Ruthenium Nitrosyl Research Articles

A synergetic effect of light and anion: near-infrared colorimetric monitoring of nitric oxide (NO) release from fluoride/cyanide anions and a water responsive ruthenium nitrosyl complex.

Near-infrared (NIR) spectral-responsive multitasking chemical systems are always advantageous in biological and environmental systems. Although ruthenium complexes are highly attractive compounds for many applications, studies on NIR optical responsive sensors are very limited because of their synthetic difficulties. The sensing of fluoride and cyanide ions using ruthenium nitrosyl complexes is not known. In this study, we report the synthesis and characterization of a new terpyridine-based ruthenium nitrosyl complex [Ru(Cl)2NO(terpy-C6H4OH)] 1·Ru-OH. The complex exhibited distinct NIR absorptions at 680 nm, as well as a visible color change with the fluoride ion in DMSO-CH3CN medium. However, when the solvent is changed to DMSO-H2O, it responds only with a cyanide ion with a distinct colorimetric change. Binding of the F- ion leads to deprotonation of 1·Ru-OH; the deprotonated complex is also used for the colorimetric detection of a trace amount of water in DMSO and acetonitrile with a limit of detection (LOD) of 0.034 wt% and 0.007 wt%, respectively. Ruthenium nitrosyl complexes have appeared as promising platforms for light-controlled release of nitric oxide (NO), which can be beneficial for therapeutic application. NO release studies of 1·Ru-OH by UV-vis and FT-IR spectroscopy confirm that it can release NO in a light-controlled manner. In addition, the NO release could be monitored by the naked eye with a color change and spectral change in the NIR region. Importantly, NO release studies revealed that the rate of NO release could be modulated in the presence of the F- ion. Here, the fluoride ion acts as an allosteric regulator. These results demonstrate that 1·Ru-OH is both a promising multitasking colorimetric and NIR sensor and a colorimetric responsive NO-releasing agent.

Cytotoxic and pro-oxidant profile of a photosensitive ruthenium nitrosyl candidate for NO delivery in healthy human fibroblasts.

Ruthenium nitrosyl (Ru-NO) complexes are of interest as photoactive nitric oxide (NO) donor candidates for local therapeutic applications. NO plays a crucial regulatory role in skin homeostasis, concentration-dependently affecting processes like the proliferation, apoptosis, autophagy and redox balance. In this context, we investigated HE-10, a ruthenium-based photoinducible NO donor, for its pro-oxidant and cytotoxic effects under light and dark conditions in VH10 human foreskin fibroblast cells. We also tested its intracellular and extracellular NO-releasing function. Our study reveals a significant dose-dependent cytotoxic effect of HE-10, an increase in intracellular reactive oxygen and nitrogen species, and the occurrence of apoptosis in skin fibroblast cells. Furthermore, exposure to both increasing doses of HE-10 and white LED light led to substantial cellular events, including a significant induction of autophagy and G2/M phase cell cycle arrest. Paradoxically, these effects were not solely attributable to NO release based on DAF2-DA NO probe results, suggesting that intracellular photochemical reactions additional to NO photolysis contribute to HE-10's biological activity. This study shows that HE-10 exhibits both cytotoxic and potential therapeutic effects, depending on concentration and light exposure. These findings are crucial for developing targeted Ru-NO complex treatments for skin diseases and potentially certain types of skin cancer, where controlled NO release could be beneficial.

Heteroleptic Complexes of Ruthenium Nitrosyl with Pyridine and Bypiridine-Synthesis and Photoisomerization.

The reaction of [RuNO(Py)2Cl2OH] with bipyridine in water-ethanol media results in trans-(NO, OH)-[RuNO(Py)(Bpy)ClOH]+ with an acceptable yield (60-70%) as hexafluorophosphate salt. Further treatment of the hydroxy-complex with concentrated HF quantitatively leads to trans-(NO, F)-[RuNO(Py)(Bpy)ClF]+. Despite the chirality of both coordination spheres, the hexafluorophosphate salts crystallized as racemates. A NO-linkage isomerism study of the obtained complexes was performed at 80 K with different excitation wavelengths (405, 450, 488 nm). The most favorable wavelengths for the MS1 isomer (Ru-ON) formation were 405 and 450 nm, where the linkage isomer populations were 17% and 1% for [RuNO(Py)(Bpy)ClOH]PF6 and [RuNO(Py)(Bpy)ClF]PF6. The shift of the excitation wavelength to the green (488 nm) sharply decreased the MS1 population. The IR-spectral signatures of MS1 were registered. Reverse-transformation Ru-ON (MS1)-Ru-NO (GS) was investigated for [RuNO(Py)(Bpy)ClOH]PF6 using IR and DSC techniques that made it possible to determine the kinetic parameters (Ea and k0) and decay temperature.

A New Heteroleptic Complex of Nitrosyl Ruthenium with Ethylenediamine and the NO–Ru–F Trans-Coordinate: Synthesis, Structure, and Photoinduced Linkage Isomerization

A New Heteroleptic Complex of Nitrosyl Ruthenium with Ethylenediamine and the NO–Ru–F Trans-Coordinate: Synthesis, Structure, and Photoinduced Linkage Isomerization

Carbon dioxide conversion to fuel over alumina-supported ruthenium catalysts

In this study, ruthenium-based catalysts were prepared for CO2 hydrogenation. Incipient-wetness-impregnation of the alumina-support with ruthenium (III) nitrosyl nitrate solution to achieve 0.5 wt% Ru loading on supports was used to prepare these catalysts. Potassium (0–3 % wt%) was used to further promote the catalysts. TPR, CO2-TPD, XRD, TEM, XPS, SEM, and EDS analyses were used to characterize catalyst properties. The hydrogenation of CO2 catalytic tests were conducted and the effect of operating conditions (temperature, pressure, and space velocity) were investigated. These studies were conducted in a tubular fixed-bed reactor. The CO2 conversion over these catalysts was found to be low and the dominating product observed was CH4 with a small amount of C2+ forming when K was added to the catalyst. The optimum potassium loading for improved C2+ product yield over Ru/Al2O3 was 1%K for CO2 hydrogenation.

Ligand Environment and Light: Two Triggers for Controlling Cytotoxicity of Ruthenium Nitrosyl Complexes

AbstractPhotoinduced nitric oxide (NO) release for complexes [RuNO(L)2(NO2)2OH], where L=methyl isonicotinate (1), ethyl isonicotinate (2), methyl nicotinate (3) and ethyl nicotinate (4) was studied in DMSO, MeCN and water solutions (PBS, CTAB) using spectroscopic methods (UV‐vis, IR, EPR) and spectrometric techniques (ESI‐MS). Additionally, we present methodological evidence for improving the calculation of the quantum yield (QY) of NO release through the utilization of a combined IR‐UV‐vis‐spectroscopy flow‐through setup. According to DFT calculations, the production of nitric oxide occurs through the photoinduced cleavage of the Ru−NO bond, triggered by irradiation at 445 or 532 nm. This cleavage is a consequence of charge transfer from the orbitals of the Ru−OH group and the equatorial ligands (HOMO, HOMO‐1) to the Ru−NO antibonding orbital (LUMO). The cytotoxicity and photoinduced cytotoxicity of the investigated compounds were assessed against the breast adenocarcinoma cell line MCF‐7. Moreover, the investigation of the lipophilic properties of compounds 1–4 unveiled a significant influence of their lipophilicity on cytotoxic behavior, allowing for the modification of cytotoxicity through changes in the ligand L or by light irradiation.

Photorelease of Nitric Oxide (NO) in Mono- and Bimetallic Ruthenium Nitrosyl Complexes: A Photokinetic Investigation with a Two-Step Model.

Two monometallic and three bimetallic ruthenium acetonitrile (RuMeCN) complexes are presented and fully characterized. All of them are built from the same skeleton [FTRu(bpy)(MeCN)]2+, in which FT is a fluorenyl-substituted terpyridine ligand and bpy is the 2,2'-bipyridine. The crystal structure of [FTRu(bpy)(MeCN)](PF6)2 is presented. A careful spectroscopic analysis allows establishing that these 5 RuMeCN complexes can be identified as the product of the photoreaction of 5 related RuNO complexes, investigated as efficient nitric oxide (NO) donors. Based on this set of complexes, the mechanism of the NO photorelease of the bimetallic complexes has been established through a complete investigation under irradiations performed at 365, 400, 455, and 490 nm wavelength. A two-step (A → B → C) kinetic model specially designed for this purpose provides a good description of the mechanism, with quantum yields of photorelease in the range 0.001-0.029, depending on the irradiation wavelength. In the first step of release, the quantum yields (ϕAB) are always found to be larger than those of the second step (ϕBC), at any irradiation wavelengths.

Visible light induced generation of nitric oxide from designed ruthenium nitrosyl complex and studies on antibacterial activity

In this article, a chloro-bridged dinuclear ruthenium complex Ru-(a) has been synthesized, which was employed for the synthesis of a photolabile NO liberating complex Ru-(b). A newly synthesized tridentate ligand 2-methyl-6-((2-phenyl-2-(pyridin-2-yl)hydrazineylidene)methyl)pyridine with three N-atoms as donating site was used to synthesize the complex Ru-(a). The molecular structure of Ru-(a) was investigated by single-crystal X-ray crystallography and, in solution was characterized by or ESI mass spectrometry. Several spectroscopic techniques were used for the characterization of the ligand as well as complexes. To understand the electronic structure of Ru-(a) and Ru-(b), DFT computations were utilized. By the utilization of visible light, photo-liberation experiments were examined. The amount of NO released during the photodissociation experiment was measured using the Griess reagent assay technique. The photodissociated NO was fruitfully transported to reduced myoglobin (Mb). The antibacterial activity against Escherichia coli was carried out with 31.2 μg/mL concentration of Ru-(b). In the final results, we detected considerable antibacterial activity against E. coli and showed >99 % inhibition of the bacterial cells after 120 min of the experiment on exposure to visible light. These investigations proposed that Ru-(b) could be employed to treat several topical deliveries of NO for treating various topical and bacterial infections.

Novel Ruthenium‐based Nitrosyl Complexes: NO Donation and Vasorelaxant Potentials for Cardiovascular Therapeutics

AbstractNitrosyl ruthenium complexes have emerged as promising platforms for the controlled delivery of nitric oxide (NO) and nitroxyl (HNO), both of which possess significant therapeutic implications. Considering this scenario, we synthesized and characterized the metal complex cis‐[RuNO(phen)2(2MIM)]3+ and its precursors, where phen and 2MIM correspond to 1,10‐phenantroline and 2‐methylimidazole, respectively. Comprehensive structural elucidation was undertaken using a combination of spectroscopic and electrochemical methodologies, including XANES/EXAFS experiments. This structural data was further validated through DFT computational analyses. We demonstrated that such compound can release NO and HNO in the presence of thiol‐based substrates. Not only this, but the same metal complex can also delivery nitric oxide under irradiation with visible light (λ=460 nm). The nitrosyl complex and its derivatives displayed marked vasodilatory capabilities as evidenced in assays involving isolated rat aorta rings. They also exhibited commendable antioxidant activity in free radical scavenging assays. Collectively, based on these data, this nitrosyl ruthenium compound is a potential therapeutic candidate, especially in the field of cardiovascular pathology like atherosclerosis, thereby deserving further in‐depth investigations.

Unveiling the electronic and molecular structure of a trinuclear ruthenium cluster containing one nitrosyl ligand

The understanding of the Ru-NO bond in Ru nitrosyl systems is of great interest due to the non-innocent nature of the NO ligand, and because of the ability of such compounds to release nitric oxide, an essential physiological regulator. The Ru-NO bond description can be even more complicated when it comes to polynuclear systems such as the μ-oxo clusters of general formula [Ru3O(CH3COO)6(L)3]n, which can be electronically localized or delocalized themselves depending on the nature of the L ligands, or present unpaired electrons depending on the Ru ions oxidation state. Herein, we present a detailed electronic- and molecular-structure description of the [Ru3O(CH3COO)6(py)2NO]PF6 (py = pyridine) cluster using multiconfigurational approaches and X-ray diffraction analysis. The X-ray data unveil a linear Ru–NO moiety with a Ru-NO angle of 180°. Although most linear {RuNO}6 complexes have been largely described as RuII–NO+, our valence bond-type analysis based on a CASSCF ground state wavefunction, with an active space comprised of 18 electrons and 16 orbitals, showed a predominance of the RuIII–NO° configuration, with minor contributions from RuIV–NO– and RuII–NO+. These findings provide a more precise framework to rationalize the electronic properties of trinuclear ruthenium nitrosyls, aiding the planning of new NO releasers based on those clusters.

CW or Pulsed laser – That is the Question: Comparative Steady‐state Photocrystallographic Analysis of Metal Nitrosyl Linkage Isomers

AbstractThe investigation of photo‐induced effects is profoundly influenced by the characteristics of photo‐excitation sources. In this study, we present a comprehensive analysis of the structures of two photoinduced linkage isomers (PLI) in a ruthenium nitrosyl complex, trans‐[Ru(py)4F(NO)](ClO4)2, following irradiation with both pulsed and continuous wave (CW) light sources under low temperature conditions. The X‐ray (photo)diffraction analysis shows that the resulting PLI generated from the two types of irradiation sources, an isonitrosyl configuration of the nitrosyl ligand in the so‐called metastable state MS1, and a side‐on configuration of the nitrosyl ligand in the metastable state MS2, are identical. In‐situ optical absorption spectroscopy was employed during CW and pulsed irradiation, enabling the monitoring of the population process of these PLI. The results obtained from the infrared spectroscopic analysis after pulsed irradiation give insight into the population mechanism illustrating that the generation of the isonitrosyl MS1 occurs through a two‐step process, via the second PLI, the side‐on configuration MS2.

The cytotoxic and antiproliferative properties of ruthenium nitrosyl complexes and their modulation effect on cytochrome P450 in the HepG2 cell line.

Ruthenium nitrosyl complexes are actively investigated as antitumor agents. Evaluation of potential interactions between cytochromes P450 (CYPs) with new compounds is carried out regularly during early drug development. In this study we have investigated the cytotoxic and antiproliferative activities of ruthenium nitrosyl complexes with methyl/ethyl esters of nicotinic and isonicotinic acids and γ-picoline against 2D and 3D cultures of human hepatocellular carcinoma HepG2 and non-cancer human lung fibroblasts MRC-5, assessed their photoinduced activity at λrad = 445 nm, and also evaluated their modulating effect on CYP3A4, CYP2C9, and CYP2C19. The study of cytotoxic and antiproliferative activities against 2D and 3D cell models was performed using phenotypic-based high content screening (HCS). The expression of CYP3A4, CYP2C9, and CYP2C19 mRNAs and CYP3A4 protein was examined using target-based HCS. The results of CYP3A4 mRNA expression were confirmed by real-time reverse transcription-polymerase chain reaction (RT-PCR). The ruthenium nitrosyl complexes exhibited a dose-dependent cytotoxic effect against HepG2 and MRC-5 cells. The cytotoxic activity of complexes with ethyl isonicotinate (1) and nicotinate (3, 4) was significantly lower for MRC-5 than for HepG2, for a complex with methyl isonicotinate (2) it was higher for MRC-5 than for HepG2, for a complex with γ-picoline (5) it was comparable for both lines. The antiproliferative effect of complexes 2 and 5 was one order of magnitude higher for MRC-5; for complexes 1, 3, and 4 it was comparable for both lines. The cytotoxic activity of all compounds for 3D HepG2 was lower than for 2D HepG2, with the exception of 4. Photoactivation affected the activity of complex 1 only. Its cytotoxic activity decreased, while the antiproliferative activity increased. The ruthenium nitrosyl complexes 1-4 acted as inducers of CYP3A4 and CYP2C19, while the complex with γ-picoline (5) induced of CYP3A4. Among the studied ruthenium nitrosyl complexes, the most promising potential antitumor compound is the ruthenium compound with methyl nicotinate (4).

Continuous synthesis of ruthenium nanoparticles with tuneable sizes using ruthenium nitrosyl nitrate precursor

Continuous synthesis of ruthenium nanoparticles with controllable sizes between 2–4 nm in the absence of organic capping ligands.

Photorelease of nitric oxide from Pluronic F127/chitosan hydrogels incorporating a water soluble ruthenium nitrosyl complex

In this paper, the NO donor trans-(Cl,Cl)-[Ru(FT)Cl2(NO)]Cl (Ru–NO) was incorporated in a Pluronic F127 (PL)–chitosan (CS) biocompatible hydrogel.

Photoinduced cytotoxic activity of a rare ruthenium nitrosyl phenanthroline complex showing NO generation in human cells.

A new nitro-nitrosyl complex [RuNO(Phen)(NO2)2OH] (1) was synthesized and characterized by X-ray diffraction, where Phen = 1,10-phenanthroline. The complex was crystallized in two different modifications without (1) and with a solvent molecule of DMF (1a). The photolysis process together with the determination of the quantum yield of NO release was investigated in acetonitrile solution using a special flow-through system for the simultaneous registration of infrared (IR) and optical absorption (UV-vis) spectra under irradiation with 450 nm light. The quantum yield of photoinduced NO release was 4.0 ± 0.2%. DFT calculations showed that the main contribution to the absorption band at 450 nm is made by the HOMO/HOMO-1 → LUMO transitions, which are represented by the transfer of electron density from the -OH and -NO2 ligands to the orbitals located on the Ru-NO bond. The dark and photoinduced cytotoxicity of the complex was studied against the human breast adenocarcinoma (MCF-7) and lung carcinoma (A549) cell lines and human non-tumor lung fibroblasts (MRC5). The complex shows a low cytotoxicity on MCF-7 cells (ICdark50 = 90.6 ± 6.2 μM and ICirr.50 = 95.3 ± 11.4 μM) and a moderate dark cytotoxicity on A549 and MRC5 cells (ICdark50 = 33.4 ± 2.6 μM and ICdark50 = 62.6 ± 3.1 μM, respectively), which slightly increases after irradiation (ICirr.50 = 21.2 ± 3.3 μM and ICirr.50 = 47.2 ± 2.3 μM, respectively).

Local force constants and charges of the nitrosyl ligand in photoinduced NO linkage isomers in a prototypical ruthenium nitrosyl complex.

Photoinduced linkage isomers (PLI) of the NO ligand in transition-metal nitrosyl compounds can be identified by vibrational spectroscopy due to the large shifts of the (NO) stretching vibration. We present a detailed experimental and theoretical study of the prototypical compound K2[RuCl5NO], where (NO) shifts by ≈150 cm-1 when going from the N-bound (κN) ground state (GS) to the oxygen-bound (κO) metastable linkage isomer MS1, and by ≈360 cm-1 when going to the side-on (κ2N,O) metastable linkage isomer MS2. We show that the experimentally observed N-O stretching modes of the GS, MS1, and MS2 exhibit strong coupling with the Ru-N and Ru-O stretching modes, which can be decoupled using the local mode vibrational theory formalism. From the resulting decoupled pure two-atomic harmonic oscillators the local force constants are determined, which all follow the same quadratic behavior on the wavenumber. A Bader charge analysis shows that the total charge on the NO ligand is not correlated to the observed frequency shift of (NO).

Ruthenium nitrosyl complexes with NO release capability: the use of fluorene as an antenna.

A ruthenium nitrosyl complex of formula [RuII(fluorene(C6)CH2O-terpy)(bipy)(NO)]3+ (AC) in which fluorene(C6) is the 9,9-dihexylfluorene, terpy the 2,2';6',2''-terpyridine, and bipy the 2,2'-bipyridine is presented with its related [RuII(MeO-terpy)(bipy)(NO)]3+ (C) and 9,9-dihexylfluorene 2-hydroxymethylfluorene (A) building blocks. The reference complex C undergoes NO release capabilities under irradiation at λ = 365 nm. The effect of the introduction of the fluorescent A antenna within the resulting AC complex is discussed both experimentally and theoretically. The importance of the encaging parameter defined as ϕAC·IAC, in which IAC is the quantity of light absorbed by AC and ϕAC the quantum yield of NO release is evidenced and found to be concentration dependent. The conditions of optimization of the antenna approach to maximize ϕAC·IAC are discussed. The crystal structure of [RuII(fluorene(C6)CH2O-terpy)(bipy)(NO2)](PF6), the last intermediate in the synthesis of AC is also presented.

Anti-bacterial, anti-biofilm and synergistic effects of phenazine-based ruthenium(II) complexes.

Antimicrobial resistance has become a global threat to human health, which is coupled with the lack of novel drugs. Metallocompounds have emerged as promising diverse scaffolds for the development of new antibiotics. Herein, we prepared some metal compounds mainly focusing on cis-[Ru(bpy)(dppz)(SO3)(NO)](PF6) (PR02, bpy = 2,2'-bipyridine, dppz = dipyrido[3,2-a:2',3'-c]phenazine), in which phenazinic and nitric oxide ligands along with sulfite conferred some key properties. This compound exhibited a redox potential for bound NO+/0 of -0.252 V (vs. Ag|AgCl) and a high pH for nitrosyl-nitro conversion of 9.16, making the nitrosyl ligand the major species. These compounds were still able to bind to DNA structures. Interestingly, reduced glutathione (GSH) was unable to promote significant NO/HNO release, an uncommon feature of many similar systems. However, this reducing agent was essential to generate superoxide radicals. Antimicrobial studies were carried out using six bacterial strains, where none or very low activity was observed for Gram-negative bacteria. However, PR02 and PR (cis-[Ru(bpy)(dppz)Cl2]) showed high antibacterial activity in some Gram-positive strains (MBC for S. aureus up to 4.9 μmol L-1), where the activity of PR02 was similar to or at least 4-fold better than that of PR. Besides, PR02 showed capacity to inhibit bacterial biofilm formation, a major health issue leading to bacterial tolerance to antibiotics. Interestingly, we also showed that PR02 can function in synergism with the known antibiotic ampicillin, improving their action up to 4-fold even against resistant strains. Altogether, these results showed that PR02 is a promising antimicrobial nitrosyl ruthenium compound combining features beyond its killing action, which deserves further biological studies.

Effect of Electron-donating Group on NO Photolysis of {RuNO}6 Ruthenium Nitrosyl Complexes with N2 O2 Lgands Bearing π-Extended Rings.

In this study, we introduced the electron-donating group (-OH) to the aromatic rings of Ru(salophen)(NO)Cl (0) (salophenH2 =N,N'-(1,2-phenylene)bis(salicylideneimine)) to investigate the influence of the substitution on NO photolysis and NO-releasing dynamics. Three derivative complexes, Ru((o-OH)2 -salophen)(NO)Cl (1), Ru((m-OH)2 -salophen)(NO)Cl (2), and Ru((p-OH)2 -salophen)(NO)Cl (3) were developed and their NO photolysis was monitored by using UV/Vis, EPR, NMR, and IR spectroscopies under white room light. Spectroscopic results indicated that the complexes were diamagnetic Ru(II)-NO+ species which were converted to low-spin Ru(III) species (d5 , S=1/2) and released NO radicals by photons. The conversion was also confirmed by determining the single-crystal structure of the photoproduct of 1. The photochemical quantum yields (ΦNO s) of the photolysis were determined to be 0>1, 2, 3 at both the visible and UV excitations. Femtosecond (fs) time-resolved mid-IR spectroscopy was employed for studying NO-releasing dynamics. The geminate rebinding (GR) rates of the photoreleased NO to the photolyzed complexes were estimated to be 0≃1, 2, 3. DFT and TDDFT computations found that the introduction of the hydroxyl groups elevated the ligand π-bonding orbitals (π (salophen)), resulting in decrease of the HOMO-LUMO gaps in 1-3. The theoretical calculations suggested that the Ru-NNO bond dissociations of the complexes were mostly initiated by the ligand-to-ligand charge transfer (LLCT) of π(salophen)→π*(Ru-NO) with both the visible and UV excitations and the decreasing ΦNO s could be explained by the changes of the electronic structures in which the photoactivable bands of 1-3 have relatively less contribution of transitions related with Ru-NO bond than those of 0.

Acetylacetonate Ruthenium Nitrosyls: A Gateway to Nitric Oxide Release in Water under Near-Infrared Excitation by Two-Photon Absorption.

A fundamental challenge for phototriggered therapies is to obtain robust molecular frameworks that can withstand biological media. Photoactivatable nitric oxide (NO) releasing molecules (photoNORMs) based on ruthenium nitrosyl (RuNO) complexes are among the most studied systems due to several appealing features that make them attractive for therapeutic applications. Nevertheless, the propensity of the NO ligand to be attacked by nucleophiles frequently manifests as significant instability in water for this class of photoNORMs. Our approach to overcome this limitation involved enhancing the Ru-NO π-backbonding to lower the electrophilicity at the NO by replacing the commonly employed 2,2'-bipyridine (bpy) ligand by an anionic, electron-rich, acetylacetonate (acac). A versatile and convenient synthetic route is developed and applied for the preparation of a large library of RuNO photoNORMs with the general formula [RuNO(tpy)(acac)]2+ (tpy = 2,2':6',2″-terpyridine). A combined theoretical and experimental analysis of the Ru-NO bonding in these complexes is presented, supported by extensive single-crystal X-ray diffraction experiments and by topological analyses of the electron charge density by DFT. The enhanced π-back-bonding, systematically evidenced by several techniques, resulted in a remarkable stability in water for these complexes, where significant NO release efficiencies were recorded. We finally demonstrate the possibility of obtaining sophisticated water-stable multipolar NO-delivery platforms that can be activated in the near-IR region by two-photon absorption (TPA), as demonstrated for an octupolar complex with a TPA cross section of 1530 GM at λ = 800 nm and for which NO photorelease was demonstrated under TPA irradiation in aqueous media.