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.

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.

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.

A Trojan horse approach for enhancing the cellular uptake of a ruthenium nitrosyl complex.

Ruthenium nitrosyl (RuNO) complexes continue to attract significant research interest due to several appealing features that make these photoactivatable nitric oxide (NO˙) donors attractive for applications in photoactivated chemotherapy. Interesting examples of molecular candidates capable of delivering cytotoxic concentrations of NO˙ in aqueous media have been discussed. Nevertheless, the question of whether most of these highly polar and relatively large molecules are efficiently incorporated by cells remains largely unanswered. In this paper, we present the synthesis and the chemical, photophysical and photochemical characterization of RuNO complexes functionalized with 17α-ethinylestradiol (EE), a semisynthetic steroidal hormone intended to act as a molecular Trojan horse for the targeted delivery of RuNO complexes. The discussion is centered around two main molecular targets, one containing EE (EE-Phtpy-RuNO) and a reference compound lacking this biological recognition fragment (Phtpy-RuNO). While both complexes displayed similar optical absorption profiles and NO˙ release efficiencies in aqueous media, important differences were found regarding their cellular uptake towards dermal fibroblasts, with EE-Phtpy-RuNO gratifyingly displaying a remarkable 10-fold increase in cellular uptake when compared to Phtpy-RuNO, thus demonstrating the potential drug-targeting capabilities of this biomimetic steroidal conjugate.

Two-photon absorption-based delivery of nitric oxide from ruthenium nitrosyl complexes.

Since the discovery of the numerous physiological roles exhibited by nitric oxide (NO), ruthenium nitrosyl (RuNO) complexes have been regarded as one of the most promising NO donors, stable, well tolerated by the body and capable of releasing NO locally and quantitatively, under light irradiation. This release can be achieved by two-photon absorption (TPA) processes, which allow the irradiation to be performed in the near infrared domain, where light has its maximum depth of penetration in biological tissues. This review provides a short introduction on the biological properties of NO, on RuNO complexes with photo-releasing capabilities, and on the origin of TPA properties in molecules. Then, the RuNO complexes with TPA capabilities are thoroughly discussed either as monometallic or polymetallic species.

Bimetallic Ruthenium Nitrosyl Complexes with Enhanced Two-Photon Absorption Properties for Nitric Oxide Delivery.

One monometallic and three bimetallic ruthenium nitrosyl (RuNO) complexes are presented and fully characterized in reference to a parent monometallic complex of formula [FTRu(bpy)(NO)]3+ , where FT is a fluorenyl-substituted terpyridine ligand, and bpy the 2,2'-bipyridine. These new complexes are built with the new ligands FFT, TFT, TFFT, and TF-CC-TF (where an alkyne C≡C group is inserted between two fluorenes). The crystal structures of the bis-RuNO2 and bis-RuNO complexes built from the TFT ligand are presented. The evolution of the spectroscopic features (intensities and energies) along the series, at one-photon absorption (OPA) correlates well with the TD-DFT computations. A spectacular effect is observed at two-photon absorption (TPA) with a large enhancement of the molecular cross-section (σTPA ), in the bimetallic species. In the best case, σTPA is equal to 1523±98 GM at 700 nm, in the therapeutic window of transparency of biological tissues. All compounds are capable of releasing NO⋅ under irradiation, which leads to promising applications in TPA-based drug delivery.

SAR and optical images correlation illuminates post-seismic landslide motion after the Mw 7.8 Gorkha earthquake (Nepal).

In the days to weeks following an earthquake, landslides can display specific post-seismic motions, including delayed initiations and post-seismic relaxations. These motions have an uncertain origin, sometimes attributed to specificities of the landslide basal interface or to fluid transports in the landslide basal shear zone. Here we address this question, by documenting the co- and post-seismic motions of slow-moving landslides accelerated by the Gorkha earthquake (Mw 7.8, 25/04/2015, Nepal). We detect 11 slow-moving landslides over an area of 750 km[Formula: see text] in the near field of the earthquake, and monitor their motions thanks to a time-series of Pléiades optical satellite images and SAR Sentinel-1 images. The post-seismic landslide motions are much larger than the co-seismic ones, reaching up to [Formula: see text] m accommodated over 2 months. A delayed initiation of several days (> 4 days) is also measured for at least two of the landslides. We analyze our findings in regards with all the previous observations on slow-moving landslides accelerated by earthquakes, and propose that the post-seismic motions are caused by diffusion of groundwater from co-seismic material contraction up to the landslide basal shear zone or from internal landslide reconfiguration. Our observations strongly suggest the main control of the hydrology in the landslide processes under seismic forcings.

Is There a Relationship Between Overactive Bladder and Sexual Dysfunction in Women With Multiple Sclerosis?

BACKGROUND: Lower urinary tract Symptoms (LUTS) and Sexual dysfunction (SD) are common in women with MS and affect quality of life. AIM: The aim of this study was to determine the relationship between sexual dysfunction (SD) and overactive bladder in women with Multiple Sclerosis (MS). METHODS: From January 2019 to January 2021, we evaluated 89 female MS patients admitted for LUTS in a Neuro-Urology Department. SD was investigated using the Female Sexual Function Index (FSFI). All subjects completed the Urinary Symptom Profile scale (USP) and Hospital Anxiety and Depression Scale (HAD A/HAD D). Neurological impairment was assessed using the Expanded Disability Status Scale (EDSS). All patients underwent neurological examination and urodynamic studies. Univariate analysis and Multivariate logistic regression analysis were performed to identify predictors of SD in women with MS (FSFI <26.55). OUTCOMES: Primary outcome was to determine the association between sexual dysfunction in women with MS and LUTS (overactive bladder, stress incontinence or voiding dysfunction). RESULTS: Sexual dysfunction (FSFI<26,55) affected 74% of women with MS, even with low physical disabilities (EDSS<5). Univariate analysis showed that overactive bladder was more frequent in SD group, but no statistical difference was found (P < .12). No relationship was found between sexual dysfunction and stress incontinence (P = ,47), voiding dysfunction (P= 0.79) or urinary retention (P= .96). Multivariate logistic regression analysis identified overactive bladder to be an independent predictor of sexual dysfunction [aOR 0.03 (CI 0,0.98)]. Sexual dysfunction was not associated with detrusor overactivity on urodynamic studies or with impairment mobility but was strongly associated with the presence of depression (P < .01). CLINICAL IMPLICATIONS: Sexual disorders in women with MS should be assessed as much as urinary disorder. STRENGTHS AND LIMITATIONS: this study included the largest cohort of women with MS. But the sample was obtained in an outpatient setting with low neurological impairment. CONCLUSION: In our study, SD was frequent affecting young women with no anticholinergic treatment and low physical impairment. Overactive bladder seemed to be independent predictor of sexual dysfunction. Conversely, SD was not associated with detrusor overactivity, neurological impairment, or duration of disease but was strongly associated with depression. Breton FL, Chesnel C, Lagnau P, et al. Is There a Relationship Between Overactive Bladder and Sexual Dysfunction in Women With Multiple Sclerosis?. J Sex Med 2022;19:729-737.

Two-Photon-Triggered NO Release via a Ruthenium-Nitrosyl Complex with a Star-Shaped Architecture.

We report herein a molecular engineering strategy based on the design of a multipolar ruthenium-nitrosyl (Ru-NO) complex with a three-branched architecture. The three Ru-NO units are introduced at the periphery of a highly π-delocalized truxene core bearing three terpyridine ligands. The two-photon absorption capabilities of the complex were investigated by the Z-scan technique. The strong electronic coupling among the individual arms gives rise to a very strong two-photon absorption response (δ800 nm ∼ 1600 GM), which corresponds to a 16-fold enhancement of the capability of a single-arm reference, thereby promoting an efficient light-driven NO release process in aqueous media.

Tuning the Cell Uptake and Subcellular Distribution in BODIPY-Carboranyl Dyads: An Experimental and Theoretical Study.

A set of BODIPY-carboranyl dyads synthesized by a Sonogashira cross-coupling reaction, where different C-substituted ortho- and meta-carboranyl fragments have been linked to a BODIPY fluorophore is described. Chemical, photophysical and physicochemical analyses are presented, including NMR and single XRD experiments, optical absorption/emission studies and partition coefficient (log P) measurements. These studies, supported by DFT computations (M06-2X/6-31G**), provide an explanation to the largely divergent cell income that these fluorescent carboranyl-based fluorophores display, for which a structural or physicochemical explanation remains elusive. By studying the cell uptake efficiency and subcellular localization for our set of dyads on living HeLa cells, we tracked the origins of these differences to significant variations in their static dipole moments and partition coefficients, which tune their ability to interact with lipophilic microenvironments in cells. Remarkably, m-carboranyl-BODIPY derivatives with a higher lipophilicity are much better internalised by cells than their homologous with o-carborane, suggesting that m-isomers are potentially better theranostic agents for in vitro bioimaging and boron carriers for boron neutron capture therapy.

Multistep Photochemical Reactions of Polypyridine-Based Ruthenium Nitrosyl Complexes in Dimethylsulfoxide.

The photorelease of nitric oxide (NO·) has been investigated in dimethylsulfoxide (DMSO) on two compounds of formula [Ru(R-tpy)(bpy)(NO)](PF6)3, in which bpy stands for 2,2'-bipyridine and R-tpy for the 4'-R-2,2':6',2″-terpyridine with R = H and MeOPh. It is observed that both complexes are extremely sensitive to traces of water, leading to an equilibrium between [Ru(NO)] and [Ru(NO2)]. The photoproducts of formula [Ru(R-tpy)(bpy)(DMSO)](PF6)2 are further subjected to a photoreaction leading to a reversible linkage isomerization between the stable Ru-DMSO(S) (sulfur linked) and the metastable Ru-DMSO(O) (oxygen linked) species. A set of 4 [Ru(R-tpy)(bpy)(DMSO)]2+ complexes (R = H, MeOPh, BrPh, NO2Ph) is investigated to characterize the ratio and mechanism of the isomerization which is tentatively related to the difference in absorbance between the Ru-DMSO(S) and Ru-DMSO(O) forms. In addition, the X-ray crystal structures of [Ru(tpy)(bpy)(NO)](PF6)3 and [Ru(MeOPh-tpy)(bpy)(DMSO(S))](PF6)2 are presented.

Rain and small earthquakes maintain a slow-moving landslide in a persistent critical state.

In tectonically active mountain belts, landslides contribute significantly to erosion. Statistical analysis of regional inventories of earthquake-triggered-landslides after large earthquakes (Mw > 5.5) reveal a complex interaction between seismic shaking, landslide material, and rainfall. However, the contributions of each component have never been quantified due to a lack of in-situ data for active landslides. We exploited a 3-year geodetic and seismic dataset for a slow-moving landslide in Peru affected by local earthquakes and seasonal rainfalls. Here we show that in combination, they cause greater landslide motion than either force alone. We also show the rigidity of the landslide's bulk clearly decreasing during Ml ≥ 5 earthquakes. The recovery is affected by rainfall and small earthquakes (Ml < 3.6), which prevent the soil from healing, highlighting the importance of the timing between forcings. These new quantitative insights into the mechanics of landslides open new perspectives for the study of the mass balance of earthquakes.

Chemical and photochemical behavior of ruthenium nitrosyl complexes with terpyridine ligands in aqueous media.

The synthesis and behavior in water of a set of various cis(Cl,Cl)-[R-tpyRuCl2(NO)](PF6) and trans(Cl,Cl)-[R-tpyRuCl2(NO)](PF6) (R = fluorenyl, phenyl, thiophenyl; tpy = 2,2':6',2''-terpyridine) complexes are presented. In any case, one chlorido ligand is substituted by a hydroxo ligand and the final species arises as a single trans(NO,OH) isomer, whatever the nature of the starting cis/trans(Cl,Cl) complexes. Six X-ray crystal structures are presented for cis(Cl,Cl)-[thiophenyl-tpyRuCl2(NO)](PF6) (cis-3a), trans(Cl,Cl)-[thiophenyl-tpyRuCl2(NO)](PF6) (trans-3a), trans(NO,OH)-[phenyl-tpyRu(Cl)(OH)(NO)](PF6) (4a), trans(NO,OH)-[thiophenyl-tpyRu(Cl)(OH)(NO)](PF6) (4b), trans(NO,OEt)-[phenyl-tpyRu(Cl)(OEt)(NO)](PF6) (5a), and trans(NO,OH)-[phenyl-tpyRu(Cl)(OEt)(NO)](PF6) (5b) compounds. The different cis/trans(Cl,Cl) complexes exhibit an intense low-lying transition in the λ = 330-390 nm range, which appears to be slightly blue-shifted after Cl → OH substitution. In water, both cis/trans(Cl,Cl) isomers are converted to a single trans(NO,OH) isomer in which one chlorido- is replaced by one hydroxo-ligand, which avoids tedious separation workout. The water stable trans(NO,OH)-species all release NO with quantum yields of 0.010 to 0.075 under irradiation at 365 nm. The properties are discussed with computational analysis performed within the framework of Density Functional Theory.

Author Correction: Effect of trans(NO, OH)-[RuFT(Cl)(OH)NO](PF6) ruthenium nitrosyl complex on methicillin-resistant Staphylococcus epidermidis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Effect of trans(NO, OH)-[RuFT(Cl)(OH)NO](PF6) ruthenium nitrosyl complex on methicillin-resistant Staphylococcus epidermidis.

Antibiotic resistance is becoming a global scourge with 700,000 deaths each year and could cause up to 10 million deaths by 2050. As an example, Staphylococcus epidermidis has emerged as a causative agent of infections often associated with implanted medical devices. S. epidermidis can form biofilms, which contribute to its pathogenicity when present in intravascular devices. These staphylococci, embedded in the biofilm matrix, are resistant to methicillin, which had long been the recommended therapy and which has nowadays been replaced by less toxic and more stable therapeutic agents. Moreover, current reports indicate that 75 to 90% of Staphylococcus epidermidis isolates from nosocomial infections are methicillin-resistant strains. The challenge of successfully combating antibiotics resistance in biofilms requires the use of compounds with a controlled mode of action that can act in combination with antibiotics. Ruthenium nitrosyl complexes are potential systems for NO release triggered by light. The influence of trans(NO, OH)-[RuFT(Cl)(OH)NO](PF6) on Staphylococcus epidermidis resistant to methicillin is described. The results show a 50% decrease in cell viability in bacteria treated with low concentrations of NO. When combined with methicillin, this low dose of NO dramatically decreases bacterial resistance and makes bacteria 100-fold more sensitive to methicillin.

trans- and cis-(Cl,Cl)-[RuII(FT)Cl2(NO)](PF6): promising candidates for NO release in the NIR region.

cis- and trans-(Cl,Cl)-[RuII(FT)Cl2(NO)](PF6) complexes show efficient NO photodelivery upon two-photon excitation in the NIR region. Moreover, cytotoxicity and phototoxicity studies provide evidence that these complexes are promising candidates as photoactivatable molecular tools for resection of malignancies.

Comparative photo-release of nitric oxide from isomers of substituted terpyridinenitrosylruthenium(II) complexes: experimental and computational investigations.

The 4'-(2-fluorenyl)-2,2':6',2''-terpyridine (FT) ligand and its cis(Cl,Cl)- and trans(Cl,Cl)-[Ru(II)(FT)Cl2(NO)](PF6) complexes have been synthesized. Both isomers were separated by HPLC and fully characterized by (1)H and (13)C NMR. The X-ray diffraction crystal structures were solved for FT (Pna21 space group, a = 34.960(4), b = 5.9306(7), c = 9.5911(10) Å), and trans(Cl,Cl)-[Ru(II)(FT)Cl2(NO)](PF6)·MeOH (P1[combining macron] space group, a = 10.3340(5), b = 13.0961(6), c = 13.2279(6) Å, α = 72.680(2), ß = 70.488(2), γ = 67.090(2)°). Photo-release of NO˙ radicals occurs under irradiation at 405 nm, with a quantum yield of 0.31 and 0.10 for cis(Cl,Cl)-[Ru(II)(FT)Cl2(NO)](PF6) and trans(Cl,Cl)-[Ru(II)(FT)Cl2(NO)](PF6), respectively. This significant difference is likely due to the trans effect of Cl(-), which favors the photo-release. UV-visible spectroscopy and cyclic voltammetry indicate the formation of ruthenium(iii) species as photoproducts. A density functional theory (DFT) analysis provides a rationale for the understanding of the photo-physical properties, and allows relating the weakening of the Ru-NO bond, and finally the photo-dissociation, to HOMO → LUMO excitations.

Structural influence on the photochromic response of a series of ruthenium mononitrosyl complexes.

In mononitrosyl complexes of transition metals two long-lived metastable states corresponding to linkage isomers of the nitrosyl ligand can be induced by irradiation with appropriate wavelengths. Upon irradiation, the N-bound nitrosyl ligand (ground state, GS) turns into two different conformations: isonitrosyl O bound for the metastable state 1 (MS1) and a side-on nitrosyl conformation for the metastable state 2 (MS2). Structural and spectroscopic investigations on [RuCl(NO)py(4)](PF(6))(2)·1/2H(2)O (py = pyridine) reveal a nearly 100% conversion from GS to MS1. In order to identify the factors which lead to this outstanding photochromic response we study in this work the influence of counteranions, trans ligands to the NO and equatorial ligands on the conversion efficiency: [RuX(NO)py(4)]Y(2)·nH(2)O (X = Cl and Y = PF(6)(-) (1), BF(4)(-) (2), Br(-)(3), Cl(-) (4); X = Br and Y = PF(6)(-) (5), BF(4)(-) (6), Br(-)(7)) and [RuCl(NO)bpy(2)](PF(6))(2) (8), [RuCl(2)(NO)tpy](PF(6)) (9), and [Ru(H(2)O)(NO)bpy(2)](PF(6))(3) (10) (bpy = 2,2'-bipyridine; tpy = 2,2':6',2"-terpyridine). Structural and infrared spectroscopic investigations show that the shorter the distance between the counterion and the NO ligand the higher the population of the photoinduced metastable linkage isomers. DFT calculations have been performed to confirm the influence of the counterions. Additionally, we found that the lower the donating character of the ligand trans to NO the higher the photoconversion yield.

Synthesis of novel rod-shaped and star-shaped fluorescent phosphane oxides--nonlinear optical properties and photophysical properties.

The design of a new class of fluorophores is presented. Some push-pull chromophores (D-pi-A) containing polyphenylethynyl units and a phosphane oxide moiety were efficiently prepared from common intermediates. Straightforward syntheses gave novel one-armed, rod-shaped and three-armed, star-shaped fluorophores. The optical properties of the resulting star-shaped derivatives were evaluated, showed high fluorescence quantum yields, and their excitation induces very efficient charge redistribution. Moreover, thanks to their push-pull character, the molecules exhibited significant second-order NLO properties with good transparency, up to 67x10(-30) esu at 1907 nm, with an absorption lambdamax at 369 nm. The effect of the donor group and of the number of phenylethynyl arms have been studied in this work.

Synthesis, crystal structures, and nonlinear optical (NLO) properties of new Schiff-base nickel(II) complexes. Toward a new type of molecular switch?

An H2L Schiff-base ligand that was obtained from the monocondensation of diaminomaleonitrile and 4-(diethylamino)salicylaldehyde is reported together with four related nickel(II) complexes formulated as [Ni(L)(L')] (L' = MePhCHNH2, iPrNH2, Py, and PPh3). Crystal structures have been solved for H2L, [Ni(L)(MePhCHNH2)], and [Ni(L)(iPrNH2)]. Surprisingly, the complexation process leads to the formation of a rather unusual nickel amido (-NH-Ni(II)) bond by deprotonation of the primary amine of H2L. A reduction of the quadratic hyperpolarizability (beta) from 38 x 10(-30) to 17.5 x 10(-30) cm5 esu(-1) is evidenced on H2L upon metal complexation by the electric-field-induced second-harmonic (EFISH) technique. Qualitative ZINDO/SCI quantum chemical calculations indicate that, in [Ni(L)(MePhCHNH2)], the beta orientation strongly depends on the laser wavelength. In particular, a beta rotation strictly equal to 90 degrees could be obtained with 1.022 microm incident light on passing from [Ni(L)(MePhCHNH2] to a hypothetical [Ni(HL)(MePhCHNH2]+ protonated complex, thus raising the possibility for a new type of molecular switch.