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

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

Organometallic cis-Dichlorido ruthenium(II) ammine complexes

Bifunctional neutral half-sandwich RuII complexes of the type [(η6-arene)Ru(NH3)Cl2] where arene is p-cym (1) or bip (2) were synthesised by the reaction of N,N-dimethylbenzylamine (dmba), NH4PF6 and the corresponding RuII arene dimer, and were fully characterised. X-ray crystallographic studies of [(η6-p-cym)Ru(NH3)Cl2]·{(dmba–H)(PF6)} (1a) and [(η6-bip)Ru(NH3)Cl2] (2) show extensive H-bond interactions in the solid state, mainly involving the NH3 and the Cl ligands, as well as weak aromatic stacking interactions. The half-lives for the sequential hydrolysis of 1 and 2 determined by UV/Vis spectroscopy at 310 K ranged from a few minutes for the first aquation to ca. 45 min for the second aquation; the diaqua adducts were the predominant species at equilibrium. Arene loss during the aquation of complex 2 was observed. Upon hydrolysis, both complexes readily formed mono- and di-9-ethylguanine (9-EtG) adducts in aqueous solution at 310 K. The reaction reached equilibrium after ca. 1.8 h in the case of complex 1 and was slower but more complete for complex 2 (before the onset of arene loss at ca. 2.7 h). Complexes 1 and 2 were not cytotoxic towards A2780 human ovarian cancer cells up to the maximum concentration tested (100 μM)

Transfer hydrogenation reactions of photoactivatable N, N '-chelated ruthenium(II) arene complexes

We show that the reaction of Ru-II arene chlorido complexes of the type [(eta(6)-arene) Ru(N, N')Cl](+) arene = p-cymene (p-cym), hexamethylbenzene (hmb), indane (ind), N, N' = bipyrimidine (bpm) and 1,10-phenanthroline (phen) with excess sodium formate generates a very stable formate adduct through spontaneous hydrolysis of the Ru-Cl bond at 310 K and pH* = 7.0. The formate adducts are also produced when Ru-II arene pyridine complexes of the type [(eta(6)-arene) Ru(N, N')(Py)](2+) (where Py = pyridine), are irradiated with UVA (lambda(irr) = 300-400 nm) or visible light (lambda(irr) = 400-660 nm) under the same conditions. The Ru-II arene formato adducts do not catalyse the reduction of acetone through transfer hydrogenation. However, all the complexes (except complex 2 which contains phen as the chelating ligand) can catalyse the regioselective reduction of NAD(+) in the presence of formate (25 mol equiv) in aqueous solution to form 1,4-NADH. The catalytic activity is dependent on the nature of the chelating ligand. Most interestingly, the regioselective reduction of NAD(+) to 1,4-NADH can be also specifically triggered by photoactivating a Ru-II arene Py complex

Photocontrolled nucleobase binding to an organometallic Ru-II arene complex

The complex [(p-cym)Ru(bpm)(py)][PF6](2) (where p-cym = para-cymene, bpm = 2,2'-bipyrimidine and py = pyridine) is the first ruthenium(II) arene complex that can selectively photodissociate a monodentate ligand (py) when excited with visible light and form a reactive aqua derivative able to bind to a DNA base