubstitutions. Group 10 Although Ni complexes have been investigated as anticancer agents.67 the cytotoxicity of cis-[Rh2 (m-O2 CCH3 )2 (CH3 CN)]2+ (Fig. and upon irradiation (l irr 365 nm) photocleaves the DNA through a mechanism involving both 1 O2 and HO∑ radicals. In contrast.69 however.75 many PtII complexes luminesce following irradiation.66 Dinuclear Rh complexes allow extension of the possible wavelength of activation. (b) dinuclear Rh complex which shows 34 ¥ increase in cytotoxicity when irradiated (lirr = 400–700 nm). 4) can be activated at wavelengths where there is no apparent absorption. with an LC50 ~12 mM in human skin cells when irradiated (l irr = 400–700 nm). O2 quenches photoaquation of this species.. photoexcitation weakens the M–L bond. The photochemistry of RhIII complexes is determined by the nature of the lowest lying state. these complexes exhibit moderate photo- toxicity in tumour cells. RhIII complexes are relatively thermally inert. making them potentially useful for PACT. have pioneered the use of complexes such as [Rh(bpy)2 (chrysi)]3+ which target single base DNA mismatches. This journal is © The Royal Society of Chemistry 2009 Dalton Trans.63 and in general Co holds considerable potential for future PACT developments. mononuclear RhIII complexes show little absorption (e. 2009. have shown that methylated derivatives of cis-[Rh(phen)2 Cl2 ]Cl such as OCTBP (see Fig.73 for example. resulting in more efficient reactions for DNA damage.g.65 This shows potential for PACT since the inability of cells to control and regulate mismatch repair is implicated in several cancers.74 Both common oxidation states of Pt show a rich photochemistry.68 Ir complexes exhibit a rich photochemistry.64 Barton et al.7 The excited states of RhIII polypyridyl complexes tend to be more strongly oxidising than their RuII counterparts. excitation of the lowest lying state (3 LC) in the tris-chelated (polypyridyl) analogues creates a strong oxidising agent. and upon photoactivation (l irr ~ 340–450 nm) cleaves the DNA next to the mismatch. 4 (a) OCTBP.7 Despite this. (c) Pd-based PDT agent TOOKAD currently in clinical trials. the spectrum is dominated by intense LC bands in the UV region. 10690–10701 | 10695 . in contrast to their RuII counterparts.72 only a few investigations consider photoactivity.CoIII complexes is well-established. MC or CT bands) in the visible region of the electronic spectrum—instead.

Irradiation of Ag complexes in the presence of DNA results in metallation but not cleavage. Clearly the action spectrum does not mirror the UV-vis electronic spectrum for these complexes. the electrons resonate in response to incoming radiation. Gold nanoparticles have also been shown to cleave DNA upon irradiation (aerobic conditions) with UV (l irr = 312 nm) light.g. 2009..g. glutathione). In collaboration with others we have investigated the photochemistry of a range of PtIV diazido complexes. or with irradiation of the cells in the absence of the Pt complex. 5 (a) Calculated (TDDFT) and experimental absorption spectrum of cis.trans. Fig. 5a).77 Briefly. non-emitting Pd-phthalocyanin complex has shown promise for photothermal therapy (PTT) since it shows considerable absorption at near-IR wavelengths 10696 | Dalton Trans. imaging and therapy for cancer cells. When the irradiation is undertaken in cell culture.82 with complexes such as [CuII (dppz)((L-lysine)(OClO3 )] being activated to cleave DNA with near-IR light by a mechanism involving 1 O2 (l irr 700–755 nm). 5b) which favour ligand dissociation once populated. In other research. A PDT photosensitiser containing Pd (TOOKAD)79 is in Phase I/II clinical trials for treatment of prostate cancer (see Fig.75. The use of targeting features such as Paclitaxel (Taxol). irradiation of the complexes into either the LMCT bands (l irr = 365 nm) or the weaker d-d transitions at longer wavelengths (l irr = 420. which can cause prolonged photosensitivity of the patient following treatment.Fig. in vivo.cis-[Pt(N3 )2 (OH)2 (NH3 )2 ] in H2 O. 10690–10701 (826 nm). which is not observed either in the dark.3¢dithiodipropionic acid) reportedly cleave DNA when irradiated (l irr = 753–799 nm) both in the presence of O2 (through 1 O2 ∑ and HO pathways) but also in the absence of O2 .89 Herceptin90 or transferrin91 conjugated to nanoparticles enables targeting. The use of weaker field donors such as iodide instead of azide typically results in dark toxicity due to thermal reactions with biological reductants (e. diode laser) and shows rapid clearance from the body.85 and although Ag compounds are often photosensitive little PACT research has been conducted. then AuIII tetraarylporphyrins have potential in PDT. a potent cytotoxic effect is seen.88 the absorption of light by the nanoparticles induces localised surface plasmon oscillations. In contrast.81 others only cleave DNA upon irradiation.3 The alternative technique of photothermal ablation uses irradiation of gold (or silver) nanoparticles to achieve a cytotoxic effect. Contrastingly. 4). causing them to both absorb and scatter light. an advantage over conventional PDT agents. Transitions S1–S4 all have dissociative character since they involve (b) the s-antibonding orbitals LUMO and LUMO+1. the combination of a phototoxic porphyrin with a cytotoxic Pt unit within the same molecule has been investigated.84 It will be of interest to see whether this translates to photocytotoxicity in cellulo or indeed. 514 nm) can cause photodissociation and/or photodecomposition of the azido ligands and reduction of the PtIV centre to PtII . all with a single agent. irradiation at wavelengths where there appears to be essentially no absorbance in the electronic spectrum can still result in photoactivity77a (as observed for Morrison’s Rh complexes)64 due to the direct excitation of dissociative low-lying LMCT states (e. The light is rapidly converted into heat which destroys the immediate tissue.83 Binuclear copper complexes [{(X)CuII }2 (m-dtdp)2 ] (where X = phen or dpq and H2 dtdp = 3. a paramagnetic.86 if the dark cytotoxicity of AuIII porphyrins87 can be controlled. the complex can be photoactivated to produce 1 O2 (l irr = 762 nm. For the PtIV complexes. due to the generation of sulfur anion radicals. Group 11 Cu complexes such as [CuII (2-(2-pyridyl)benzthiazole)Br2 ] have been shown to oxidatively cleave DNA in the presence of O2 without direct irradiation. Time-dependent DFT calculations show that such transitions involve s-antibonding orbitals (Fig. behaviour. in an effort to develop selective PACT agents. The excited states are shown as vertical bars with heights equal to their extinction coefficients. S1–S4.80 in PTT tumour cells are killed by the heat generated from the efficient radiationless decay to ground state of such a Pd derivative.78 but in general the photochemistry of the Pt centre itself remains largely unexploited for PACT applications.92 This journal is © The Royal Society of Chemistry 2009 . Au compounds are well-known for their anticancer potential.77f Extension of the wavelength of activation of these complexes is a balance between thermal stability and activation with the longest wavelengths possible.

85 Trp -0. in a synergistic fashion.15 +1. Fig. ∑ Polyazaaromatic RuII complexes: photoactive molecules for a gene silencing approach in chemotherapy Kirsch-De Mesmaeker and coworkers have recently developed a new class of RuII polyazaaromatic complexes containing TAP and HAT ligands. presumably for toxicity reasons. acetonitrile) for selected polyazaaromatic RuII derivatives Complex [Ru(HAT)3 ]2+ [Ru(TAP)3 ]2+ [Ru(HAT)2 (phen)]2+ [Ru(HAT)2 (bpy)]2+ [Ru(TAP)2 (phen)]2+ [Ru(TAP)2 (bpy)]2+ [Ru(TAP)2 (dppz)]2+ E red (V/SCE) -0.)(TAP)(L¢)]1+ + H+ → [Ru(II)(TAP+H)∑ (TAP)(L¢)]2+ [Ru(II)(TAP+H)∑ (TAP)(L¢)]2+ + G(-H)∑ → photoproduct (1) (2) (3) (4) (5) (6) Fig.Group 12 Aside from the use of Zn-porphyrin and Zn-phthalocyanine derivatives in PDT. while only the highly oxidizing complexes Dalton Trans.98 promising variants involving Pt are being developed.17 +1. the complexes reported in Table 1 are able to react with DNA bases or oligomers and amino acids such as tyrosine (Tyr) and tryptophan (Trp).)(TAP)(L¢)]2+ * [Ru(III)(TAP∑ .g.78 (e.)(TAP)(L¢)]2+ * + G → [Ru(II)(TAP∑ .62 -0. the mixed-metal system [{RuII (dppz)(tpm)}(m-dpp[5]){fac(CO)3 ReI (dppz)}]3+ (tpm = tris(1-pyrazolyl)methane.g.10 +1. in the presence of a guanine residue (G) from guanosine-5¢-monophosphate (GMP) or DNA. which can selectively form photoadducts with DNA bases and amino acids when their MLCT state is excited.100 A potential drawback of some multimetal systems is that a high formal charge is thought to make cell uptake of such complexes more challenging.93 QD can be used to generate reactive radicals to kill tumours.21 Cd-based quantum dots (QD) represent the most promising development of group 12 for PACT application. GMP +1.25 +1. For example. the latter acts as an electron acceptor and subsequently cleaves DNA. ∑ Mixed-metal systems Combining different metals in a multinuclear complex is a powerful way to exploit the (photo)chemical properties of each metal.76 -0.94 QD which are activated by X-rays—behaving as a PDT agent as well as a fluorescent marker—are particularly promising.)(TAP)(L¢)]1+ + G∑ + → [Ru(TAP)2 (L¢)]2+ + G G∑ + → G(-H)∑ + H+ [Ru(II)(TAP∑ . complexes with lower overall charges which have not been photobiologically investigated may prove promising in this regard. dpp[5] = 4.102 Although many RuII polypyridyl complexes have both oxidizing and reducing properties in the excited state.80 E * red (V/SCE) +1. 6) has highlighted that complexes which demonstrate DNA photocleavage (e.99 In other work. 4+ charge) can readily enter cells. resulting in a series of redox reactions which eventually lead to the formation of photoproducts..101 However it is notable that some multinuclear PtII complexes with high charge The potentials were obtained as described in reference 102. [Ru(TAP)2 (L¢)]2+ complexes can undergo the following reactions (where * represents an excited state): [Ru(TAP)2 (L¢)]2+ + hn → [Ru(III)(TAP∑ .)(TAP)(L¢)]1+ + G∑ + [Ru(II)(TAP∑ .30 +1.95 Explorations of Hg photochemistry do not appear to have been applied yet to biological systems.3-bis(2-pyridyl)pyrazine.and double-strand cleavage of pBR322 plasmid DNA. 6 Mixed metal Ru–Rh–Ru complex of Brewer et al.20 Biomolecule E red (V/SCE) Highlights In the following section we consider the potential offered by mixedmetal systems and Ru complexes. SCE. The analogous system in which Rh is substituted by Ir showed no DNA photocleavage in vitro. demonstrating activity both in the presence and absence of oxygen. The mechanism of the phototoxic effect involves 1 MLCT excitation of the RuII followed by conversion to a low-lying reactive 3 MMCT state in which charge transfers from RuII —via a bridging p-ligand—to RhIII .83 -0.49 +1.96 Table 1 Ground-state and excited-state potentials of the first reduction wave (vs. 2009. Activation (l irr = 355 nm) results in both single.66 -0.4¢-dipyridylpentane) combines the strong DNA binding ability of the RuII with the DNA photocleavage ability of the ReI centre.97 In contrast.05 Tyr -0. 10690–10701 | 10697 This journal is © The Royal Society of Chemistry 2009 . the RuII analogue showed evidence of cell death for concentrations ≥ 10 mM following irradiation (l irr > 460 nm) with no cytotoxic activity in the dark. where M = OsII ) do not necessarily exhibit photocytotoxicity in mammalian cell lines. so pathways for the transport of charged species into cells do exist. BBR3464. Ru-TAP and Ru-HAT complexes show a more pronounced oxidizing character. at the same time offering highly tunable absorption and emission properties.83 -0. When excited with visible light. Steady-state and time-resolved studies103 have highlighted that the direct (2) and back (3) electron-transfer process from G is likely to occur through a proton-coupled electron-transfer mechanism (4 and 5).75 -0. Two TAP and HAT ligands are necessary to achieve oxidation of GMP. Work on trinuclear complexes [{M(bpy)2 (dpp)}2 RhCl2 ]Cl5 (where M = Ru or Os and dpp = 2.

In fact. the guanine is covalently linked to the complex by the exocyclic amino group of the base. Fig. These include measurements of action spectra.104 Modified ODNs with anchored Ru-TAP and Ru-HAT complexes (Ru-ODNs) can be successfully employed to increase the stability of the ODN aggregates. and can vary depending on the conditions. 8). possible reactants (e. All these Ru-ODNs have been tested in the presence of their target sequence under light irradiation with the aim of assessing the general principle governing the photoadduct formation. presence/absence of oxygen. each with unique photophysical and photochemical properties gives a broad spectrum from which to choose.) In addition to the photochemistry described. The soformed adducts have improved stability and are more resistant to enzyme action. The improvement obtained with the Ru-ODNs(G) is relevant for in vivo gene silencing applications. selective formation of inter-strand photo-crosslinks is observed and no self-inhibition. IR) to characterise the excited states and photochemical pathways more accurately. Their application has been limited by the poor stability of the ODNDNA/mRNA aggregates and by the activity of enzymes that can recognize and destroy such aggregates.. On the contrary. Synthetic oligodeoxynucleotides (ODNs) have been used for gene expression. Ru-TAP and RuHAT derivatives also damage DNA by 1 O2 photosensitization. Therefore. In the photoproduct obtained from the reaction between Ru-TAP and Ru-HAT complexes. 2009.105 In both cases cycRu-ODN(G) photoadducts are formed. The selectivity towards inter-strand adducts in the presence of a complementary target strand can be explained by the increased rigidity of the duplex. oligonucleotides hybridized with oxidizing Ru polyazaaromatic complexes can irreversibly form photo-induced cross-links with a target strand. It is anticipated that future improvements in This journal is © The Royal Society of Chemistry 2009 .g. which substitutes a H atom in the polyazaaromatic ligand ring (TAP: a-position with respect of the non-coordinating nitrogen. it was considered necessary to avoid Ru-ODNs containing G to reduce self-inhibition. solvent. otherwise only fluorescence quenching occurs. The photoactivation pathways taken by metal complexes can be complicated. targeting either double-strand DNA (antigen strategy) or single-strand mRNA (antisense strategy). The availability of a wide array of different metals. 7 Photoadduct formation during the photoirradiation of [Ru(TAP)3 ]2+ in the presence of GMP. GG sites exhibit lower redox potentials than G sites) and by the distance between the Ru complex and G. In the case of non-complementary (containing G as well) strands self-inhibition reaches an 80% yield. the same authors have developed Ru-ODNs containing guanine residues (RuODN(G) ). The photoproduct is obtained after several steps of purification and acidification. The Ru-ODN complexes are activated by light and form strong cross-links between the ODN strand and a guanine residue (G) on the target sequence. 7. This strategy can be used to develop specific anticancer agents based on gene silencing (inhibition of gene expression).Fig. where they can exploit a novel mechanism of action. This spectrum dramatically widens once the multitude of possible ligands (and ligand arrangements) are considered and the potential for tuning the photochemistry is further expanded by combining several metals within the same complex. DNA/proteins) and on the wavelength of light used. However. Several different Ru-ODNs have prepared by attaching covalently one ruthenium polyazaaromatic unit to thymidine residues or to the 5¢-terminal phosphate group. since it reduces the possibility of secondary photoeffects (as for example seen with proteins). The percentage of photocross-links is determined by the ionization potential of G (e. the photoinduced electron transfer process that leads to the formation of stable and specific photoproducts makes this class of complexes potential candidates in PACT. [Ru(TAP)3 ]2+ and [Ru(HAT)3 ]2+ can react with adenosine-5¢monophosphate (AMP). when a complementary strand is added and the Ru-ODN(G) is irradiated. which are able to self-inhibit when irradiated in the absence of the complementary target strand or in the presence of noncomplementary strands (Fig. Many elegant techniques have been developed by the photochemical community in order to better understand and therefore control the photochemistry of such systems. singlet oxygen quantum yields and the use of TD-DFT and ultrafast (fs) time-resolved techniques (e. 10698 | Dalton Trans. a minimum distance is required to have a good photocross-linking percentage. e. Photoactivation provides scope for another dimension—one of highly controllable activity—of more potent.g.g.g. However. Outlook Platinum complexes have a proven track record of being well suited to the treatment of cancer and those of other transition metals have much potential. 10690–10701 Until recently. highly targeted drugs with reduced side-effects.

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