A nitric oxide releaser based on the μ-oxo-hexaacetate-bis(4-methylpyridine)triruthenium nitrosyl complex

doi:10.1016/j.ica.2004.08.004

Inorganica Chimica Acta

Volume 358, Issue 10, 15 June 2005, Pages 2891-2899

Dedicated in memory of Professor Rex Shepherd

https://doi.org/10.1016/j.ica.2004.08.004 Get rights and content

Abstract

The properties of the trinuclear cluster [Ru₃OAc₆(pic)₂(NO)]PF₆ (pic = 4-methyl pyridine, Ac = acetate ion) and the photochemical behavior of the corresponding molecular films are reported in this paper. In this compound, the unpaired π* electron from NO and the unpaired electron from the π-orbitals of the Ru₃O unity are strongly coupled; as a consequence, the changes in electronic distribution associated with the several successive redox states promote dramatic effects in the spectroscopic and electrochemical properties of the nitric oxide ligand and the entire complex. NO release has been observed by light irradiation (ϕ = 0.038 at 365 nm and ϕ = 0.019 at 468 nm, in acetonitrile solution), changing the original violet color into deep blue. The same behavior has been observed in solid state and in PVA films incorporating this compound, revealing its potential usefulness as NO photoreleaser, as well as for the monitoration of light exposure intensities.

Graphical abstract

NO release has been observed by light irradiation of the trinuclear cluster, either in solution, solid state or in PVA films, allowing one to monitor the UV-B light exposure intensities from the absorbance changes accompanying the photochemical process.

Introduction

In recent years, a great number of reports dealing with NO activity in biological systems have been published [1], [2], [3], [4], [5], [6], [7], [8] and ruthenium complexes have been studied as scavengers of NO, or reciprocally, their nitrosyl complexes have been investigated as NO delivery systems toward biological targets [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24]. In this field, important contributions have been made by Shepherd and co-workers [25], [26], [27], [28], [29], [30], [31], [32], specially in the design and evaluation of a number of new transition metal complexes as NO carriers for biological applications.

It should be noticed that nitric oxide is a non-innocent ligand which can coordinate to a metal center yielding either a linear or a bent MNO geometry [33], [34], [35], [36], assuming three possible oxidation states: NO⁺, NO⁰ or NO⁻ [37]. Therefore, the NO behavior is rather puzzling, since in the NO⁺ form the ligand is a very strong π-acceptor and would prefer metal ions in low oxidation states, but in the NO⁰ form it can combine with metal ions either in intermediate or high oxidation states, remaining formally in the neutral form or converting into NO⁺ by reducing the metal center. On the other hand, NO can also be converted into NO⁻ species, under more reducing conditions.

Because of the systematic changes in the electronic properties for the several successive oxidation states, the triangular ruthenium acetate clusters [Ru₃O(CH₃CO₂)₆L₃]ⁿ (L = H₂O, N-heterocyclic, etc.) [38] provide rather unique species to interact with NO, as we reported in our preliminary work on the [Ru₃O(CH₃CO₂)₆(py)₂(NO)]PF₆ complex [39]. In this system, the strong interaction between the unpaired π* electron from NO and the unpaired electron from the π-orbitals of the (Ru^III,III,III)₃O unity is responsible for its pronounced NO⁰ character, as evidenced by the vibrational and spectroelectrochemical data. Here, in order to enhance the NO⁰ character further, the pyridine ligand was replaced by the 4-methyl pyridine (picoline) analogue (Fig. 1), and a full characterization of the complex was carried out by means of mass spectrometry, spectroscopy, electrochemistry, spectroelectrochemistry and scanning probe microscopy. Due to its higher basicity, the picoline ligand is expected to decrease the electron acceptor properties of the (Ru^III,III,III)₃O unity, diminishing the extent of electron donation from the NO ligand. In addition, NO release was observed under UV–Vis light irradiation, changing the complex from original violet color into deep blue. This effect was also probed at the nanoparticle level by means of MAC mode atomic force microscopy, revealing intriguing morphology changes accompanying the NO release.

Section snippets

Materials

Tetraethylammonium perchlorate (TEAClO₄) [40] and the starting complex [Ru₃O(CH₃CO₂)₆(pic)₂(CH₃OH)]PF₆ were prepared as previously described in the literature [41]. Acetonitrile (HPLC grade, Aldrich) was kept in the presence of 3 Å molecular sieves.

Synthesis of [Ru₃O(CH₃CO₂)₆(pic)₂(NO)]PF₆

Dichloromethane, 50 mL, containing 0.52 g [Ru₃O(CH₃CO₂)₆(pic)₂(CH₃OH)]PF₆ was saturated with Ar for 20 min, then with NO for 35 min and finally with Ar for 60 min. After this, the product was precipitated by adding petroleum ether. The violet solid

ESI spectra and CID pattern

The positive ion ESI mass spectrum of the [Ru₃O(CH₃CO₂)₆(pic)₂(NO)]PF₆ complex in methanol:water solution is shown in Fig. 2(a). In the electrospray positive ion mode, the complex can be directly transferred by ESI to the mass spectrometer and can be detected as a multicomponent structure of isotopomeric ions; the most abundant ion being that of m/z 891. Ru possesses seven isotopes: ¹⁰⁴Ru (18.7%), ¹⁰²Ru (31.6%), ¹⁰¹Ru (17.0%), ¹⁰⁰Ru (12.6%), ⁹⁹Ru (12.7%), ⁹⁸Ru (1.88%), and ⁹⁶Ru (5.52%).

The CID

Conclusion

Extending our previous work on the interaction of the pyridine–ruthenium–acetate clusters with NO [39], we have confirmed the existence of a strong Ru–NO electronic coupling, responsible for the loss of the metal and NO ligand identities in the EPR, cyclic voltammetry and FT-IR spectroelectrochemistry results. Such conclusion has been corroborated by semi-empirical theoretical calculations, supporting a predominantly NO⁰ character for the nitrosyl ligand in the [Ru₃O(CH₃CO₂)₆(C₅H₅N)₂(NO)]PF₆

Acknowledgments

Financial support from FAPESP, CNPq, RENAMI and IM2C is gratefully acknowledged.

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Recent advances on the development of NO-releasing molecules (NORMs) for biomedical applications
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Nitric oxide (NO) is an important biological messenger as well as a signaling molecule that participates in a broad range of physiological events and therapeutic applications in biological systems. However, due to its very short half-life in physiological conditions, its therapeutic applications are restricted. Efforts have been made to develop an enormous number of NO-releasing molecules (NORMs) and motifs for NO delivery to the target tissues. These NORMs involve organic nitrate, nitrite, nitro compounds, transition metal nitrosyls, and several nanomaterials. The controlled release of NO from these NORMs to the specific site requires several external stimuli like light, sound, pH, heat, enzyme, etc. Herein, we have provided a comprehensive review of the biochemistry of nitric oxide, recent advancements in NO-releasing materials with the appropriate stimuli of NO release, and their biomedical applications in cancer and other disease control.
Oxo-centered trinuclear ruthenium acetates: Structure and applications
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Polynuclear μ-oxo complexes are commonly observed for second and third row transition metals. This review is particularly interested in the μ₃-oxo-bridged ruthenium trinuclear clusters of general formula [Ru₃O(CH₃COO)₆(L)₃]ⁿ, where typically L are coordinating solvents, N-heterocyclic ligands, phosphines or small species such as CO, NO, and CN^–; and n = 0 or + 1. These molecules are very versatile coordination compounds, characterized by an absorption profile with high coverage of the ultraviolet and visible regions, depending on their formal charges, and rich multi-electron redox behavior, yielding, for example, electrochromic devices and sensors. More recently, innovative approaches allowed the community to explore previously unfathomable applications for this type of system, such as trypanocidal or anticancer agents. Besides their intrinsic characteristics, they have also been used as building blocks for extended structures, opening up a whole new range of options. This text invites the readers to a description, from a structural point of view, of monomeric and extended compounds obtained from the primary unit [Ru₃O(RCOO)₆]ⁿ, reported on the last 20 years. In addition, we present an overview of the compounds' applications, focusing on their use as catalysts, in the construction of devices, or as final acceptors of excitation energy and electrons in photoinduced processes. Finally, we address the newest application reported in the literature: their biological activities as an anticancer, trypanocidal, or vasorelaxant agent and their interactions with target biomolecules such as DNA and HSA.
A ruthenium nitrosyl cyclam complex with appended anthracenyl fluorophore
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The complex trans-[Ru(NO)(H₂O)(L)](ClO₄)₃ (L = (1-anthracen-9-ylmethyl)-1,4,8,11-tetraazacyclotetradecane) (RuNOL) was synthesized and characterized, and its photophysics and reactivity were investigated. The FTIR spectrum displays a νNO band at 1840 cm⁻¹, indicating a nitrosonium character. ¹H and ¹³C signals in 1D and 2D NMR spectra were assigned and are consistent with the trans configuration. The UV–Vis spectrum displays maximal absorption bands at 341 nm (log ε 3.74), 363 nm (log ε 3.91), 378 nm (log ε 3.97) and 397 nm (log ε 3.91). Coordination of the [RuNO] moiety to the L ligand strongly quenches the anthracenyl fluorescence, and thus RuNOL exhibits only very weak emission at 390, 418, 440 and 472 nm. Electrochemical studies indicate that cathodic peak potentials at +1.10 V(I_c), −0.1 V(II_c) and −0.4 V(III_c) (vs Ag/AgCl) are related to An⁺/An, {RuNO}^6/7 and {RuNO}^7/8 reduction processes, respectively. The pK_a of coordinated water was estimated as 2.8 ± 0.2 by DPV. The emission of the pendant fluorophore increases upon electrochemical or chemical reduction of RuNOL, and the resulting switch-ON fluorescence is possibly due to NO release from the target complex. Spectroscopic titrations with DNA resulted in hypochromism and red shifts and allowed estimation of binding constants of 1.9 × 10³ (L) and 1.8 × 10³ (RuNOL). Molecular docking showed that RuNOL complex has a great affinity with DNA. The RuNOL complex showed low cytotoxicity toward MCF-7 and NIH-3T3 and was ineffective in healthy HUVEC and A7r5 cell lines in the range of concentration of 1 × 10⁻⁷–1 × 10⁻⁴ mol L⁻¹.
The role of ancillary ligand substituents in the biological activity of triruthenium-NO complexes
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Citation Excerpt :
This removes the electronic pairing verified in the ground state, to reduce interaction between the species and consequently prompt NO release. The [Ru3O] center becomes paramagnetic after NO release, as probed by the photoproduct typical spectral profile (Figs. S10 and S11) [17,19,20]. Therefore, when the complex is in the excited state, the metallic core formal charge is indeed +1, which is more stabilized by interaction with a σ-donor ancillary ligand such as 4-tbpy as compared to a more π-acid ligand like 4-acpy [17].
Two novel triruthenium clusters, [Ru₃(μ₃-O)(μ-OOCCH₃)₆(NO)L₂]PF₆ (L = 4‑acetylpyridine, 1, or 4‑tert‑butylpyridine, 2) release NO. Their spectroscopic and electrochemical characterization confirmed their structure. These complexes efficiently deliver NO in solution under irradiation at λ_irrad = 377 nm and/or through chemical reduction with ascorbic acid. Clusters 1 and 2 elicit vasodilation and, at concentrations of 10⁻⁵ M, can relax up to 100% of pre-contracted rat aorta. Complex 2 is more cytotoxic to murine melanoma B16F10 cells than complex 1: at 50 times lower concentration than complex 1, complex 2 decreases cell viability to 50% in the dark or under irradiation with visible light (λ_irrad = 527 nm). The higher cytotoxicity of complex 2 can be assigned to its larger hydrophobicity, promoted by the methylated tert‑butylpyridine ancillary ligand in its structure. Investigation into human serum albumin (HSA) fluorescence quenching by clusters 1 or 2 revealed that complex 2 quenches HSA luminescence with a very high Stern-Vomer constant (K_SV = 9.49 × 10⁷ M⁻¹ at T = 298 K) and suggested that the nature of the interaction between complex 2 and HSA is hydrophobic (ΔH = 80.81 kJ/mol and ΔS = 334.71 J/K mol). HSA lifetime and circular dichroism data pointed to a static quenching mechanism for both complexes. Together, our results show that a hydrophobic substituent in the cluster ancillary ligand improves NO release ability, cytotoxicity, and interaction with a bio-target.
Studying the interaction between trinuclear ruthenium complexes and human serum albumin by means of fluorescence quenching
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Citation Excerpt :
Such as iron, ruthenium ion has low toxicity due to their various oxidation states available in physiological environment (II, III, IV) [17]. Also, their complexes can act both as NO scavengers or releasers, increasing the interest on the development of a variety of nitrosyl ruthenium complexes [17–26]. Of interest to this work, trinuclear ruthenium complexes of general formula [Ru3O(CH3COO)6(L)3]PF6, with L=N-heterocycles, have been widely studied in recent decades due to its rich mixed-valence chemistry and catalytic properties [27].
This work reports for the first time a systematic investigation of the interaction between HSA and trinuclear ruthenium complexes, by using fluorescence spectroscopy and the Stern–Volmer model. The compounds investigated have general formula [Ru₃O(CH₃COO)₆(3-pic)₂(L)]PF₆, where L=NO or H₂O and 3-pic=3-methylpyridine. For both complexes it was observed that the increase of K_sv values (in the order of 10⁴ M⁻¹) with increasing temperature, signaling a dynamic quenching of HSA fluorescence. However, analysis of the quenching rate constants and K_b values shows that the contribution of the static quenching is significant. Particularly in the case of the nitrosyl complex, the relatively high value of K_b observed (178.44×10³ M⁻¹, 308 K) suggests that this compound can be efficiently stored and transported in the body by HSA. The interaction of the complexes with HSA is spontaneous (ΔG<0). Complex [Ru₃O(CH₃COO)₆(3-pic)₂(NO)]PF₆ displays interaction with HSA by hydrophobic forces (∆H=215 kJ mol⁻¹ and ∆S=796 J mol⁻¹ K⁻¹), likely because of the nitrosyl lipophilicity, while complex [Ru₃O(CH₃COO)₆(₃-pic)₂(H₂O)]PF₆ is involved in the formation of hydrogen bonds with HSA (∆H=−75.5 kJ mol⁻¹ and ∆S=−231 J mol⁻¹ K⁻¹), through its aquo ligand.

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A nitric oxide releaser based on the μ-oxo-hexaacetate-bis(4-methylpyridine)triruthenium nitrosyl complex

Abstract

Graphical abstract

Introduction

Section snippets

Materials

Synthesis of [Ru3O(CH3CO2)6(pic)2(NO)]PF6

ESI spectra and CID pattern

Conclusion

Acknowledgments

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Synthesis of [Ru₃O(CH₃CO₂)₆(pic)₂(NO)]PF₆