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Trafficking of intracellular cholesterol (Ch) to and into mitochondria of steroidogenic cells is required for steroid hormone biosynthesis. This trafficking is typically mediated by one or more proteins of the steroidogenic acute regulatory (StAR) family. Our previous studies revealed that 7-OOH, a redox-active cholesterol hydroperoxide, could be co-trafficked with Ch to/into mitochondria of MA-10 Leydig cells, thereby inducing membrane lipid peroxidation (LPO) which impaired progesterone biosynthesis. These negative effects of 7-OOH were inhibited by endogenous selenoperoxidase GPx4, indicating that this enzyme could protect against 7-OOH-induced oxidative damage/dysfunction. In the present study, we advanced our Leydig focus to cultured murine TM3 cells and then to primary cells from rat testis, both of which produce testosterone. Using a fluorescent probe, we found that extensive free radical-mediated LPO occurred in mitochondria of stimulated primary Leydig cells during treatment with liposomal Ch+7-OOH, resulting in a significant decline in testosterone output relative to that with Ch alone. Strong enhancement of LPO and testosterone shortfall by RSL3 (a GPx4 inhibitor) and reversal thereof by Ebselen (a GPx4 mimetic), suggested that endogenous GPx4 was playing a key antioxidant role. 7-OOH in increasing doses was also cytotoxic to these cells, RSL3 exacerbating this in Ebselen-reversable fashion. Moreover, GPx4 knockdown increased cell sensitivity to LPO with reduced testosterone output. These findings, particularly with primary Leydigs (which best represent cells in intact testis) suggest that GPx4 plays a key protective role against peroxidative damage/dysfunction induced by 7-OOH co-trafficking with Ch.

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In recent years, the accumulation of phosphate ions and the increase in acidity have been described as crucial metabolic fatigue-leading factors that disturb muscle fiber contractions. This fact is especially important in the context of mitochondrial dysfunctions in which excessive fatigue is one of the possible symptoms. However, little is known about the precise fatigue-inducing thresholds of work intensity in mitochondrial dysfunctions of various types and at various stages of their severity. Possible interactions of additional factors such as disturbances in electrolyte concentrations (i.e. magnesium ions) were also not precisely defined. One of the best-suited tools for this kind of problem is systems biology, which enables modeling of metabolic pathways. In this research, a computer model of working skeletal muscle was adapted. The relationship between the decrease in oxidative phosphorylation and the workload shows a linear dependence for dysfunctions that evenly disturb the activity of each element of the pathway (which is equivalent to the decrease in mitochondrial mass). In case of dysfunctions that disrupt only one element of the pathway, the relationship between fatigue threshold and exercise intensity is exponential, but with higher threshold deficiency values. Muscle phosphate levels were the most vulnerable to disruptions of complex III and ATP synthase. Surprisingly, disruptions of the ATP/ADP exchanger emerged as equally disruptive and capable of significantly increasing phosphate concentrations also in the rest state, whereas the impact of the impairment of the phosphate transporter was negligible. Perturbations in magnesium concentration also did not show a significant effect in any of these models.

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Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid containing taurine conjugated with the ursodeoxycholic acid (UDCA), has been known and used from ancient times as a therapeutic compound in traditional Chinese medicine. TUDCA has recently been gaining significant interest as a neuroprotective agent, also exploited in the visual disorders. Among several mechanisms of TUDCA's protective action, its antioxidant activity and stabilizing effect on mitochondrial and plasma membranes are considered. In this work we investigated antioxidant activity of TUDCA and its impact on structural properties of model membranes of different composition using electron paramagnetic resonance spectroscopy and the spin labeling technique. Localization of TUDCA molecules in a pure POPC bilayer has been studied using a molecular dynamics simulation (MD). The obtained results indicate that TUDCA is not an efficient singlet oxygen (1O2 (1Δg)) quencher, and the determined rate constant of its interaction with 1O2 (1Δg) is only 1.9 × 105 M-1s-1. However, in lipid oxidation process induced by a Fenton reaction, TUDCA reveals substantial antioxidant activity significantly decreasing the rate of oxygen consumption in the system studied. In addition, TUDCA induces slight, but noticeable changes in the polarity and fluidity of the investigated model membranes. The results of performed MD simulation correspond very well with the experimental results.

RESUMEN

The synthesis, structural characterization, and reactivity of an iron(III) chloride compound of 6,6'-di(3,5-di-tert-butyl-2-hydroxybenzene)-2,2'-bipyridine (Fe(tbudhbpy)Cl), under electrochemically reducing conditions is reported. In the presence of carbon dioxide (CO2) under anhydrous conditions in N,N-dimethylformamide (DMF), this complex mediates the 2e- reductive disproportionation of two equivalents of CO2 to carbon monoxide (CO) and carbonate (CO32-). Upon addition of phenol (PhOH) as a proton source under CO2 saturation, catalytic current is observed; product analysis from controlled potential electrolysis experiments shows the majority product is formate (68 ± 4% Faradaic efficiency), with H2 as a minor product (30 ± 10% Faradaic efficiency) and minimal CO (1.1 ± 0.3% Faradaic efficiency). On the basis of data obtained from cyclic voltammetry and infrared spectroelectrochemistry (IR-SEC), the release of CO from intermediate Fe carbonyl species is extremely slow and undergoes competitive degradation, limiting the activity and lifetime of this catalyst. Mechanistic studies also indicate the phenolate moieties coordinated to Fe are sensitive to protonation in the reduced state, suggesting the possibility of cooperative pendent proton interactions being involved in CO2 reduction.

RESUMEN

The effects of an electron-withdrawing group on the organic chemistry of an η2-bound benzene ring are explored using the complex TpW(NO)(PMe3)(η2-PhCF3). This trifluorotoluene complex was found to undergo a highly regio- and stereoselective 1,2-addition reaction involving protonation of an ortho carbon followed by addition of a carbon nucleophile. The resulting 1,3-diene complexes can undergo a second protonation and nucleophilic addition with a range of nucleophiles including hydrides, amines, cyanide, and protected enolates. Interestingly, the addition of the second proton and nucleophile occurs in a 1,4-fashion, again with a high degree of regio- and stereocontrol. Oxidation of the metal allows for the isolation of highly substituted trifluoromethylcyclohexenes with as many as four stereocenters set by the metal. The ability to synthesize enantio-enriched organics was also demonstrated for a diene and a trisubstituted cyclohexene. Substitution from an enantio-enriched η2-dimethoxybenzene complex in neat trifluorotoluene yielded enantio-enriched trifluorotoluene complex, which was elaborated into cyclohexadienes and cyclohexenes with ee's ranging from 92 to 99%.

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Mechanochromic luminescent (ML) materials, which show a change in emission due to an applied mechanical stimulus, are useful components in a variety of applications, including organic light-emitting diodes, force sensors, optical memory storage, and next-generation lighting materials. While there are many different ML active derivatives, few show room temperature self-erasing. Thin films of the methoxy substituted ß-diketone, gbmOMe, initially exhibited blue (428 nm) emission; however, green (478 nm) emission was observed after smearing. The mechanically generated smeared state recovered so rapidly that characterization of its emission was difficult at room temperature using traditional luminescence techniques. Thus, a new complementary metal oxide semiconductor camera imaging method was developed and used to calculate the decay time of the mechanically generated smeared state (i.e., smeared-state decay; τSM) for gbmOMe thin films. Additionally, this method was used to evaluate substrate and film thickness effects on ML recovery for glass and weighing paper films. The recovery behavior of gbmOMe was largely substrate-independent for the indicated matrixes; however, thickness effects were observed. Thus, film thickness may be the main factor in determining ML recovery behavior and must be accounted for when comparing the recovery dynamics of different ML materials. Moreover, when heated above the melting point (Tm = 119 °C), bulk gbmOMe powders assumed a metastable state that eventually crystallized after a few minutes at room temperature. However, melted thin films remained in an amorphous state indefinitely despite annealing at different temperatures (50-110 °C). The amorphous phase was identified as a supercooled liquid via changing the rate of cooling in differential scanning calorimetry thermograms.

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Condensation between the tetrabutylammonium salt of 2,2-diphenylglycine and aldehydes results in a decarboxylative Erlenmeyer reaction, affording 1,2-diaryl-2-iminoalcohols as a mixture of diastereomers in good yields. The diastereomeric ratio shifts over time, with the anti diastereomer and the syn oxazolidine tautomer serving as the kinetic and thermodynamic products, respectively. Addition of Lewis acids can catalyze the rates of reaction and product equilibration. The results highlight the stereochemical promiscuity of 1,2-diaryl-2-iminoalcohols in the presence of Lewis acids and Brønsted bases.

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1,1'-Bi-2-naphthol in combination with ZnEt2, Ti(O(i)Pr)4, and dicyclohexylamine have been employed to catalyze asymmetric alkyne addition to an ynal to synthesize optically active propargylic alcohols containing two alkyne functions with excellent yields and enantioselectivities. These chiral alcohols are readily converted to the corresponding optically active propargyl 2,4-hexadienyl ethers. These diene-diyne substrates are found to undergo a highly chemoselective and stereoselective domino Pauson-Khand and Diels-Alder cycloaddition catalyzed by [RhCl(CO)2]2 under CO to generate a class of tetracyclic compounds with high enantiomeric purity. This is a very efficient method for the asymmetric synthesis of polycyclic compounds.

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Traditional C-H bond activation by a concerted metalation-deprotonation (CMD) mechanism involves precoordination of the C-H bond followed by deprotonation from an internal base. Reported herein is a "through-arene" activation of an uncoordinated benzylic C-H bond that is 6 bonds away from a Rh(III) ion. The mechanism, which was investigated by experimental and DFT studies, proceeds through a dearomatized xylene intermediate. This intermediate was observed spectroscopically upon addition of a pyridine base to provide a thermodynamic trap.

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The Rh(III) complexes [((t)bpy)2Rh(OMe)(L)][X]n ((t)bpy = 4,4'-di-tert-butyl-2,2'-bipyridyl; L = MeOH, n = 2, X = OTf (OTf = trifluoromethanesulfonate), TFA (TFA = trifluoroacetate); L = TFA, n = 1, X = OTf) have been shown to activate dihydrogen via net 1,2-addition of the H-H bond across the Rh(III)-OMe bond. The bis(methoxide) complex [((t)bpy)2Rh(OMe)2][OTf] was synthesized by addition of CsOH·H2O in methanol to [((t)bpy)2Rh(OTf)2][OTf] in CH3CN. The addition of HTFA to [((t)bpy)2Rh(OMe)2][OTf] leads to the formation of [((t)bpy)2Rh(OMe)(MeOH)][OTf][TFA], which exists in equilibrium with [((t)bpy)2Rh(OMe)(TFA)][OTf]. The mixture of [((t)bpy)2Rh(OMe)(MeOH)][OTf][TFA] and [((t)bpy)2Rh(OMe)(TFA)][OTf] activates dihydrogen at 68 °C to give methanol and [((t)bpy)2Rh(H)(TFA)][OTf]. Studies indicate that the activation of dihydrogen has a first-order dependence on the Rh(III) methoxide complex and a dependence on hydrogen that is between zero and first order. Combined experimental and computational studies have led to a proposed mechanism for hydrogen activation by [((t)bpy)2Rh(OMe)(MeOH)][OTf][TFA] that involves dissociation of MeOH, coordination of hydrogen, and 1,2-addition of hydrogen across the Rh-OMe bond. DFT calculations indicate that there is a substantial energy penalty for MeOH dissociation and a relatively flat energy surface for subsequent hydrogen coordination and activation.

RESUMEN

Previously, hydridotris(pyrazolyl)borate (Tp) Ru(II) alkyl and aryl complexes of the type TpRu(L)(NCMe)R (R = methyl or aryl; L = charge-neutral two-electron donating ligand) were demonstrated to activate aromatic C-H bonds. To determine the impact of replacing the anionic Tp ligand with charge-neutral poly(pyrazolyl)alkane ligands, [(C(pz)4)Ru(P(OCH2)3CEt)(NCMe)Me][BAr'4] (pz = pyrazolyl, BAr'4 = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) was prepared. Heating a C6D6 solution of [(C(pz)4)Ru(P(OCH2)3CEt)(NCMe)Me][BAr'4] with 1 equiv of NCMe resulted in C-H activation of the 5-position of a pyrazolyl ring to yield [(κ(3)-(N,C(5),N)C(pz)4)Ru(P(OCH2)3CEt)(NCMe)2][BAr'4] and CH4. Intramolecular C-H activation of the 5-position of a pyrazolyl ring also occurred when (η(6)-p-cymene)Ru(P(OCH2)3CEt)(Br)Ph was heated in the presence of C(pz)4 to yield [(κ(3)-N,C(5),N)C(pz)4]Ru(P(OCH2)3CEt)(NCMe)Br and C6H6. Density functional theory calculations revealed that the different reactivities of TpRu(P(OCH2)3CEt)(NCMe)R and [(C(pz)4)Ru(P(OCH2)3CEt)(NCMe)Me][BAr'4] result from the stronger binding of the Tp pyrazolyl rings to Ru(II) compared to that of C(pz)4.

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The fluorescent responses of 3,3'-di(trifluoroacetyl)-1,1'-bi-2-naphthol toward a variety of amines have been studied. It was found that the aliphatic primary 1,2- and 1,5-diamines can greatly enhance the fluorescence of this compound, but under the same conditions, primary, secondary, and tertiary monoamines cannot turn on the fluorescence of this compound. In addition, this compound was shown to be an enantioselective and diastereoselective fluorescent sensor for chiral diamines. UV absorption and NMR spectroscopic methods have been used to study the interaction of the sensor with amines. These studies have demonstrated that the intramolecular OH···O═C hydrogen bonding of the sensor is important for both the reactivity of its trifluoroacetyl group with the amines and its fluorescent responses. The interaction of both of the two amine groups of a diamine molecule with the sensor is essential for the observed fluorescent sensitivity and selectivity.

RESUMEN

The facile and high-yield reaction between aniline and cis-positioned nitriles of [((t)bpy)(2)Rh(NCR)(2)][OTf](3) [R = Me (2), Ph (3); (t)bpy = 4,4'-di-tert-butyl-2,2'-bipyridine; OTf = CF(3)SO(3)(-)] produces the Rh(III)-triazapentadiene species [((t)bpy)(2)[upper bond 1 start]Rh{NH=C(R)N(Ph)C(R=N[upper bond 1 end]H}][OTf](3) [R = Me (4), Ph (5)]. It represents the first example of direct coupling between two RCN ligands and a primary amine to form this type of metallacycle. X-ray structures of 2 and 4 are reported.

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Highly chemoselective and stereoselective tandem Pauson-Khand/[4+2] cycloaddition leads to efficient construction of the spirotricyclic core analogue of mangicol A.

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RESUMEN

Treatment of RuCl(2)(PPh(3))(3) with sodium 2,2,2-tris(pyrazolyl)ethoxide [NaOCH(2)C(pz)(3); pz = pyrazolyl] affords the asymmetric heteroscorpionate complex cis-(Ep(OX))RuCl(PPh(3))(2) (1), (Ep(OX) = κ(3)-N,N,O-OCH(2)C(pz)(3)), which can be converted to Ru(II) compounds (2-6), (Ep(OX))RuCl(L)(L') [(2) L = PPh(3), L' = P(OCH(2))(3)CEt; (3) L = L' = P(OCH(2))(3)CEt; (5) L, L' = PPh(3), CO; (6) L = L' = CO]. Compounds 1 and 3 react with CHCl(3) at 60 and 100 °C, respectively, to yield cationic tris(pyrazolyl)methane Ru(II) complexes, [(κ(3)-N,N,N-Mp)RuCl(L)(2)]Cl [Mp = HC(pz)(3); (7) L = PPh(3); (8) L = P(OCH(2))(3)CEt]. The complexes have been characterized by (1)H, (13)C, and (31)P{(1)H} NMR spectroscopy, elemental analysis, high resolution mass spectrometry, and cyclic voltammetry. Complexes 1 and 3 have also been characterized by single crystal X-ray analysis.

RESUMEN

The complexes TpRu[P(OCH(2))(2)(OCCH(3)](PPh(3))Cl (2) [Tp = hydridotris(pyrazolyl)borate; P(OCH(2))(2)(OCCH(3)) (1) = (4-methyl-2,6,7-trioxa-1-phosphabicyclo[2,2,1]heptane] and TpRu(L)(PPh(3))Cl [L = P(OCH(2))(3)CEt (3), PMe(3) (4) or P(OMe)(3) (5)], (η(6)-C(6)H(6))Ru(L)Cl(2) [L = PPh(3) (6), P(OMe)(3) (7), PMe(3) (8), P(OCH(2))(3)CEt (9), CO (10) or P(OCH(2))(2)(OCCH(3)) (11)] and (η(6)-p-cymene)Ru(L)Cl(2) [L = P(OCH(2))(3)CEt (12), P(OCH(2))(2)(OCCH(3))P(OCH(2))(2)(OCCH(3)) (13), P(OMe)(3) (14) or PPh(3) (15)] have been synthesized, isolated, and characterized by NMR spectroscopy, cyclic voltammetry, mass spectrometry, and, for some complexes, single crystal X-ray diffraction. Data from cyclic voltammetry and solid-state structures have been used to compare the properties of (1) with other phosphorus-based ligands as well as carbon monoxide. Data from the solid-state structures of Ru(II) complexes show that P(OCH(2))(2)(OCCH(3)) has a cone angle of 104°. Cyclic voltammetry data reveal that the Ru(II) complexes bearing P(OCH(2))(2)(OCCH(3)) have more positive Ru(III/II) redox potentials than analogous complexes with the other phosphorus ligands; however, the Ru(III/II) potential for (η(6)-C(6)H(6))Ru[P(OCH(2))(2)(OCCH(3))]Cl(2) is more negative compared to the Ru(III/II) potential for the CO complex (η(6)-C(6)H(6))Ru(CO)Cl(2). For the Ru(II) complexes studied herein, these data are consistent with the overall donor ability of 1 being less than other common phosphines (e.g., PMe(3) or PPh(3)) or phosphites [e.g., P(OCH(2))(3)CEt or P(OMe)(3)] but greater than carbon monoxide.

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The synthesis of some heteroleptic, cyclometalated iridium(III) complexes is described. The utility of these [Ir(ppy)(2)(N-N)]Cl (ppy = 2-phenylpyridine and N-N = substituted bipyridine, biquinoline, or phenanthroline) complexes as luminescence-based sensors is assessed. The emission intensity of an Ir(III) complex featuring the 3,3'-H(n)dcbpy ligand (H(n)dcbpy = dicarboxylic acid-2,2'-bipyridine; n = 0,1,2 to indicate deprotonated, mono- and diprotonated species, respectively) is seen to increase in the presence of Pb(II). Insight into the structure and analyte-sensing capability is achieved by X-ray crystallography in conjunction with computational modeling. Complexes incorporating carboxylic acid-functionalized bipyridine and biquinoline as the polypyridyl ligand show pH sensitivity while similar phenanthroline complexes do not.

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Cationic platinum(II) complexes [((t)bpy)Pt(Ph)(L)](+) [(t)bpy =4,4'-di-tert-butyl-2,2'-bipyridyl; L = THF, NC(5)F(5), or NCMe] catalyze the hydrophenylation of ethylene to generate ethylbenzene and isomers of diethylbenzene. Using ethylene as the limiting reagent, an 89% yield of alkyl arene products is achieved after 4 h at 120 °C. Catalyst efficiency for ethylene hydrophenylation is diminished only slightly under aerobic conditions. Mechanistic studies support a reaction pathway that involves ethylene coordination to Pt(II), insertion of ethylene into the Pt-phenyl bond, and subsequent metal-mediated benzene C-H activation. Studies of stoichiometric benzene (C(6)H(6) or C(6)D(6)) C-H/C-D activation by [((t)bpy)Pt(Ph-d(n))(THF)](+) (n = 0 or 5) indicate a k(H)/k(D) = 1.4(1), while comparative rates of ethylene hydrophenylation using C(6)H(6) and C(6)D(6) reveal k(H)/k(D) = 1.8(4) for the overall catalytic reaction. DFT calculations suggest that the transition state for benzene C-H activation is the highest energy species along the catalytic cycle. In CD(2)Cl(2), [((t)bpy)Pt(Ph)(THF)][BAr'(4)] [Ar' = 3,5-bis(trifluoromethyl)phenyl] reacts with ethylene to generate [((t)bpy)Pt(CH(2)CH(2)Ph)(η(2)-C(2)H(4))][BAr'(4)] with k(obs) = 1.05(4) × 10(-3) s(-1) (23 °C, [C(2)H(4)] = 0.10(1) M). In the catalytic hydrophenylation of ethylene, substantial amounts of diethylbenzenes are produced, and experimental studies suggest that the selectivity for the monoalkylated arene is diminished due to a second aromatic C-H activation competing with ethylbenzene dissociation.

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A new method for the preparation of functionalized piperidines is described in which various dihydropyridine (DHP) complexes of {TpW(NO)(PMe(3))} that are derived from pyridine-borane undergo [4 + 2] cyclocondensation with enones, enals, nitrosobenzene, and several isocyanates to form [2.2.2] bicyclic species. In several cases the diazabicyclooctene products derived from DHP complexes and isocyanates can be further elaborated into novel syn-2,5-disubstituted and 2,3,6-trisubstituted piperidinamides.

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(S)-1,1'-Binaphth-2-ol (BINOL) in combination with ZnEt(2), Ti(O(i)Pr)(4), and biscyclohexylamine was found to catalyze the highly enantioselective (83-95% ee) addition of various 1,3-diynes to aldehydes of diverse structures. This method provides a convenient pathway to generate a number of optically active dienediynes as the acyclic precursors to polycyclic compounds. The chiral dienediynes undergo highly chemoselective Pauson-Khand (PK) cycloaddition in benzaldehyde by using [Rh(cod)Cl](2) as the catalyst in the presence of rac-BINAP. High diastereoselectivity (up to >20:1) has also been achieved with the chiral dienediyne substrates containing a bulky substituent adjacent to the chiral center. In the presence of the Grubbs II catalyst, ring-closing enyne metathesis of the PK cycloaddition products led to the formation of the desired 5,5,7- and 5,5,8-fused tricyclic compounds. Further highly diastereoselective Diels-Alder reaction of a 5,5,7-tricyclic compound with maleic anhydride produced a 5,5,7,6-polycyclic product. The asymmetric synthesis of polycyclic compounds from optically active dienediynes has established a novel and efficient synthetic route to the structural framework of many biologically significant molecules.

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