Solvation and Proton-Coupled Electron Transfer Reduction Potential of ²NO^• to ¹HNO in Aqueous Solution: A Theoretical Investigation

In this work, quantum mechanical calculations and Monte Carlo statistical mechanical simulations were carried out to investigate the solvation properties of HNO in aqueous solution and to evaluate the proton-coupled one electron reduction potential of ²NO to ¹HNO, which is essential missing information to understand the fate of ²NO in the biological medium. Our results showed that the ¹HNO molecule acts mainly as a hydrogen bond donor in aqueous solution with an average energy of −5.5 ± 1.3 kcal/mol. The solvation free energy of ¹HNO in aqueous solution, computed using three approaches based on the linear response theory, revealed that the current prediction of the hydration free energy of HNO is, at least, 2 times underestimated. We proposed two pathways for the production of HNO through reduction of NO. The first pathway is the direct reduction of NO through proton-coupled electron transfer to produce HNO, and the second path is the reduction of the radical anion HONO^•–, which is involved in equilibrium with NO in aqueous solution. We have shown that both pathways are viable processes under physiological conditions, having reduction potentials of <i>E</i>°′ = −0.161 V and <i>E</i>°′ ≈ 1 V for the first and second pathways, respectively. The results shows that both processes can be promoted by well-known biological reductants such as NADH, ascorbate, vitamin E (tocopherol), cysteine, and glutathione, for which the reduction potential at physiological pH is around −0.3 to −0.5 V. The computed reduction potential of NO through the radical anion HONO^•– can also explain the recent experimental findings on the formation of HNO through the reduction of NO, promoted by H₂S, vitamin C, and aromatic alcohols. Therefore, these results contribute to shed some light into the question of whether and how HNO is produced in vivo and also for the understanding of the biochemical and physiological effects of NO

[Ag(L)NO₃] Complexes with 2‑Benzoylpyridine-Derived Hydrazones: Cytotoxic Activity and Interaction with Biomolecules

Complexes [Ag­(H2BzPh)­NO₃] (<b>1</b>), [Ag­(H2Bz<i>p</i>CH₃Ph)­NO₃] (<b>2</b>), [Ag­(H2Bz<i>p</i>ClPh)­NO₃] (<b>3</b>), and [Ag­(H2Bz<i>p</i>NO₂Ph)­NO₃] (<b>4</b>) were synthesized with 2-benzoylpyridine benzoylhydrazone (H2BzPh) and its <i>para</i>-methyl-benzoylhydrazone (H2Bz<i>p</i>CH₃Ph), <i>para</i>-chloro-benzoylhydrazone (H2Bz<i>p</i>ClPh), and <i>para</i>-nitro-benzoylhydrazone (H2Bz<i>p</i>NO₂Ph) derivatives. Experimental data indicate that the nitrate ligand binds more strongly to the silver center through one of the oxygen atoms, whereas the second oxygen atom from nitrate and the hydrazone oxygen makes much weaker interactions with the metal. Dissociation of nitrate most probably occurs in solution and in biological media. Interestingly, theoretical calculations suggested that when dissociation of the nitrate takes place, all bond orders involving the metal and the atoms from the hydrazone ligand increase significantly, showing that the bonding of nitrate results in the weakening of all other interactions in the metal coordination sphere. Upon complexation of the hydrazones to silver­(I), cytotoxicity against B16F10 metastatic murine melanoma cells increased in all cases. Complexes (<b>1–3</b>) proved to be more cytotoxic than cisplatin. All compounds were more cytotoxic to B16F10 cells than to nontumorigenic murine Melan-A melanocyte cells. Interestingly, the selectivity index (SI = IC_{50 non‑malignant cells}/IC_{50 tumor cells}) of complex (<b>1</b>), SI = 23, was much higher than that of the parent hydrazone ligand, SI = 9.5. Studies on the interactions of complexes (<b>1–3</b>) with DNA suggested that although (<b>1–3</b>) interact with calf thymus DNA by an intercalative mode, direct covalent binding of silver­(I) to DNA probably does not occur. Complexes (<b>1–3</b>) interact in vitro with human serum albumin indicating that these compounds could be transported by albumin

Water Solvent Effect on Theoretical Evaluation of ¹H NMR Chemical Shifts: <i>o</i>‑Methyl-Inositol Isomer

In this paper, density functional theory calculations of nuclear magnetic resonance (NMR) chemical shifts for l-quebrachitol isomer, previously studied in our group, are reported with the aim of investigating in more detail the water solvent effect on the prediction of ¹H NMR spectra. In order to include explicit water molecules, 20 water-l-quebrachitol configurations obtained from Monte Carlo simulation were selected to perform geometry optimizations using the effective fragment potential method encompassing 60 water molecules around the solute. The solvated solute optimized geometries were then used in B3LYP/6-311+G­(2d,p) NMR calculations with PCM-water. The inclusion of explicit solvent in the B3LYP NMR calculations resulted in large changes in the ¹H NMR profiles. We found a remarkable improvement in the agreement with experimental NMR profiles when the explicit hydrated l-quebrachitol structure is used in B3LYP ¹H NMR calculations, yielding a mean absolute error (MAE) of only 0.07 ppm, much lower than reported previously for the gas phase optimized structure (MAE = 0.11 ppm). In addition, a very improved match between theoretical and experimental ¹H NMR spectrum measured in D₂O was achieved with the new hydrated optimized l-quebrachitol structure, showing that a fine-tuning of the theoretical NMR spectra can be accomplished once solvent effects are properly considered

[Ag(L)NO₃] Complexes with 2‑Benzoylpyridine-Derived Hydrazones: Cytotoxic Activity and Interaction with Biomolecules

Complexes [Ag­(H2BzPh)­NO₃] (<b>1</b>), [Ag­(H2Bz<i>p</i>CH₃Ph)­NO₃] (<b>2</b>), [Ag­(H2Bz<i>p</i>ClPh)­NO₃] (<b>3</b>), and [Ag­(H2Bz<i>p</i>NO₂Ph)­NO₃] (<b>4</b>) were synthesized with 2-benzoylpyridine benzoylhydrazone (H2BzPh) and its <i>para</i>-methyl-benzoylhydrazone (H2Bz<i>p</i>CH₃Ph), <i>para</i>-chloro-benzoylhydrazone (H2Bz<i>p</i>ClPh), and <i>para</i>-nitro-benzoylhydrazone (H2Bz<i>p</i>NO₂Ph) derivatives. Experimental data indicate that the nitrate ligand binds more strongly to the silver center through one of the oxygen atoms, whereas the second oxygen atom from nitrate and the hydrazone oxygen makes much weaker interactions with the metal. Dissociation of nitrate most probably occurs in solution and in biological media. Interestingly, theoretical calculations suggested that when dissociation of the nitrate takes place, all bond orders involving the metal and the atoms from the hydrazone ligand increase significantly, showing that the bonding of nitrate results in the weakening of all other interactions in the metal coordination sphere. Upon complexation of the hydrazones to silver­(I), cytotoxicity against B16F10 metastatic murine melanoma cells increased in all cases. Complexes (<b>1–3</b>) proved to be more cytotoxic than cisplatin. All compounds were more cytotoxic to B16F10 cells than to nontumorigenic murine Melan-A melanocyte cells. Interestingly, the selectivity index (SI = IC_{50 non‑malignant cells}/IC_{50 tumor cells}) of complex (<b>1</b>), SI = 23, was much higher than that of the parent hydrazone ligand, SI = 9.5. Studies on the interactions of complexes (<b>1–3</b>) with DNA suggested that although (<b>1–3</b>) interact with calf thymus DNA by an intercalative mode, direct covalent binding of silver­(I) to DNA probably does not occur. Complexes (<b>1–3</b>) interact in vitro with human serum albumin indicating that these compounds could be transported by albumin

[Ag(L)NO₃] Complexes with 2‑Benzoylpyridine-Derived Hydrazones: Cytotoxic Activity and Interaction with Biomolecules

Complexes [Ag­(H2BzPh)­NO₃] (<b>1</b>), [Ag­(H2Bz<i>p</i>CH₃Ph)­NO₃] (<b>2</b>), [Ag­(H2Bz<i>p</i>ClPh)­NO₃] (<b>3</b>), and [Ag­(H2Bz<i>p</i>NO₂Ph)­NO₃] (<b>4</b>) were synthesized with 2-benzoylpyridine benzoylhydrazone (H2BzPh) and its <i>para</i>-methyl-benzoylhydrazone (H2Bz<i>p</i>CH₃Ph), <i>para</i>-chloro-benzoylhydrazone (H2Bz<i>p</i>ClPh), and <i>para</i>-nitro-benzoylhydrazone (H2Bz<i>p</i>NO₂Ph) derivatives. Experimental data indicate that the nitrate ligand binds more strongly to the silver center through one of the oxygen atoms, whereas the second oxygen atom from nitrate and the hydrazone oxygen makes much weaker interactions with the metal. Dissociation of nitrate most probably occurs in solution and in biological media. Interestingly, theoretical calculations suggested that when dissociation of the nitrate takes place, all bond orders involving the metal and the atoms from the hydrazone ligand increase significantly, showing that the bonding of nitrate results in the weakening of all other interactions in the metal coordination sphere. Upon complexation of the hydrazones to silver­(I), cytotoxicity against B16F10 metastatic murine melanoma cells increased in all cases. Complexes (<b>1–3</b>) proved to be more cytotoxic than cisplatin. All compounds were more cytotoxic to B16F10 cells than to nontumorigenic murine Melan-A melanocyte cells. Interestingly, the selectivity index (SI = IC_{50 non‑malignant cells}/IC_{50 tumor cells}) of complex (<b>1</b>), SI = 23, was much higher than that of the parent hydrazone ligand, SI = 9.5. Studies on the interactions of complexes (<b>1–3</b>) with DNA suggested that although (<b>1–3</b>) interact with calf thymus DNA by an intercalative mode, direct covalent binding of silver­(I) to DNA probably does not occur. Complexes (<b>1–3</b>) interact in vitro with human serum albumin indicating that these compounds could be transported by albumin

Synthesis, Magnetostructural Correlation, and Catalytic Promiscuity of Unsymmetric Dinuclear Copper(II) Complexes: Models for Catechol Oxidases and Hydrolases

Herein, we report the synthesis and characterization, through elemental analysis, electronic spectroscopy, electrochemistry, potentiometric titration, electron paramagnetic resonance, and magnetochemistry, of two dinuclear copper­(II) complexes, using the unsymmetrical ligands <i>N</i>′,<i>N</i>′,<i>N</i>-tris­(2-pyridylmethyl)-<i>N</i>-(2-hydroxy-3,5-di-<i>tert</i>-butylbenzyl)-1,3-propanediamin-2-ol (<b>L1</b>) and <i>N</i>′,<i>N</i>′-bis­(2-pyridylmethyl)-<i>N</i>,<i>N</i>-(2-hydroxybenzyl)­(2-hydroxy-3,5-di-<i>tert</i>-butylbenzyl)-1,3-propanediamin-2-ol (<b>L2</b>). The structures of the complexes [Cu₂(<b>L1</b>)­(μ-OAc)]­(ClO₄)₂·(CH₃)₂CHOH (<b>1</b>) and [Cu₂(<b>L2</b>)­(μ-OAc)]­(ClO₄)·H₂O·(CH₃)₂CHOH (<b>2</b>) were determined by X-ray crystallography. The complex [Cu₂(<b>L3</b>)­(μ-OAc)]²⁺ [<b>3</b>; <b>L3</b> = <i>N</i>-(2-hydroxybenzyl)-<i>N</i>′,<i>N</i>′,<i>N</i>-tris­(2-pyridylmethyl)-1,3-propanediamin-2-ol] was included in this study for comparison purposes only (Neves et al. <i>Inorg. Chim. Acta</i> <b>2005</b>, <i>358</i>, 1807–1822). Magnetic data show that the Cu^II centers in <b>1</b> and <b>2</b> are antiferromagnetically coupled and that the difference in the exchange coupling <i>J</i> found for these complexes (<i>J</i> = −4.3 cm^–1 for <b>1</b> and <i>J</i> = −40.0 cm^–1 for <b>2</b>) is a function of the Cu–O–Cu bridging angle. In addition, <b>1</b> and <b>2</b> were tested as catalysts in the oxidation of the model substrate 3,5-di-<i>tert</i>-butylcatechol and can be considered as functional models for catechol oxidase. Because these complexes possess labile sites in their structures and in solution they have a potential nucleophile constituted by a terminal Cu^II-bound hydroxo group, their activity toward hydrolysis of the model substrate 2,4-bis­(dinitrophenyl)­phosphate and DNA was also investigated. Double electrophilic activation of the phosphodiester by monodentate coordination to the Cu^II center that contains the phenol group with <i>tert</i>-butyl substituents and hydrogen bonding of the protonated phenol with the phosphate O atom are proposed to increase the hydrolase activity (<i>K</i>_ass. and <i>k</i>_cat.) of <b>1</b> and <b>2</b> in comparison with that found for complex <b>3</b>. In fact, complexes <b>1</b> and <b>2</b> show both oxidoreductase and hydrolase/nuclease activities and can thus be regarded as man-made models for studying catalytic promiscuity

Synthesis, Magnetostructural Correlation, and Catalytic Promiscuity of Unsymmetric Dinuclear Copper(II) Complexes: Models for Catechol Oxidases and Hydrolases

Herein, we report the synthesis and characterization, through elemental analysis, electronic spectroscopy, electrochemistry, potentiometric titration, electron paramagnetic resonance, and magnetochemistry, of two dinuclear copper­(II) complexes, using the unsymmetrical ligands <i>N</i>′,<i>N</i>′,<i>N</i>-tris­(2-pyridylmethyl)-<i>N</i>-(2-hydroxy-3,5-di-<i>tert</i>-butylbenzyl)-1,3-propanediamin-2-ol (<b>L1</b>) and <i>N</i>′,<i>N</i>′-bis­(2-pyridylmethyl)-<i>N</i>,<i>N</i>-(2-hydroxybenzyl)­(2-hydroxy-3,5-di-<i>tert</i>-butylbenzyl)-1,3-propanediamin-2-ol (<b>L2</b>). The structures of the complexes [Cu₂(<b>L1</b>)­(μ-OAc)]­(ClO₄)₂·(CH₃)₂CHOH (<b>1</b>) and [Cu₂(<b>L2</b>)­(μ-OAc)]­(ClO₄)·H₂O·(CH₃)₂CHOH (<b>2</b>) were determined by X-ray crystallography. The complex [Cu₂(<b>L3</b>)­(μ-OAc)]²⁺ [<b>3</b>; <b>L3</b> = <i>N</i>-(2-hydroxybenzyl)-<i>N</i>′,<i>N</i>′,<i>N</i>-tris­(2-pyridylmethyl)-1,3-propanediamin-2-ol] was included in this study for comparison purposes only (Neves et al. <i>Inorg. Chim. Acta</i> <b>2005</b>, <i>358</i>, 1807–1822). Magnetic data show that the Cu^II centers in <b>1</b> and <b>2</b> are antiferromagnetically coupled and that the difference in the exchange coupling <i>J</i> found for these complexes (<i>J</i> = −4.3 cm^–1 for <b>1</b> and <i>J</i> = −40.0 cm^–1 for <b>2</b>) is a function of the Cu–O–Cu bridging angle. In addition, <b>1</b> and <b>2</b> were tested as catalysts in the oxidation of the model substrate 3,5-di-<i>tert</i>-butylcatechol and can be considered as functional models for catechol oxidase. Because these complexes possess labile sites in their structures and in solution they have a potential nucleophile constituted by a terminal Cu^II-bound hydroxo group, their activity toward hydrolysis of the model substrate 2,4-bis­(dinitrophenyl)­phosphate and DNA was also investigated. Double electrophilic activation of the phosphodiester by monodentate coordination to the Cu^II center that contains the phenol group with <i>tert</i>-butyl substituents and hydrogen bonding of the protonated phenol with the phosphate O atom are proposed to increase the hydrolase activity (<i>K</i>_ass. and <i>k</i>_cat.) of <b>1</b> and <b>2</b> in comparison with that found for complex <b>3</b>. In fact, complexes <b>1</b> and <b>2</b> show both oxidoreductase and hydrolase/nuclease activities and can thus be regarded as man-made models for studying catalytic promiscuity

Synthesis, Magnetostructural Correlation, and Catalytic Promiscuity of Unsymmetric Dinuclear Copper(II) Complexes: Models for Catechol Oxidases and Hydrolases

Herein, we report the synthesis and characterization, through elemental analysis, electronic spectroscopy, electrochemistry, potentiometric titration, electron paramagnetic resonance, and magnetochemistry, of two dinuclear copper­(II) complexes, using the unsymmetrical ligands <i>N</i>′,<i>N</i>′,<i>N</i>-tris­(2-pyridylmethyl)-<i>N</i>-(2-hydroxy-3,5-di-<i>tert</i>-butylbenzyl)-1,3-propanediamin-2-ol (<b>L1</b>) and <i>N</i>′,<i>N</i>′-bis­(2-pyridylmethyl)-<i>N</i>,<i>N</i>-(2-hydroxybenzyl)­(2-hydroxy-3,5-di-<i>tert</i>-butylbenzyl)-1,3-propanediamin-2-ol (<b>L2</b>). The structures of the complexes [Cu₂(<b>L1</b>)­(μ-OAc)]­(ClO₄)₂·(CH₃)₂CHOH (<b>1</b>) and [Cu₂(<b>L2</b>)­(μ-OAc)]­(ClO₄)·H₂O·(CH₃)₂CHOH (<b>2</b>) were determined by X-ray crystallography. The complex [Cu₂(<b>L3</b>)­(μ-OAc)]²⁺ [<b>3</b>; <b>L3</b> = <i>N</i>-(2-hydroxybenzyl)-<i>N</i>′,<i>N</i>′,<i>N</i>-tris­(2-pyridylmethyl)-1,3-propanediamin-2-ol] was included in this study for comparison purposes only (Neves et al. <i>Inorg. Chim. Acta</i> <b>2005</b>, <i>358</i>, 1807–1822). Magnetic data show that the Cu^II centers in <b>1</b> and <b>2</b> are antiferromagnetically coupled and that the difference in the exchange coupling <i>J</i> found for these complexes (<i>J</i> = −4.3 cm^–1 for <b>1</b> and <i>J</i> = −40.0 cm^–1 for <b>2</b>) is a function of the Cu–O–Cu bridging angle. In addition, <b>1</b> and <b>2</b> were tested as catalysts in the oxidation of the model substrate 3,5-di-<i>tert</i>-butylcatechol and can be considered as functional models for catechol oxidase. Because these complexes possess labile sites in their structures and in solution they have a potential nucleophile constituted by a terminal Cu^II-bound hydroxo group, their activity toward hydrolysis of the model substrate 2,4-bis­(dinitrophenyl)­phosphate and DNA was also investigated. Double electrophilic activation of the phosphodiester by monodentate coordination to the Cu^II center that contains the phenol group with <i>tert</i>-butyl substituents and hydrogen bonding of the protonated phenol with the phosphate O atom are proposed to increase the hydrolase activity (<i>K</i>_ass. and <i>k</i>_cat.) of <b>1</b> and <b>2</b> in comparison with that found for complex <b>3</b>. In fact, complexes <b>1</b> and <b>2</b> show both oxidoreductase and hydrolase/nuclease activities and can thus be regarded as man-made models for studying catalytic promiscuity