RESUMO
Efforts to find compounds selectively affecting cancer cells while sparing normal ones have continued to grow. Nitric oxide (NO) is critical in physiology and pathology, including cancer. It influences cellular processes like proliferation, apoptosis, and angiogenesis. The intricate interaction of NO with cancer cells offers innovative treatment possibilities, but its effects can vary by concentration and site. Ruthenium complexes capable of releasing NO upon stimulation show for this purpose. These versatile compounds can also enhance photodynamic therapy (PDT), a light-activated approach, which induces cellular damage. Ruthenium-based photosensitizers (PSs), delivering NO and producing reactive oxygen species (ROS), offer a novel strategy for improved cancer treatments. In this study, a nitro-ruthenium porphyrin conjugate: {TPyP[Ru(NO2)(bpy)2]4}(PF6)4, designated RuNO2TPyP, which releases NO upon irradiation, was investigated for its effects on lung cells (non-tumor MRC-5 and tumor A549) in 2D and 3D cell cultures. The findings suggest that this complex has potential for PDT treatment in lung cancer, as it exhibits photocytotoxicity at low concentrations without causing cytotoxicity to normal lung cells. Moreover, treatment of cells with RuNO2TPyP followed by light irradiation (4 J cm-2) can induce apoptosis, generate ROS, promote intracellular NO formation, and has anti-migratory effects. Additionally, the complex can modify tumor cell structures and induce photocytotoxicity and apoptosis in a 3D culture. These outcomes are attributed to the internalization of the complex and its subsequent activation upon light irradiation, resulting in NO release and singlet oxygen production.
Assuntos
Complexos de Coordenação , Luz , Neoplasias Pulmonares , Óxido Nítrico , Fármacos Fotossensibilizantes , Rutênio , Óxido Nítrico/metabolismo , Humanos , Rutênio/química , Rutênio/farmacologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Complexos de Coordenação/farmacologia , Complexos de Coordenação/química , Complexos de Coordenação/síntese química , Porfirinas/química , Porfirinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/química , Metaloporfirinas/química , Metaloporfirinas/farmacologia , Fotoquimioterapia , Espécies Reativas de Oxigênio/metabolismo , Apoptose/efeitos dos fármacos , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacosRESUMO
Dinitrosyl iron complexes (DNICs) are spontaneously and rapidly generated in cells. Their assembly requires nitric oxide (NO), biothiols, and nonheme iron, either labile iron or iron-sulfur clusters. Despite ubiquitous detection by electron paramagnetic resonance in NO-producing cells, the DNIC's chemical biology remains only partially understood. In this Forum Article, we address the reaction mechanisms for endogenous DNIC formation, with a focus on a labile iron pool as the iron source. The capability of DNICs to promote S-nitrosation is discussed in terms of S-nitrosothiol generation associated with the formation and chemical reactivity of DNICs. We also highlight how elucidation of the chemical reactivity and the dynamics of DNICs combined with the development of detection/quantification methods can provide further information regarding their participation in physiological and pathological processes.
Assuntos
FerroRESUMO
Thiyl radicals are detected by EPR as co-products of dinitrosyl iron complex (DNIC) formation. In demonstrating that DNIC formation generates RSË in a NO rich environment, these results provide a novel route for S-nitroso thiol formation.
RESUMO
The ruthenium(II) compounds cis-[Ru(bpy)2(4-bzpy)(CO)](PF6)2 (I) and cis-[Ru(bpy)2(4-bzpy)(Cl)](PF6) (II) (4-bzpy=4-benzoylpyridine, bpy=2,2'-bipyridine) were synthesized and characterized by spectroscopic and electrochemical techniques. The crystal structure of II was determined by X-ray diffraction. The photochemical behavior of I in aqueous solution shows that irradiation with ultraviolet light (365nm) releases both CO and 4-bzpy leading to the formation of the cis-[Ru(bpy)2(H2O)2]2+ ion as identified by NMR and electronic spectroscopy. Carbon monoxide release was confirmed with the myoglobin method and by gas chromatographic analysis of the headspace. CO release was not observed when aqueous I was irradiated with blue light (453nm). Changes in the electronic and 1H NMR spectra indicate that I undergoes photoaquation of 4-bzpy to form cis-[Ru(bpy)2(CO)(H2O)]2+. Blue light irradiation of aqueous II released the coordinated 4-bzpy to give the cis-[Ru(bpy)2(H2O)(Cl)]2+ ion. When the latter reaction was carried out in the presence of the nucleobase guanine, Ru-guanine adducts were formed, indicating that the metal containing photoproduct may also participate in biologically relevant reactions. The photochemical behavior of I indicates that it can release either CO or 4-bzpy depending on the wavelength chosen, a feature that may have therapeutic application.
Assuntos
2,2'-Dipiridil/síntese química , Luz , Fotoquímica/métodos , Piridinas/química , Compostos de Rutênio/química , Monóxido de Carbono/química , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Difração de Raios XRESUMO
We describe the use of cadmium telluride quantum dots (CdTe QDs) as antennas for the photosensitization of nitric oxide release from a ruthenium nitrosyl complex with visible light excitation. The CdTe QDs were capped with mercaptopropionic acid to make them water-soluble, and the ruthenium nitrosyl complex was cis-[Ru(NO)(4-ampy)(bpy)2](3+) (Ru-NO; bpy is 2,2'-bipyridine, and 4-ampy is 4-aminopyridine). Solutions of these two components demonstrated concentration-dependent quenching of the QD photoluminescence (PL) as well as photoinduced release of NO from Ru-NO when irradiated by 530 nm light. A NO release enhancement of â¼8 times resulting from this association was observed under longer wavelength excitation in visible light range. The dynamics of the quenching determined by both PL and transient absorption measurements were probed by ultrafast flash photolysis. A charge transfer mechanism is proposed to explain the quenching of the QD excited states as well as the photosensitized release of NO from Ru-NO.
Assuntos
Óxidos de Nitrogênio/química , Processos Fotoquímicos , Pontos Quânticos/química , Rutênio/química , Compostos de Cádmio/química , Telúrio/químicaRESUMO
Nitric oxide (NO) plays an important role in the control of the vascular tone and the most often employed NO donors have limitations due to their harmful side-effects. In this context, new NO donors have been prepared, in order to minimize such undesirable effects. cis-[Ru(bpy)2(py)NO2](PF6) (RuBPY) is a new nitrite complex synthesized in our laboratory that releases NO in the presence of the vascular tissue only. In this work the vasorelaxation induced by this NO donor has been studied and compared to that obtained with the well known NO donor SNP. The relaxation induced by RuBPY is concentration-dependent in denuded rat aortas pre-contracted with phenylephrine (EC50). This new compound induced relaxation with efficacy similar to that of SNP, although its potency is lower. The time elapsed until maximum relaxation is achieved (E max=240s) is similar to measured for SNP (210s). Vascular reactivity experiments demonstrated that aortic relaxation by RuBPY is inhibited by the soluble guanylyl-cyclase inhibitor 1H-[1,2,4] oxadiozolo[4,3-a]quinoxaline-1-one (ODQ 1µM). In a similar way, 1µM ODQ also reduces NO release from the complex as measured with DAF-2 DA by confocal microscopy. These findings suggest that this new complex RuBPY that has nitrite in its structure releases NO inside the vascular smooth muscle cell. This ruthenium complex releases significant amounts of NO only in the presence of the aortic tissue. Reduction of nitrite to NO is most probably dependent on the soluble guanylyl-cyclase enzyme, since NO release is inhibited by ODQ.
Assuntos
Aorta Torácica/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Óxido Nítrico/metabolismo , Pró-Fármacos/farmacologia , Vasodilatadores/farmacologia , Animais , Guanilato Ciclase/antagonistas & inibidores , Guanilato Ciclase/metabolismo , Técnicas In Vitro , Masculino , Doadores de Óxido Nítrico/uso terapêutico , Oxidiazóis/farmacologia , Fenilefrina/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Pró-Fármacos/uso terapêutico , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/metabolismo , Compostos de Rutênio/metabolismo , Guanilil Ciclase Solúvel , Vasodilatação , Vasodilatadores/uso terapêuticoRESUMO
The synthesis of [Ru(NO(2))L(bpy)(2)](+) (bpy = 2,2'-bipyridine and L = pyridine (py) and pyrazine (pz)) can be accomplished by addition of [Ru(NO)L(bpy)(2)](PF(6))(3) to aqueous solutions of physiological pH. The electrochemical processes of [Ru(NO(2))L(bpy)(2)](+) in aqueous solution were studied by cyclic voltammetry and differential pulse voltammetry. The anodic scan shows a peak around 1.00 V vs. Ag/AgCl attributed to the oxidation process centered on the metal ion. However, in the cathodic scan a second peak around -0.60 V vs. Ag/AgCl was observed and attributed to the reduction process centered on the nitrite ligand. The controlled reduction potential electrolysis at -0.80 V vs. Ag/AgCl shows NO release characteristics as judged by NO measurement with a NO-sensor. This assumption was confirmed by ESI/MS(+) and spectroelectrochemical experiment where cis-[Ru(bpy)(2)L(H(2)O)](2+) was obtained as a product of the reduction of cis-[Ru(II)(NO(2))L(bpy)(2)](+). The vasorelaxation observed in denuded aortic rings pre-contracted with 0.1 mumol L(-1) phenylephrine responded with relaxation in the presence of cis-[Ru(II)(NO(2))L(bpy)(2)](+). The potential of rat aorta cells to metabolize cis-[Ru(II)(NO(2))L(bpy)(2)](+) was also followed by confocal analysis. The obtained results suggest that NO release happens by reduction of cis-[Ru(II)(NO(2))L(bpy)(2)](+) inside the cell. The maximum vasorelaxation was achieved with 1 x 10(-5) mol L(-1) of cis-[Ru(II)(NO(2))L(bpy)(2)](+) complex.
Assuntos
Óxido Nítrico/metabolismo , Nitritos/química , Compostos Organometálicos/química , Compostos Organometálicos/farmacologia , Rutênio/química , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/citologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/fisiologia , Eletroquímica , Masculino , Compostos Organometálicos/metabolismo , Oxirredução , Ratos , Ratos WistarRESUMO
Metal-to-ligand charge transfer photolysis of the ruthenium(II) pyrazine complex Ru(NH3)5pz2+ (I) in pH 7.4 oxygenated phosphate buffer solution generates the Ru(III) analog Ru(NH3)5pz3+ plus the reactive oxygen species singlet oxygen and superoxide. Based on the very short MLCT lifetime (re-measured as approximately 250 ps in D2O) of I* and the quantum yield for singlet oxygen formation (0.01 for aerated D2O) the rate constant for oxygen quenching of I* was calculated to be approximately (3+/-1)x10(10) M-1 s-1.
RESUMO
The photochemical behavior of the tetraazamacrocyclic complex trans-RuCl([15]ane)(NO)2+ (RuNO2+) in a 10 mM phosphate buffer solution, pH 7.4, and in the presence of Ru(NH3)5pz2+ (Rupz2+) is reported. Irradiation (436 nm) of an aqueous solution containing both cationic complexes as PF6- salts labilizes NO from RuNO2+ with a quantum yield (phiNO) dependent on the concentration of Rupz2+ with a maximum value of phiNO (1.03(11)x10(-3) einstein mol-1) found for a solution with equimolar concentrations (5x10(-5) M) of the two complexes in phosphate buffer solution. The quantitative behavior of this system suggests that the two cations undergo preassociation such that photoexcitation of the visible absorbing Rupz2+ is followed by electron or energy transfer to RuNO2+, which does not absorb appreciably at the excitation wavelength, and this leads to NO release from the reduced nitrosyl complex. Notably, the NO release was not seen in the absence of phosphate buffer; thus, it appears that phosphate ions mediate NO generation, perhaps by facilitating formation of a supramolecular complex between the two ruthenium cations. Reexamination of the cyclic voltammetry of Rupz2+ showed that the electrochemical behavior of this species is also affected by the presence of the phosphate buffer.
Assuntos
Compostos Aza/química , Doadores de Óxido Nítrico/química , Fosfatos/química , Pirazinas/química , Compostos de Rutênio/química , Raios Ultravioleta , Cátions/química , Transporte de Elétrons , FotóliseRESUMO
We present a combined density functional theory (DFT)/time-dependent density functional theory (TDDFT) study of the geometry, electronic structure, and absorption and emission properties of the tetranuclear "cubane" Cu4I4py4 (py = pyridine) system. The geometry of the singlet ground state and of the two lowest triplet states of the title complex were optimized, followed by TDDFT excited-state calculations. This procedure allowed us to characterize the nature of the excited states involved in the absorption spectrum and those responsible for the dual emission bands observed for this complex. In agreement with earlier experimental proposals, we find that while in absorption the halide-to-pyridine charge-transfer excited state (XLCT*) has a lower energy than the cluster-centered excited state (CC*), a strong geometrical relaxation on the triplet cluster-centered state surface leads to a reverse order of the excited states in emission.
RESUMO
Light activation leads to release of NO from a silicate sol-gel material SG-RuNO prepared from the ruthenium complex, [Ru(salen)(OH2)(NO)]+ (salen = N,N'-bis-(salicylidene)ethyl-enediaminato); after photochemical NO photolabilization, SG-RuNO can be regenerated from the spent material via the subsequent reaction with aqueous nitrite.