Photocytotoxicity and photoinduced phosphine ligand exchange in a Ru(ii) polypyridyl complex

Two new tris-heteroleptic Ru(ii) complexes with triphenylphosphine (PPh₃) coordination, cis-[Ru(phen)₂(PPh₃)(CH₃CN)]²⁺ (1a, phen = 1,10-phenanthroline) and cis-[Ru(biq)(phen)(PPh₃)(CH₃CN)]²⁺ (2a, biq = 2,2′-biquinoline), were synthesized and characterized for photochemotherapeutic applications. Upon absorption of visible light, 1a exchanges a CH₃CN ligand for a solvent water molecule. Surprisingly, the steady-state irradiation of 2a followed by electronic absorption and NMR spectroscopies reveals the photosubstitution of the PPh₃ ligand. Phosphine photoinduced ligand exchange with visible light from a Ru(ii) polypyridyl complex has not previously been reported, and calculations reveal that it results from a trans-type influence in the excited state. Complexes 1a and 2a are not toxic against the triple negative breast cancer cell line MDA-MB-231 in the dark, but upon irradiation with blue light, the activity of both complexes increases by factors of >4.2 and 5.8, respectively. Experiments with PPh₃ alone show that the phototoxicity observed for 2a does not arise from the released phosphine ligand, indicating the role of the photochemically generated ruthenium aqua complex on the biological activity. These complexes represent a new design motif for the selective release of PPh₃ and CH₃CN for use in photochemotherapy.

New Ru(ii) complexes exhibit selective ligand dissociation driven by an excited state trans-type influence. The complexes are not toxic to triple-negative breast cancer cells in the dark, but induce cell death upon irradiation with visible light.     

Effect of electronic structure on the photoinduced ligand exchange of Ru(II) polypyridine complexes

The series of complexes [Ru(bpy)(2)(L)](2+), where bpy = 2,2'-bipyridine and L = 3,6-dithiaoctane (bete, 1), 1,2-bis(phenylthio)ethane (bpte, 2), ethylenediamine (en, 3), and 1,2-dianilinoethane (dae, 4), were synthesized, and their photochemistry was investigated. Photolysis experiments show that the bisthioether ligands in 1 and 2 are more easily photosubstituted by chloride ions, bpy, and H(2)O than the corresponding diammine complexes in 3 and 4 to generate the bis-substituted products. Electronic structure calculations show that bond elongation in the lowest energy triplet metal-to-ligand charge transfer ((3)MLCT) state compared to the ground state is greater for complexes containing bisthioether ligands than those with coordinated bidentate nitrogen atoms. This elongation in the excited state is attributed to Ru-S π-bonding character of the highest occupied molecular orbitals, which is not present in the diamine complexes. In the Ru→bpy (3)MLCT state, the lower electron density on the metal-centered highest occupied molecular orbital (HOMO) weakens the Ru-S bond and results in the greater photoreactivity of 1 and 2 relative to that of 3 and 4. The more efficient photoinduced ligand exchange of the complexes possessing thioether ligands results in binding of 1 and 2 to DNA upon irradiation.     

Structure and oxygenase activity of the iron(ii) complex with pyridylcarboxamide ligand

A reaction of Fe(ClO₄)₂·6H₂O or Fe(OTf)₂(MeCN)₂ with one equivalent of the tetradentate ligand bis(2-pyridyl)methyl-2-pyridylcarboxamide (Py₂CHNHCOPy, tpcaH) furnished dimeric iron(II) complexes [Fe(tpcaH)]₂X₄ (X = ClO₄ ^? (1a), OTf^? (1b)). According to the X-ray diffraction data for the complex 1a, each iron atom is bound to the two pyridyl fragments of one ligand and the pyridylcarboxamide pair of the other one. Complex 1a is a dimer in the crystalline state, while in MeCN solution according to the mass spectrometric data with the electrospray ionization, ¹H NMR spectroscopic data, and quantum chemical calculations, it is apparently in the equilibrium with monomers of different structures. Complex 1 catalyzes selective oxidation of saturated hydrocarbons with hydrogen peroxide presumably involving the perferryl intermediate, which has an N,N,O-facial coordination of potentially tetradentate ligand tpcaH structurally modeling the 2-histidine-1-carboxylate-facial triad of the nonheme oxygenases.     

A quantum chemical consideration of ligand exchange in palladium(ii) aqueous and chloride complexes

The behavior of potassium tetrachloropalladate(II) in media simulating biological fluids has been studied. In aqueous solutions of NaCl, the aquation rate is higher than the rate of chloro ligand introduction into the internal coordination sphere of palladium. In HCl solutions, on the contrary, the process of palladium chloro complex formation predominates. The latter is apparently due to protonation of water molecules composing aqua complexes. By means of the ZINDO/1 method, the substitution of ligands – water molecules and hydronium ion – in planar complexes of palladium(II) by chloride ion has been investigated. All complexes containing H₂O and H₃O⁺ ligands, other than [Pd(H₂O)₄]²⁺, have intramolecular hydrogen bonds. In [Pd(H₂O)₃(H₃O)]³⁺ and trans-[Pd(H₂O)₂(H₃O)Cl]²⁺, a “non-classic” symmetric hydrogen bond O ··· H ··· O is established (ZINDO/1, RHF/STO-6G*). By the first three steps the substitution of hydronium ion in the internal sphere of palladium atom is more favorable thermodynamically, compared to water molecules. Logarithms of stepwise stability constants of palladium(II) chloride complexes correlate linearly to enthalpies (ZINDO/1, PM3) of water substitution by chloride ion.     

Formation of a tetranuclear nickel(ii) complex containing an unusual bridging ligand

Russian Chemical Bulletin -     

Combination of Ru(ii) complexes and light: new frontiers in cancer therapy

The synergistic action of light, oxygen and a photosensitizer (PS) has found applications for decades in medicine under the name of photodynamic therapy (PDT) for the treatment of skin diseases and, more recently, for the treatment of cancer. However, of the thirteen PSs currently approved for the treatment of cancer over more than 10 countries, only two contain a metal ion. This fact is rather surprising considering that nowadays around 50% of conventional chemotherapies involve the use of cisplatin and other platinum-containing drugs. In this perspective article, we review the opportunities brought by the use of Ru(ii) complexes as PSs in PDT. In addition, we also present the recent achievements in the application of Ru(ii) complexes in photoactivated chemotherapy (PACT). In this strategy, the presence of oxygen is not required to achieve cell toxicity. This is of significance since tumors are generally hypoxic. Importantly, this perspective article focuses particularly on the Ru(ii) complexes for which an in vitro biological evaluation has been performed and the mechanism of action (partially) unveiled.     

Coupling of C-amino aza-substituted heterocycles with an isocyanide ligand in palladium(ii) complex

The reaction of cis-dichlorobis(2,6-xylylisocyanide)palladium(ii) with 2-aminopyrazine affords a binuclear palladium complex, in which one of the metal atoms is involved in the palladacyclic ligand. In the contrast, the coupling of isocyanide ligands in cis-dichlorobis-(2,6-xylylisocyanide)palladium(ii) with another C-amino aza-substituted heterocycle, viz.,4-acetyl-3-amino-5-methylpyrazole, gives a mononuclear cationic palladium diaminocarbene complex. Both compounds were characterized by elemental analysis, IR spectroscopy, ¹H, ¹³C{₁H}, DEPT90/DEPT135, and ¹H,¹³C-HSQC/¹H,¹³C-HMBC NMR spectroscopy, high-resolution electrospray ionization mass spectrometry, and X-ray diffraction.     

Near-infrared absorbing Ru(ii) complexes act as immunoprotective photodynamic therapy (PDT) agents against aggressive melanoma

Mounting evidence over the past 20 years suggests that photodynamic therapy (PDT), an anticancer modality known mostly as a local treatment, has the capacity to invoke a systemic antitumor immune response, leading to protection against tumor recurrence. For aggressive cancers such as melanoma, where chemotherapy and radiotherapy are ineffective, immunomodulating PDT as an adjuvant to surgery is of interest. Towards the development of specialized photosensitizers (PSs) for treating pigmented melanomas, nine new near-infrared (NIR) absorbing PSs based on a Ru(ii) tris-heteroleptic scaffold [Ru(NNN)(NN)(L)]Cl_n, were explored. Compounds 2, 6, and 9 exhibited high potency toward melanoma cells, with visible EC₅₀ values as low as 0.292–0.602 μM and PIs as high as 156–360. Single-micromolar phototoxicity was obtained with NIR-light (733 nm) with PIs up to 71. The common feature of these lead NIR PSs was an accessible low-energy triplet intraligand (³IL) excited state for high singlet oxygen (¹O₂) quantum yields (69–93%), which was only possible when the photosensitizing ³IL states were lower in energy than the lowest triplet metal-to-ligand charge transfer (³MLCT) excited states that typically govern Ru(ii) polypyridyl photophysics. PDT treatment with 2 elicited a pro-inflammatory response alongside immunogenic cell death in mouse B16F10 melanoma cells and proved safe for in vivo administration (maximum tolerated dose = 50 mg kg⁻¹). Female and male mice vaccinated with B16F10 cells that were PDT-treated with 2 and challenged with live B16F10 cells exhibited 80 and 55% protection from tumor growth, respectively, leading to significantly improved survival and excellent hazard ratios of ≤0.2.

Ru(ii) photosensitizers (PSs) destroy aggressive melanoma cells, triggering an immune response that leads to protection against tumor challenge and mouse survival.     

Redox,spectroscopic, photo-induced ligand exchange,and DNA interaction studies of a new Ru(II)Pt(II) bimetallic complex

A new bimetallic complex, [Ru(biq)₂(dpp)PtCl₂](PF₆)₂ (where biq = 2,2′-biquinoline and dpp = 2,3-bis(2-pyridyl)pyrazine), containing a cis-PtCl₂ moiety coupled to a sterically strained Ru(II)-based chromophore was designed, synthesized, and investigated with respect to its spectroscopic, redox, photo-induced ligand exchange, and DNA-interaction properties. The electrochemistry of the designed complex was found to be consistent with the bridging coordination of the dpp ligand and formation of the bimetallic complex. The complex displays intense ligand-based π → π* transitions in the UV region and metal-to-ligand charge-transfer transitions (MLCT) in the visible region. The loss of bridging coordination of the dpp ligand and formation of complexes, [Ru(biq)₂(CH₃CN)₂]²⁺ and [Pt(dpp)(CH₃CN)₂]²⁺ was observed when an acetonitrile solution of the metal complex was irradiated with visible light (λ_irr ≥ 550 nm). The designed complex displays covalent binding with DNA in dark through the cis-PtCl₂ moiety, as confirmed by agarose gel electrophoresis. Upon photoirradiation, the complex dissociates into two DNA-binding moieties and displays covalent binding through: (i) a cis-PtL₂ subunit of [Ptdpp(L)₂]²⁺ and (ii) open coordination sites of the ruthenium of [Ru(biq)₂(L)₂]²⁺ (L = solvent). The designed complex represents the first Ru(II)Pt(II) complex that undergoes photo-induced ligand exchange and displays multifunctional interactions with DNA upon photoirradiation.     

Strain-induced substitutional lability in a Ru(II) complex of a hypodentate polypyridine ligand

The ruthenium(II) complex of heptadentate N,N,N',N'-tetrakis(2-pyridylmethyl)-2,6-bis(aminomethyl)pyridine (tpap) was isolated as the hexafluorophosphate complex Ru(tpap)(PF6)2. The crystal structure has been determined for the triflate salt Ru(tpap)(CF3SO3)2.2H2O, which crystallizes in the monoclinic space group P2(1)/n. The structure was refined to a final R value of 0.0549 for 5894 observed reflections. The heptadentate ligand coordinates with six nitrogens, i.e. with two tertiary nitrogens and four pyridine nitrogens, one of the pyridines remaining un-coordinated. The resulting structure is significantly distorted from octahedral geometry with an equatorial Nsp3-Ru-Npyridine angle of 120 degrees. The consequence of the above steric strain is a labilization of the system and fluxional behaviour involving exchange between equatorially coordinated and non-coordinated pyridines has been observed by 1H NMR for Ru(tpap)(PF6)2 in d6-acetone solution. The activation parameters of DeltaG(not equal to 298) = 53 kJ mol(-1), DeltaH(not equal) = 56 +/- 1 kJ mol(-1) and DeltaS(not equal) = -10 +/- 3 J mol(-1) K(-1) were determined on the basis of NMR experiments. In addition electronic structure calculations applying density functional theory (DFT) have been performed in order to identify a transition state and to estimate the activation barrier. On the basis of NMR and DFT results the mechanism of isoexchange involving a hepta-coordinated intermediate has been proposed.     

Effect of the addition of a fused donor-acceptor ligand on a Ru(II) complex: synthesis, characterization, and photoinduced electron transfer reactions of [Ru(TTF-dppz)2(Aqphen)]2+

The synthesis and the photophysical properties of the complex [Ru(TTF-dppz)(2)(Aqphen)](2+) (TTF = tetrathiafulvalene, dppz = dipyrido-[3,2-a:2',3'-c]phenazine, Aqphen = anthraquinone fused to phenanthroline via a pyrazine bridge) are described. In this molecular triad excitation into the metal-ligand charge transfer bands results in the creation of a long-lived charge separated state with TTF acting as electron donor and anthraquinone as terminal acceptor. The lifetime of the charge-separated state is 400 ns in dichloromethane at room temperature. A mechanism for the charge separation involving an intermediate charge-separated state is proposed based on transient absorption spectroscopy.     

CO/light dual-activatable Ru(ii)-conjugated oligomer agent for lysosome-targeted multimodal cancer therapeutics

Stimuli-activatable and subcellular organelle-targeted agents with multimodal therapeutics are urgently desired for highly precise and effective cancer treatment. Herein, a CO/light dual-activatable Ru(ii)-oligo-(thiophene ethynylene) (Ru-OTE) for lysosome-targeted cancer therapy is reported. Ru-OTE is prepared via the coordination-driven self-assembly of a cationic conjugated oligomer (OTE-BN) ligand and a Ru(ii) center. Upon the dual-triggering of internal gaseous signaling molecular CO and external light, Ru-OTE undergoes ligand substitution and releases OTE-BN followed by dramatic fluorescence recovery, which could be used for monitoring drug delivery and imaging guided anticancer treatments. The released OTE-BN selectively accumulates in lysosomes, physically breaking their integrity. Then, the generated cytotoxic singlet oxygen (¹O₂) causes severe lysosome damage, thus leading to cancer cell death via photodynamic therapy (PDT). Meanwhile, the release of the Ru(ii) core also suppresses cancer cell growth as an anticancer metal drug. Its significant anticancer effect is realized via the multimodal therapeutics of physical disruption/PDT/chemotherapy. Importantly, Ru-OTE can be directly photo-activated using a two-photon laser (800 nm) for efficient drug release and near-infrared PDT. Furthermore, Ru-OTE with light irradiation inhibits tumor growth in an MDA-MB-231 breast tumor model with negligible side effects. This study demonstrates that the development of an activatable Ru(ii)-conjugated oligomer potential drug provides a new strategy for effective subcellular organelle-targeted multimodal cancer therapeutics.

The anticancer therapeutics of lysosome disruption/PDT/chemotherapy based on Ru-OTE complex was achieved, which provides a new strategy for developing multimodal and effective stimuli-activatable subcellular organelle-targeted cancer therapeutics.     

Preparation of technetium-99m-humic complex by ligand exchange from hexakis (thiourea-S)technetium(III) complex

The preparation of technetium-99m-humic complex without presence of any metal reductant was studied. For the preparation of Tc-HA complex by ligand substitution hexakis(thiourea-S)technetium(III) complex was used as a precursor. Ligand exchanging reaction was studied with two different humate/thiourea concentration ratios. After mixing of [^99mTc(tu)₆]³⁺ complex with natrium humate under a nitrogen atmosphere a formation of technetium humate wasobserved. The determination of reaction products was performed by combination of gel and paper chromatography. Reaction yields are dependent on humate/thiourea concentration ratio and reaction time. Tc-HA complex was obtained with the highest yield of 62%. Reaction mixture also contains a technetium dioxide as a side product of exchanging reaction and other technetium species, which are also discussed. Oxidation state of technetium in prepared Tc-HA complex is apparently unchanged.     

Photochemical and thermal ligand exchange in a ruthenium(II) complex based on a scorpionate terpyridine ligand

A ruthenium(II) complex containing a 1,10-phenanthroline unit and a terpyridine fragment covalently linked to a benzonitrile group has been synthesised; coordination and decoordination of the benzonitrile group can be induced thermally and photochemically respectively, in an acetone-water mixture.     

Correspondence of Ru(III) Ru(II) and Ru(IV) Ru(III) mixed valent states in a small dinuclear complex

The diruthenium(III) compound [(μ-oxa){Ru(acac)(2)}(2)] [1, oxa(2-) =oxamidato(2-), acac(-) =2,4-pentanedionato] exhibits an S=1 ground state with antiferromagnetic spin-spin coupling (J=-40 cm(-1)). The molecular structure in the crystal of 1?2 C(7)H(8) revealed an intramolecular metal-metal distance of 5.433 ? and a notable asymmetry within the bridging ligand. Cyclic voltammetry and spectroelectrochemistry (EPR, UV/Vis/NIR) of the two-step reduction and of the two-step oxidation (irreversible second step) produced monocation and monoanion intermediates (K(c) =10(5.9)) with broad NIR absorption bands (ε ca. 2000 M(-1)cm(-1)) and maxima at 1800 (1(-)) and 1500 nm (1(+)). TD-DFT calculations support a Ru(III)Ru(II) formulation for 1(-) with a doublet ground state. The 1(+) ion (Ru(IV)Ru(III)) was calculated with an S=3/2 ground state and the doublet state higher in energy (ΔE=694.6 cm(-1)). The Mulliken spin density calculations showed little participation of the ligand bridge in the spin accommodation for all paramagnetic species [(μ-oxa){Ru(acac)(2)}(2)](n), n=+1, 0, -1, and, accordingly, the NIR absorptions were identified as metal-to-metal (intervalence) charge transfers. Whereas only one such NIR band was observed for the Ru(III)Ru(II) (4d(5)/4d(6)) system 1(-), the Ru(IV)Ru(III) (4d(4)/4d(5)) form 1(+) exhibited extended absorbance over the UV/Vis/NIR range.     

Syntheses of homopolymer and water-soluble polymers containing tetraphenylporphinatomanganese(III) complex,and ligand substitution reaction for anionic ligand

A vinyl monomer containing the pendant tetraphenylporphyrin (TPP) group, 4-vinyltetraphenylporphyrin (VTPP), was synthesized. A homopolymer (PVTPP) which is insoluble in water, and three water-soluble polymers were obtained by radical polymerization. The water-soluble polymers are two anionic polymers (PVPTSPP and PVTPP-StSO₃) and a cationic polymer (PVTPP-VPyM). PVPTSPP has sulfonic acid groups in a TPP group and very high charge density. PVTPP-StSO₃ was obtained by copolymerization of VTPP and sodium 4-styrenesulfonate. PVTPP-VPyM was obtained by quarternarization of a copolymer of VTPP and 4-vinylpyridine. Polymeric manganese(III) complexes (PMn-VTPP, PMnVPTSPP, PMnVTPP-StSO₃, and PMnVTPP-VPyM) were prepared from the polymers and manganese acetate. The acetate ligand in PMnVTPP can be easily substituted by another ligand such as Cl^?, AcO^?, OH^?, and SCN^?. The substitution reaction occurs in the interface between water and chloroform. The sulfonated homopolymer, PMnVPTSPP, cannot incorporate with anionic ligands because of the strong electrostatic repulsion. In the anionic copolymer, PMnVTPP-StSO₃, the ligand substitution reaction with SCN ligand needs activation energy of 53 kJ/mol. In the cationic polymer complex, PMnVTPP-VPyM, the OH ligand can be easily substituted with the SCN ligand and the equilibrium constant of the reaction was estimated at 1.38 × 10^?3. © 1994 John Wiley & Sons, Inc.     

Azide ligand substitution reaction in zinc bis(diethyldithiocarbamate)

The azide ligand substitution reaction in tetrahedral zinc bis(diethyldithiocarbamate) has been studied by extraction. The reaction has been shown to proceed by both solvent and azide ion interactions with k₀ = 5.0 × 10⁻⁴ s⁻¹ and k₁ = 1.9 × 10⁻³ M⁻¹ s⁻¹. A general discussion of the reaction mechanism is provided.     

Charge transfer interactions of a Ru(II) dye complex and related ligand molecules adsorbed on Au(111)

The interaction of the dye molecule, N3 (cis-bis(isothiocyanato)bis(2,2(')-bipyridyl-4,4(')-dicarboxylato)-ruthenium(II)), and related ligand molecules with a Au(111) surface has been studied using synchrotron radiation-based electron spectroscopy. Resonant photoemission spectroscopy (RPES) and autoionization of the adsorbed molecules have been used to probe the coupling between the molecules and the substrate. Evidence of charge transfer from the states near the Fermi level of the gold substrate into the lowest unoccupied molecular orbital (LUMO) of the molecules is found in the monolayer RPES spectra of both isonicotinic acid and bi-isonicotinic acid (a ligand of N3), but not for the N3 molecule itself. Calibrated x-ray absorption spectroscopy and valence band spectra of the monolayers reveals that the LUMO crosses the Fermi level of the surface in all cases, showing that charge transfer is energetically possible both from and to the molecule. A core-hole clock analysis of the resonant photoemission reveals a charge transfer time of around 4 fs from the LUMO of the N3 dye molecule to the surface. The lack of charge transfer in the opposite direction is understood in terms of the lack of spatial overlap between the π?-orbitals in the aromatic rings of the bi-isonicotinic acid ligands of N3 and the gold surface.     

Ferromagnetic exchange in a dinuclear copper(II) complex mediated by a methanolate bridging ligand

The copper(II) complex Cu(2)L(OMe)(H(2)O)(3), [middle dot]3H(2)O [H(3)L = 2-(2-hydroxyphenyl)-1,3-bis[4-(2-hydroxyphenyl)-3-azabut-3-enyl]-1,3-imidazolidine] was obtained and recrystallised in methanol to yield crystals of [[Cu(2)L(OMe)]](2).2.5MeOH.4H(2)O, 1.2.5MeOH.4H(2)O. Its single X-ray study shows that it contains two crystallographically different but chemically equivalent dinuclear [Cu(2)L(OMe)] 1 molecules in the asymmetric unit cell. The copper atoms of each dinuclear moiety are in distorted square-pyramidal environments, with both pyramids sharing an apical phenolate and a basal methanolate oxygen atom. Magnetic characterisation of 1.3H(2)O shows a quite strong intramolecular ferromagnetic coupling between both metal atoms. Extended Huckel calculations reveal that the intradinuclear magnetic interaction seems to be mediated by the exogenous methanolate bridging ligand.