Water-Soluble Nitroxyl Porphyrin Complexes FeIITPPSHNO and FeIITPPSNO- Obtained from Isolated FeIITPPSNO•.

The first biomimetic water-soluble FeII-porphyrin nitroxyl complexes were obtained and characterized by UV-vis in protonated and deprotonated forms by reduction of previously isolated and characterized FeIITPPSNO•. The pKa involved in the FeII-HNO ⇄ FeII-NO- + H+ equilibrium was estimated to be around 9.7. The FeIITPPSHNO complex spontaneously reoxidizes to the nitrosyl form following a first-order kinetic decay with a measured kinetic constant of k = 0.017 s-1. Experiments show that the HNO adduct undergoes unimolecular homolytic cleavage of the H-NO bond. DFT calculations suggest a phlorin radical intermediate for this reaction. The deprotonated NO- complex resulted to be more stable, with a half-life of about 10 min.

Reactions of HNO with metal porphyrins: underscoring the biological relevance of HNO.

Azanone ((1)HNO, nitroxyl) shows interesting yet poorly understood chemical and biological effects. HNO has some overlapping properties with nitric oxide (NO), sharing its biological reactivity toward heme proteins, thiols, and oxygen. Despite this similarity, HNO and NO show significantly different pharmacological effects. The high reactivity of HNO means that studies must rely on the use of donor molecules such as trioxodinitrate (Angeli's salt). It has been suggested that azanone could be an intermediate in several reactions and that it may be an enzymatically produced signaling molecule. The inherent difficulty in detecting its presence unequivocally prevents evidence from yielding definite answers. On the other hand, metalloporphyrins are widely used as chemical models of heme proteins, providing us with invaluable tools for the study of the coordination chemistry of small molecules, like NO, CO, and O2. Studies with transition metal porphyrins have shown diverse mechanistic, kinetic, structural, and reactive aspects related to the formation of nitrosyl complexes. Porphyrins are also widely used in technical applications, especially when coupled to a surface, where they can be used as electrochemical gas sensors. Given their versatility, they have not escaped their role as key players in chemical studies involving HNO. This Account presents the research performed during the last 10 years in our group concerning azanone reactions with iron, manganese, and cobalt porphyrins. We begin by describing their HNO trapping capabilities, which result in formation of the corresponding nitrosyl complexes. Kinetic and mechanistic studies of these reactions show two alternative operating mechanisms: reaction of the metal center with HNO or with the donor. Moreover, we have also shown that azanone can be stabilized by coordination to iron porphyrins using electron-attracting substituents attached to the porphyrin ring, which balance the negatively charged NO¯. Second, we describe an electrochemical HNO sensing device based on the covalent attachment of a cobalt porphyrin to gold. A surface effect affects the redox potentials and allows discrimination between HNO and NO. The reaction with the former is fast, efficient, and selective, lacking spurious signals due to the presence of reactive nitrogen and oxygen species. The sensor is both biologically compatible and highly sensitive (nanomolar). This time-resolved detection allows kinetic analysis of reactions producing HNO. The sensor thus offers excellent opportunities to be used in experiments looking for HNO. As examples, we present studies concerning (a) HNO donation capabilities of new HNO donors as assessed by the sensor, (b) HNO detection as an intermediate in O atom abstraction to nitrite by phosphines, and (c) NO to HNO interconversion mediated by alcohols and thiols. Finally, we briefly discuss the key experiments required to demonstrate endogenous HNO formation to be done in the near future, involving the in vivo use of the HNO sensing device.

Structural characterization of the water-soluble porphyrin complexes [FeII(TPPS) (NO•)]4─ and [µ-O-([FeIII(TPPS)])2]8─.

Iron water-soluble porphyrins have been long used as biomimetic compounds for modelling the active sites found in heme-enzymes. In this regard, the anionic porphyrin [FeIII(TPPS)]3─ and its coordination complexes have been repeatedly chosen as suitable water-soluble platforms for bioinorganic chemistry studies. In this work we report for the first time the crystal structure of the water-soluble nitrosyl complex [FeII(TPPS) (NO•)]4─ along with that of oxodimeric ferric species [µ-O-([FeIII(TPPS)])2]8─.

H2S/Thiols, NO•, and NO-/HNO: Interactions with Iron Porphyrins.

In the past decade, gasotransmitters NO• and H2S have been thoroughly studied in biological contexts, as their biosynthesis and physiological effects became known. Moreover, an additional intricate crosstalk reaction scheme between these compounds and related species is thought to exist as part of the cascade signaling processes in physiological conditions. In this context, heme enzymes, as modeled by iron porphyrins, play a central role in catalyzing the key interconversions involved. In this work, iron porphyrin interactions with sulfide and nitric-oxide-related species are described. The stability and reactivity of mixed ternary systems are also described, and future perspectives are discussed.

Spectroelectrochemical evidence for the nitrosyl redox siblings NO+, NO*, and NO- coordinated to a strongly electron-accepting Fe(II) porphyrin: DFT calculations suggest the presence of high-spin states after reduction of the Fe(II)-NO- complex.

Experimental and computational results for the electron-deficient porphyrin complex [Fe(NO)(TFPPBr(8))] (1; TFPPBr(8)=2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetrakis(pentafluorophenyl)porphyrin) are reported with respect to its electron-transfer behavior. Complex 1 undergoes three one-electron processes: two reversible reductions and one irreversible oxidation. Spectroelectrochemical measurements (IR and UV/Vis/NIR spectroscopy) of (14)NO- and (15)NO-containing material indicate that the first reduction to 1(-) occurs largely on the NO ligand to produce nitroxyl anion (NO(-)) character, as evident from the considerable change in ν(NO) from 1715 to around 1550 cm(-1). The second reduction to 1(2)(-) does not result in a further shift of ν(NO) to lower frequencies, but to a surprising high-energy shift to 1590 cm(-1). This and the notable changes of the characteristic porphyrin vibrations as well as significant changes of the UV/Vis absorptions indicate a porphyrin-centered process; DFT calculations predict the shift of ν(NO) to higher frequencies for the intermediate- and high-spin states of 1(2-). The oxidation of 1 is irreversible on the voltammetry timescale, but chemically reversible in spectroelectrochemical experiments, suggesting that the cationic form dissociates to the corresponding ferric porphyrin and NO. DFT calculations support the interpretation of the experimental results.

Azanone (HNO): generation, stabilization and detection.

HNO (nitroxyl, azanone), joined the 'biologically relevant reactive nitrogen species' family in the 2000s. Azanone is impossible to store due to its high reactivity and inherent low stability. Consequently, its chemistry and effects are studied using donor compounds, which release this molecule in solution and in the gas phase upon stimulation. Researchers have also tried to stabilize this elusive species and its conjugate base by coordination to metal centers using several ligands, like metalloporphyrins and pincer ligands. Given HNO's high reactivity and short lifetime, several different strategies have been proposed for its detection in chemical and biological systems, such as colorimetric methods, EPR, HPLC, mass spectrometry, fluorescent probes, and electrochemical analysis. These approaches are described and critically compared. Finally, in the last ten years, several advances regarding the possibility of endogenous HNO generation were made; some of them are also revised in the present work.

Solid-gas reactions for nitroxyl (HNO) generation in the gas phase.

We present a novel nitroxyl (HNO) generation method, which avoids the need of using a liquid system or extreme experimental conditions. This method consists of the reaction between a gaseous base and an HNO donor (Piloty's acid) in the solid phase, allowing the formation of gaseous HNO in a fast and economical way. Detection of HNO was carried out indirectly, measuring the nitrous oxide (N2O) byproduct of HNO dimerization using infrared spectroscopy, and directly, using mass spectrometry techniques and an electrochemical HNO sensor.

Successful stabilization of the elusive species {FeNO}8 in a heme model.

Nitroxyl (HNO/NO(-)) heme-adducts have been postulated as intermediates in a variety of catalytic processes carried out by different metalloenzymes. Hence, there is growing interest in obtaining and characterizing heme model nitroxyl complexes. The one-electron chemical reduction of the {FeNO}(7) nitrosyl derivative of Fe(III)(TFPPBr(8))Cl, Fe(II)(TFPPBr(8))NO (1) (TFPPBr(8) = 2,3,7,8,12,13,17,18-octabromo-5,10,15,20-[Tetrakis-(pentafluorophenyl)]porphyrin) with cobaltocene yields the significantly stable {FeNO}(8) complex, [Co(C(5)H(5))(2)](+)[Fe(TFPPBr(8))NO](-) (2). Complex 2 was isolated and characterized by UV-vis, FTIR, (1)H and (15)N NMR spectroscopies. In addition, DFT calculations were performed to get more insight into the structure of 2. According to the spectroscopic and DFT results, we can state unequivocally that the surprisingly stable complex 2 is the elusive {FeNO}(8) species. Both experimental and computational data allow to assign the electronic structure of 2 as intermediate between Fe(II)NO(-) and Fe(I)NO, which is contrasted with the predominant Fe(II)NO(-) character of known nonheme {FeNO}(8) complexes. The enhanced stability achieved for a heme model {FeNO}(8) is expected to allow further studies related to the reactivity of this elusive species.

Synthesis, structure and reactivity of NO+, NO˙ and NO- pincer PCN-Rh complexes.

Synthesis of a pincer-type linear nitrosyl complex [Rh(PtBu2CNEt2)(NO)]+ (3+) is described. The product and all intermediates involved were fully characterized by FTIR, NMR, cyclic voltammetry and X-ray crystallography. Attempts at obtaining (3+) from its chlorinated precursor Rh(PCN)(NO)Cl (2) revealed that a relative stabilization of this complex ion is introduced by the BArF- counteranion, as other counteranions-PF6-, BF4- and triflate-proved to coordinate to the metal center. Redox reactivity both of (3+) and of that of its five-coordinate derivatives (2) and [Rh(PCN)(NO)(CH3CN)]+ (4+) was found to distinguish itself from analogous PCP complexes due to a relative stabilization of higher oxidation states. Oxidation of these three complexes was studied by FTIR spectroelectrochemistry. Reduction of complex (3+) to yield a short-lived {RhNO}9 species [Rh(PCN)(NO)]˙ (3˙) was also carried out. Complex (3˙) was proved able to activate carbon-halogen bonds in aryl halides, in much a similar way as that of its PCP analogue. Complex (3+) was also seen to establish a linear ↔ bent nitrosyl equilibrium upon addition of CO which could not be fully displaced with excess CO.

NO˙ disproportionation by a {RhNO}9 pincer-type complex.

The reactivity of the {RhNO}9 complex [Rh(PCPtBu)(NO)]˙ (1˙) with NO˙ was studied. A disproportionation reaction takes place in which N2O is released quantitatively, while the complex Rh(PCPtBu)(NO)(NO2) (2), with coordinated nitrite, is formed. The new complex 2 was fully characterized by multinuclear NMR techniques, IR and X-ray diffraction. The X-ray structure reveals a square pyramidal geometry with an N-bound nitro ligand trans to the Cipso of the PCP ligand and a bent nitrosyl ligand in the apical position. IR measurement of released N2O confirms that one equivalent forms for each molecule of 1˙. Infrared spectroscopic experiments with 1˙-15NO and 14NO˙ suggest that the reaction occurs through the intermediacy of a dinitrosyl complex. In addition, DFT calculations were performed to provide more evidence on the structure of the intermediates and to support the observed reactivity.

Narcolepsia / Narcolepsy

El siguiente relato se origina a partir de la consulta de un paciente que concurre a la cátedra de los jueves por la tarde, donde es profesor titular quien escribe. Actúan como docentes adjuntos los doctores Jorge Traverso y Roberto Zaldúa. A continuación, la referencia al mismo. (AU)

The following story originates in a consultation made by a patient who visits the chairo on Thursdays afternoon, where this paper's autor is the head teacher and Dr. Jorge Traverso and Dr. Roberto Zaldúa are auxiliary teachers. Below is said reference. (AU)

Enfermedades crónicas, reflexión y formación de subjetividad / Chronic illnesses, reflection and formation of subjectivity

En el arduo trabajo de conceptualizar una epistemología homeopática, uno de los temas a tratar debe ser el de la formación de la subjetividad homeopática, ésta es parte importante y supuestamente natural en el acto médico-paciente. Una manera de no naturalizarla y por ende ignorarla, es su estudio crítico, como intenta en este artículo

Aportes repertoriales / Adding repertoire rubrics

Este trabajo fue presentado al VII Congreso Ecuatoriano de Medicina Homeopática, realizado en Quito, en agosto de 1997. Tiene por objeto tratar de consensuar criterios para desagregar o agregar remedios a los distintos rubros repertoriales, en base a reglas creíbles y verificables

Creer o ser crédulo / To believe or to be credulous

Se indaga la semiología del rubro crédulo, la dinámica mórbida de los medicamentos que lo cubren y su relación con otros rubros del repertorio

Reflexiones sobre el parágrafo 3 del Organón / Analysis of the third paragraph of the \"Organon\"

Se trata de analizar el parágrafo tercero del Organón de Hahnemann desde una ideología que permita contribuir a la formación de una epistemología homeopática

Los especialistas que estudian Homeopatía / The specialist that studing Homeopathy

Este artículo alerta sobre los riesgos de la actitud del especialista en enfermedades y su consecuencia en la prescripción cuando no ha cambiado su concepto de salud y enfermedad en el estudio de la homeopatía

Aclaraciones sobre simbología / To clarify the symbolism

Intento de clarificar lo relacionado con el sombolismo como método de aproximación a la dinámica homeopática, fundamentos y carencias

Hongos, manjar de los dioses / The fungi, food of the godhead

Se trata de relacionar en cuanto a los hongos, lo tabú, lo ritual y el peso de su toxicología como base del medicamento homeopático y su utilización terapéutica

De brujas y espiritus maleficos / Of witches and malefic spirits

Se trata de analizar un rubro que considero incompleto, como es el denominado supersticioso en el repertorio; en base a su historia y observacion clinica.

Asclepio, medicina clásica y medicina homeopática / Asclepio, classical and homeopathic medicine

Se trata de relacionar desde la mitología griega y el culto de Asclepio, a la medicina clásica en sus orígenes, con el poder simbólico en la cultura médica