Design, synthesis and activation of ruthenium arene anticancer complexes

The synthesis and characterisation of RuII complexes of the form [(η6-arene)Ru(N,N')X]+ (where N,N' is a bidentate chelating ligand and X is a halogen) are described; including the X-ray crystal structures of four of these complexes. The hydrolysis rates at 310 K of the complexes vary over many orders of magnitude and in some cases are followed by partial arene loss. Density Functional Theory (DFT) calculations suggest that the aquation mechanism occurs via a more associative pathway. The significant cytotoxic activity towards A2780 human ovarian cancer cells of some of the complexes is found to be dependent on the chelating ligand. Selective binding to 9-ethylguanine (9-EtG) but not to 9- ethyladenine (9-EtA) is observed in aqueous solution at 310 K in all cases. The X-ray crystal structure of a RuII arene 9-EtG adduct is also described. DFT calculations show that the 9- EtG nucleobase adducts of all complexes are thermodynamically preferred compared to those of 9-EtA. Preliminary CT-DNA studies in cell-free media suggest that some of these complexes can interact with DNA. A family of piano-stool RuII arene complexes of the form [(η6-arene)Ru(N,N')(L)]2+ (where N,N' is a chelating ligand and L is a pyridine or a pyridine-derivative), that can selectively photodissociate the monodentate ligand (L) when excited with UVA or visible light is described. The X-ray crystal structures of five of these complexes are also discussed. Their photoactivation allows the formation of a reactive aqua species that otherwise would not form in the dark. Results from TD-DFT calculations suggest that all the RuII pyridine complexes follow a relatively similar L-ligand photodissociation mechanism, likely to occur from a series of 3MC triplet states. It is shown how light activation can be used to phototrigger binding of these complexes to nucleobases with specific preference towards 9- EtG over 9-EtA. CT-DNA studies suggest that photoirradiated complexes interact with DNA via a combined coordinative, intercalative, and monofunctional binding mode. Some of the complexes are also cytotoxic against A2780 human ovarian cancer cell line in the absence of irradiation. The possibility of photo(triggering) hydride-transfer reactions using RuII arene complexes, NAD+, and formate as the hydride source under biologically relevant conditions is shown. The reactions occur either upon the spontaneous hydrolysis of a Ru–Cl bond in complexes of the form [(η6-arene)Ru(N,N')Cl]+ (where N,N' is a bidentate chelating ligand) or upon the photolysis of a Ru–N(Py) bond in [(η6-arene)Ru(N,N')Py]2+ (Py is pyridine). A mechanism involving the formation of a stable formate adduct followed by a hydrogen β- elimination is proposed. It is also demonstrated how a hydride-transfer from 1,4-NADH to some RuII arene chlorido complexes can occur in aqueous solution. Neutral RuII arene complexes of the form [(η6-arene)Ru(NH3)Cl2] which are constitutional analogues of cisplatin were synthesised by a novel synthetic method. These analogues display extensive H-bond interactions in the solid state as shown by X-ray crystal structures determination and their biexponential hydrolysis rates at 310 K vary over many orders of magnitude. The complexes are found to readily form mono- and di-guanine adducts upon hydrolysis but are not cytotoxic against the A2780 human ovarian cancer cell line up to the maximum concentration tested (100 μM)

Design, synthesis and activation of ruthenium arene anticancer complexes

The synthesis and characterisation of RuII complexes of the form [(η6-arene)Ru(N,N')X]+ (where N,N' is a bidentate chelating ligand and X is a halogen) are described; including the X-ray crystal structures of four of these complexes. The hydrolysis rates at 310 K of the complexes vary over many orders of magnitude and in some cases are followed by partial arene loss. Density Functional Theory (DFT) calculations suggest that the aquation mechanism occurs via a more associative pathway. The significant cytotoxic activity towards A2780 human ovarian cancer cells of some of the complexes is found to be dependent on the chelating ligand. Selective binding to 9-ethylguanine (9-EtG) but not to 9- ethyladenine (9-EtA) is observed in aqueous solution at 310 K in all cases. The X-ray crystal structure of a RuII arene 9-EtG adduct is also described. DFT calculations show that the 9- EtG nucleobase adducts of all complexes are thermodynamically preferred compared to those of 9-EtA. Preliminary CT-DNA studies in cell-free media suggest that some of these complexes can interact with DNA. A family of piano-stool RuII arene complexes of the form [(η6-arene)Ru(N,N')(L)]2+ (where N,N' is a chelating ligand and L is a pyridine or a pyridine-derivative), that can selectively photodissociate the monodentate ligand (L) when excited with UVA or visible light is described. The X-ray crystal structures of five of these complexes are also discussed. Their photoactivation allows the formation of a reactive aqua species that otherwise would not form in the dark. Results from TD-DFT calculations suggest that all the RuII pyridine complexes follow a relatively similar L-ligand photodissociation mechanism, likely to occur from a series of 3MC triplet states. It is shown how light activation can be used to phototrigger binding of these complexes to nucleobases with specific preference towards 9- EtG over 9-EtA. CT-DNA studies suggest that photoirradiated complexes interact with DNA via a combined coordinative, intercalative, and monofunctional binding mode. Some of the complexes are also cytotoxic against A2780 human ovarian cancer cell line in the absence of irradiation. The possibility of photo(triggering) hydride-transfer reactions using RuII arene complexes, NAD+, and formate as the hydride source under biologically relevant conditions is shown. The reactions occur either upon the spontaneous hydrolysis of a Ru–Cl bond in complexes of the form [(η6-arene)Ru(N,N')Cl]+ (where N,N' is a bidentate chelating ligand) or upon the photolysis of a Ru–N(Py) bond in [(η6-arene)Ru(N,N')Py]2+ (Py is pyridine). A mechanism involving the formation of a stable formate adduct followed by a hydrogen β- elimination is proposed. It is also demonstrated how a hydride-transfer from 1,4-NADH to some RuII arene chlorido complexes can occur in aqueous solution. Neutral RuII arene complexes of the form [(η6-arene)Ru(NH3)Cl2] which are constitutional analogues of cisplatin were synthesised by a novel synthetic method. These analogues display extensive H-bond interactions in the solid state as shown by X-ray crystal structures determination and their biexponential hydrolysis rates at 310 K vary over many orders of magnitude. The complexes are found to readily form mono- and di-guanine adducts upon hydrolysis but are not cytotoxic against the A2780 human ovarian cancer cell line up to the maximum concentration tested (100 μM).EThOS - Electronic Theses Online ServiceEuropean Union (EU)University of WarwickOverseas Research Students Awards Scheme (ORSAS)Consejo Nacional de Ciencia y Tecnología (Mexico) (CONACYT)GBUnited Kingdo

Photoactivatable organometallic pyridyl ruthenium(II) arene complexes

The synthesis and characterization of a family of piano-stool RuII arene complexes of the type [(η6-arene)Ru(N,N′)(L)][PF6]2, where arene is p-cymene (p-cym), hexamethylbenzene (hmb), or indane (ind), N,N′ is 2,2′-bipyrimidine (bpm), 1,10-phenanthroline (phen), 1,10-phenanthroline-5,6-dione (phendio), or 4,7-diphenyl-1,10-phenanthroline (bathophen), and L is pyridine (Py), 4-methylpyridine (4-MePy), 4-methoxypyridine (4-MeOPy), 4,4′-bipyridine (4,4′-bpy), 4-phenylpyridine (4-PhPy), 4-benzylpyridine (4-BzPy), 1,2,4-triazole (trz), 3-acetylpyridine (3-AcPy), nicotinamide (NA), or methyl nicotinate (MN), are reported, including the X-ray crystal structures of [(η6-p-cym)Ru(bpm)(4-MePy)]2+ (2), [(η6-p-cym)Ru(bpm)(4-BzPy)]2+ (6), [(η6-p-cym)Ru(bpm)(trz)]2+ (7), [(η6-p-cym)Ru(phen)(Py)]2+ (10), and [(η6-ind)Ru(bpy)(Py)]2+ (13). These complexes can selectively photodissociate the monodentate ligand (L) when excited with UVA or white light, allowing strict control of the formation of the reactive aqua species [(η6-arene)Ru(N,N′)(OH2)]2+ that otherwise would not form in the dark. The photoproducts were characterized by UV–vis absorption and 1H NMR spectroscopy. DFT and TD-DFT calculations were employed to characterize the excited states and to obtain information on the photochemistry of the complexes. All the RuII pyridine complexes follow a relatively similar photochemical L-ligand dissociation mechanism, likely to occur from a series of 3MC triplet states with dissociative character. The photochemical process proved to be much more efficient when UVA-range irradiation was used. More strikingly, light activation was used to phototrigger binding of these potential anticancer agents with discriminating preference toward 9-ethylguanine (9-EtG) over 9-ethyladenine (9-EtA). Calf thymus (CT)-DNA binding studies showed that the irradiated complexes bind to CT-DNA, whereas the nonirradiated forms bind negligibly. Studies of CT-DNA interactions in cell-free media suggest combined weak monofunctional coordinative and intercalative binding modes. The RuII arene complexes [(η6-p-cym)Ru(bpm)(Py)]2+ (1), [(η6-p-cym)Ru(bpm)(4-MeOPy)]2+ (3), [(η6-p-cym)Ru(4,4′-bpy)]2+ (4), [(η6-hmb)Ru(bpm)(Py)]2+ (8), [(η6-ind)Ru(bpm)(Py)]2+ (9), [(η6-p-cym)Ru(phen)(Py)]2+ (10), [(η6-p-cym)Ru(bathophen)(Py)]2+ (12), [(η6-p-cym)Ru(bpm)(NA)]2+ (15), and [(η6-p-cym)Ru(bpm)(MN)]2+ (16) were cytotoxic toward A2780 human ovarian cancer cell line in the absence of photoirradiation (IC50 values in the range of 9.0–60 μM)

Bipyrimidine ruthenium(II) arene complexes : structure, reactivity and cytotoxicity

The synthesis and characterization of complexes [(η6-arene)Ru(N,N′)X][PF6], where arene is para-cymene (p-cym), biphenyl (bip), ethyl benzoate (etb), hexamethylbenzene (hmb), indane (ind) or 1,2,3,4-tetrahydronaphthalene (thn), N,N′ is 2,2′-bipyrimidine (bpm) and X is Cl, Br or I, are reported, including the X-ray crystal structures of [(η6-p-cym)Ru(bpm)I][PF6], [(η6-bip)Ru(bpm)Cl][PF6], [(η6-bip)Ru(bpm)I][PF6] and [(η6-etb)Ru(bpm)Cl][PF6]. Complexes in which N,N′ is 1,10-phenanthroline (phen), 1,10-phenanthroline-5,6-dione or 4,7-diphenyl-1,10-phenanthroline (bathophen) were studied for comparison. The RuII arene complexes undergo ligand-exchange reactions in aqueous solution at 310 K; their half-lives for hydrolysis range from 14 to 715 min. Density functional theory calculations on [(η6-p-cym)Ru(bpm)Cl][PF6], [(η6-p-cym)Ru(bpm)Br][PF6], [(η6-p-cym)Ru(bpm)I][PF6], [(η6-bip)Ru(bpm)Cl][PF6], [(η6-bip)Ru(bpm)Br][PF6] and [(η6-bip)Ru(bpm)I][PF6] suggest that aquation occurs via an associative pathway and that the reaction is thermodynamically favourable when the leaving ligand is I > Br ≈ Cl. pK a* values for the aqua adducts of the complexes range from 6.9 to 7.32. A binding preference for 9-ethylguanine (9-EtG) compared with 9-ethyladenine (9-EtA) was observed for [(η6-p-cym)Ru(bpm)Cl][PF6], [(η6-hmb)Ru(bpm)Cl]+, [(η6-ind)Ru(bpm)Cl]+, [(η6-thn)Ru(bpm)Cl]+, [(η6-p-cym)Ru(phen)Cl]+ and [(η6-p-cym)Ru(bathophen)Cl]+ in aqueous solution at 310 K. The X-ray crystal structure of the guanine complex [(η6-p-cym)Ru(bpm)(9-EtG-N7)][PF6]2 shows multiple hydrogen bonding. Density functional theory calculations show that the 9-EtG adducts of all complexes are thermodynamically preferred compared with those of 9-EtA. However, the bmp complexes are inactive towards A2780 human ovarian cancer cells. Calf thymus DNA interactions for [(η6-p-cym)Ru(bpm)Cl][PF6] and [(η6-p-cym)Ru(phen)Cl][PF6] consist of weak coordinative, intercalative and monofunctional coordination. Binding to biomolecules such as glutathione may play a role in deactivating the bpm complexes

Design of photoactivatable metallodrugs : selective and rapid light-induced ligand dissociation from half-sandwich [Ru([9]aneS3)(N–N′)(py)]2+ complexes

The synthesis of the inert Ru(II) half-sandwich coordination compounds, [Ru([9]aneS3)(bpy)(py)][PF6]2 (1, [9]aneS3 = 1,4,7-trithiacyclononane, bpy = 2,2′-bipyridine, py = pyridine), [Ru([9]aneS3)(en)(py)][PF6]2 (2, en = 1,2-diaminoethane), and [Ru([9]aneN3)(en)(dmso-S)][PF6]2 (3, [9]aneN3 = 1,4,7-triazacyclononane), is reported along with the X-ray crystal structure of 1. We investigated whether these complexes have photochemical properties which might make them suitable for use as pro-drugs in photochemotherapy. Complexes 1 and 2 underwent rapid (minutes) aquation with dissociation of the pyridine ligand in aqueous solution when irradiated with blue light (λ = 420 or 467 nm). The photodecomposition of 3 was much slower. All complexes readily formed adducts with 9-ethylguanine (9-EtG) when this model nucleobase was present in the photolysis solution. Similarly, complex 1 formed adducts with the tripeptide glutathione (GSH), but only when photoactivated. HPLC and MS studies of 1 showed that irradiation promoted rapid formation of 1:1 (major) and 1:2 (minor) adducts of the oligonucleotide d(ATACATGCTACATA) with the fragment {Ru([9]aneS3)(bpy)}2+. Density functional theory (DFT) calculations and time-dependent DFT reproduced the major features of the absorption spectra and suggested that the lowest-lying triplet state with 3MLCT character, which is readily accessible via intersystem crossing, might be responsible for the observed dissociative behavior of the excited states. These complexes are promising for further study as potential photochemotherapeutic agents

Redox-active and DNA-binding coordination complexes of clotrimazole

DNA interactions of anticancer mononuclear Cu2+, Co2+, Zn2+, and Ni2+ complexes with the biologically active ligand clotrimazole (clotri) are reported. To fully characterize DNA binding modes for these complexes of the formulae [M(clotri)2Cl2]·nH2O (1–4), [M(clotri)2Br2]·nH2O (5,6), [M(clotri)3NO3]NO3·nH2O (9), and [M(clotri)3(NO3)2] (10), circular dichroism (CD) and linear dichroism (LD) spectroscopy, UV melting experiments, atomic force microscopy (AFM) and ethidium bromide (EtBr) displacement methods were used. Results indicate mixed electrostatic interactions, possibly through groove binding, that result in accretion and coiling of DNA. Electrochemical studies indicate that the Cu2+ complex 9 readily reduces to the reactive-oxygen-species-generating Cu+, which oxidatively damages DNA. There is a subtle correlation between log P values, calculated electrostatic potentials, and cytotoxicity of the complexes. The extent of cell-nucleus DNA-metal adduct formation in the HeLa cervix-uterine carcinoma cell line does not necessarily correlate with cytotoxicity, indicating that the nature of DNA lesions may be crucial to activity

The potent oxidant anticancer activity of organoiridium catalysts

YesPlatinum complexes are the most widely used anticancer drugs; however, new generations of agents are needed. The organoiridium(III) complex [(η5-Cpxbiph)Ir(phpy)(Cl)] (1-Cl), which contains π-bonded biphenyltetramethylcyclopentadienyl (Cpxbiph) and C^N-chelated phenylpyridine (phpy) ligands, undergoes rapid hydrolysis of the chlorido ligand. In contrast, the pyridine complex [(η5-Cpxbiph)Ir(phpy)(py)]+ (1-py) aquates slowly, and is more potent (in nanomolar amounts) than both 1-Cl and cisplatin towards a wide range of cancer cells. The pyridine ligand protects 1-py from rapid reaction with intracellular glutathione. The high potency of 1-py correlates with its ability to increase substantially the level of reactive oxygen species (ROS) in cancer cells. The unprecedented ability of these iridium complexes to generate H2O2 by catalytic hydride transfer from the coenzyme NADH to oxygen is demonstrated. Such organoiridium complexes are promising as a new generation of anticancer drugs for effective oxidant therapy.We thank the ERC (247450), SNSF (PA00P2_145308 for N.P.E.B.), IAS (for I.R.C.), BBSRC (for J.M.H.), Science City (AWM and ERDF), and the EPSRC for support, and Prof. Timothy Bugg and members of EC COST Action CM1105 for stimulating discussions. We also thank Professor Pat Unwin, Mike Snowden, and Rob Lazenby for their help with the electrochemical experiments and the National Cancer Institute for NCI-60 human tumor cell panel screening

Designing organometallic compounds for catalysis and therapy

Bioorganometallic chemistry is a rapidly developing area of research. In recent years organometallic compounds have provided a rich platform for the design of effective catalysts, e.g. for olefin metathesis and transfer hydrogenation. Electronic and steric effects are used to control both the thermodynamics and kinetics of ligand substitution and redox reactions of metal ions, especially Ru II. Can similar features be incorporated into the design of targeted organometallic drugs? Such complexes offer potential for novel mechanisms of drug action through incorporation of outer-sphere recognition of targets and controlled activation features based on ligand substitution as well as metal- and ligand-based redox processes. We focus here on η 6-arene, η 5-cyclopentadienyl sandwich and half-sandwich complexes of Fe II, Ru II, Os II and Ir III with promising activity towards cancer, malaria, and other conditions. © 2012 The Royal Society of Chemistry

The contrasting chemical reactivity of potent isoelectronic iminopyridine and azopyridine osmium(ii) arene anticancer complexes

A wide variety of steric and electronic features can be incorporated into transition metal coordination complexes, offering the prospect of rationally-designed therapeutic agents with novel mechanisms of action. Here we compare the chemical reactivity and anticancer activity of organometallic OsII complexes [Os(η6-arene)(XY)Z]PF6 where arene = p-cymene or biphenyl, XY = N,N′-chelated phenyliminopyridine or phenylazopyridine derivatives, and Z = Cl or I. The X-ray crystal structure of [Os(η6-p-cym)(Impy-OH)I]PF6·0.5CH2Cl2·H2O (Impy-OH = 4-[(2-pyridinylmethylene)amino]-phenol) is reported. Like the azopyridine complexes we reported recently (Dalton Trans., 2011, 40, 10553–10562), some iminopyridine complexes are also potently active towards cancer cells (nanomolar IC50 values). However we show that, unlike the azopyridine complexes, the iminopyridine complexes can undergo aquation, bind to the nucleobase guanine, and oxidize coenzyme nicotine adenine dinucleotide (NADH). We report the first detection of an Os-hydride adduct in aqueous solution by 1H NMR (−4.2 ppm). Active iminopyridine complexes induced a dramatic increase in the levels of reactive oxygen species (ROS) in A549 lung cancer cells. The anticancer activity may therefore involve interference in the redox signalling pathways in cancer cells by a novel mechanism