Synthesis of fluorinated aminium cations coupled with carborane anions for use as strong one-electron oxidants.

Synthesis of a series of hydrocarbon-soluble triarylamines bearing F, CF3, and Br substituents showing quasi-reversible redox events in the 0.59-1.32 V range is reported. Chemical oxidation of the amines was carried out with 0.5PhI(OAc)2/Me3SiX/Na[RCB11Cl11] (X = Cl or OTf, R = H or Me), and a few aminium salts were isolated as pure solids.

The prostaglandin EP4 receptor is a master regulator of the expression of PGE2 receptors following inflammatory activation in human monocytic cells.

Prostaglandin E2 (PGE2) is responsible for inflammatory symptoms. However, PGE2 also suppresses pro-inflammatory cytokine production. There are at least 4 subtypes of PGE2 receptors, EP1-EP4, but it is unclear which of these specifically control cytokine production. The aim of this study was to determine which of the different receptors, EP1R-EP4R modulate production of tumor necrosis factor-α (TNF-α) in human monocytic cells. Human blood, or the human monocytic cell line THP-1 were stimulated with LPS. The actions of PGE2, alongside selective agonists of EP1-EP4 receptors, were assessed on LPS-induced TNF-α, IL-1ß and IL-10 release. The expression profiles of EP2R and EP4R in monocytes and THP-1 cells were characterised by RT-qPCR. In addition, the production of cytokines was evaluated following knockdown of the receptors using siRNA and over-expression of the receptors by transfection with constructs. PGE2 and also EP2 and EP4 agonists (but not EP1 or EP3 agonists) suppressed TNF-α production in blood and THP-1 cells. LPS also up regulated expression of EP2R and EP4R but not EP1 or EP3. siRNA for either EP2R or EP4R reversed the suppressive actions of PGE2 on cytokine production and overexpression of EP2R and EP4R enhanced the suppressive actions of PGE2. This indicates that PGE2 suppression of TNF-α by human monocytic cells occurs via EP2R and EP4R expression. However EP4Rs also control their own expression and that of EP2 whereas the EP2R does not affect EP4R expression. This implies that EP4 receptors have an important master role in controlling inflammatory responses.

Comparison of the electronic properties of diarylamido-based PNZ pincer ligands: redox activity at the ligand and donor ability toward the metal.

This paper presents the synthesis and characterization of a series of pincer ligands and their Ni, Pd, Pt, and Rh complexes. The ligands under examination are based on a diarylamine which is modified either by two phosphino (-PR2) substituents in the ortho-positions (PNP ligands) or by a combination of a phosphino and an iminyl (-CH═NX) substituent (PNN ligands). The ligands can be broken down into three groups: (a) C2v-symmetric PNP ligands with identical side -PR2 donors, (b) Cs-symmetric PNP' ligands with different -PR2 side donors, and (c) PNN ligands containing a -P(i)Pr2 side donor. All of the ligands under study readily formed square-planar complexes of the types (PNZ)PdCl, (PNZ)Pd(OAc), and (PNZ)RhCO, where PNZ is the corresponding anionic tridentate pincer ligand. For select PNP ligands, (PNP)NiCl and (PNP)PtCl were also studied. The (PNZ)MCl complexes (M = Ni, Pd, Pt) underwent quasireversible oxidation in cyclic voltammetry experiments. Based on the close similarity of formal potentials for Ni, Pd, and Pt analogs, and based on the previous literature evidence, these oxidation events are ascribed primarily to the PNZ ligand, and the E1/2 values can be used to compare the ease of oxidation of different ligands. A (PNP)PdCl complex containing methoxy substituents para- to the central nitrogen underwent two quasireversible oxidations. Two mono-oxidized complexes were isolated and structurally characterized in comparison to their neutral analog, revealing minimal changes in the bond distances and angles. Several other neutral complexes were also structurally characterized. The carbonyl stretching frequency in (PNZ)RhCO complexes was used to gauge the donating ability of the various pincer ligands toward the metal. Comparison of E1/2 values for (PNZ)PdCl and νCO values for (PNZ)RhCO revealed that the two are not consistently correlated across all the studied ligands and can be tuned to different degrees through judicious ligand alteration.

Zirconium-mediated synthesis of arsaalkene compounds from arsines and isocyanides.

An atom-economical synthesis of arsaalkenes via a net coupling of aryl arsines with aryl or alkyl isocyanides at zirconium is presented. Reaction of zirconium arsenido complexes (N3N)ZrAsHAr [N3N = N(CH2CH2NSiMe3)3(3-); Ar = Ph, (2) Mes (3)] with aryl and alkyl isocyanides yields arsaalkene products of the general form (N3N)Zr[NRC(H)═As(Ar)]. Two examples (5: R = Mes, Ar = Ph; 6: R = CH2Ph, Ar = Mes) were structurally characterized. Observation of intermediates in the reaction and structural characterization of the previously reported 1,1-insertion product benzylisocyanide with (N3N)ZrAsPh2 (8), (N3N)Zr[η(2)-C(PPh2)=NCH2Ph] (9), support the mechanistic hypothesis that these reactions occur via 1,1-insertion followed by rearrangement.

Eicosapentaenoic acid suppression of systemic inflammatory responses and inverse up-regulation of 15-deoxyΔ(12,14) prostaglandin J2 production.

BACKGROUND AND PURPOSE: Eicosapentaenoic acid (EPA) has been shown to suppress immune cell responses, such as cytokine production and downstream PG production in vitro. Studies in vivo, however, have used EPA as a minor constituent of fish oil with variable results. We investigated the effects of EPA on systemic inflammatory responses as pure EPA has not been evaluated on immune/inflammatory responses in vivo. EXPERIMENTAL APPROACH: Rabbits were administered polyinosinic: polycytidylic acid (poly I:C) i.v. before and after oral treatment with EPA for 42 days (given daily). The responses to IL-1ß and TNF-α were also studied. Immediately following administration of poly I:C, body temperature was continuously monitored and blood samples were taken. Plasma levels of IL-1ß, PGE2 (PGE2), and 15-deoxy-Δ(12,14)-PGJ2 (15d-PGJ2) were measured by enzyme immunoassay. KEY RESULTS: Following EPA treatment, the fever response to poly I:C was markedly suppressed compared with pretreatment responses. This was accompanied by a parallel reduction in the poly I:C-stimulated elevation in plasma levels of IL-1ß and PGE2. Paradoxically, the levels of 15d-PGJ2 were higher following EPA treatment. EPA treatment did not significantly alter the fever response or plasma levels of PGE2 in response to either IL-1ß or TNF-α. CONCLUSION AND IMPLICATIONS: Oral treatment with EPA can suppress immune/inflammatory responses in vivo via a suppression of upstream cytokine production resulting in a decreased fever response and indirectly reducing circulating levels of PGE2. EPA also enhances the production of the cytoprotective prostanoid 15d-PGJ2 indicating the therapeutic benefit of EPA.

Characterisation of the prostaglandin E2-ethanolamide suppression of tumour necrosis factor-α production in human monocytic cells.

BACKGROUND AND PURPOSE: Prostaglandin ethanolamides or prostamides are naturally occurring neutral lipid derivatives of prostaglandins that have been shown to be synthesised in vivo following COX-facilitated oxygenation of arachidonoyl ethanolamine (anandamide). Although the actions of prostaglandins have been extensively studied, little is known about the physiological or pathophysiological effects of prostamides. Since prostaglandin E2 has potent immunosuppressive/immunomodulating actions, the aim of the present study was to determine whether the derivative, prostaglandin E2 ethanolamide (PGE2-EA), could modulate the production of the pro-inflammatory cytokine tumour necrosis factor-α in human blood and human monocytic cells and indicate whether this action involved the same receptor systems/signals as PGE2. EXPERIMENTAL APPROACH: Whole human blood, monocytes isolated from the blood or the human monocytic cell line THP-1 was incubated with LPS and the level of TNF-α produced was measured by ELISA assay. The actions of PGE2-EA were assessed on the LPS-induced TNF-α release. In addition, in order to ascertain the receptors involved, the levels of cyclic AMP in cells were measured in monocytes and THP-1 cells in response to PGE2-EA and directly compared to those of PGE2. The effect of PGE2-EA on the binding of radiolabelled PGE2 to cells was also measured. Cells were incubated with radiolabelled arachidonic acid and ethanolamine to estimate the production of PGE2-EA. KEY RESULTS: PGE2-EA potently suppressed TNF-α production in blood, monocytes and the cell line THP-1 in a concentration-dependent manner. This occurred via cyclic AMP pathways as indicated by agents which interfere with these pathways and also direct ligand binding experiments. It was also shown that the cells were able to endogenously produce PGE2-EA. CONCLUSIONS AND IMPLICATIONS: This study reports that PGE2-EA can downregulate the production of TNF-α by human mononuclear cells in response to an immune stimulus, i.e. LPS-activated TLR4, and that this appears to occur via a cAMP-dependent mechanism that most likely involves binding to the EP2 receptor.

7beta-hydroxy-epiandrosterone modulation of 15-deoxy-delta12,14-prostaglandin J2, prostaglandin D2 and prostaglandin E2 production from human mononuclear cells.

7beta-hydroxy-epiandrosterone (7beta-OH-EPIA) has been shown to be cytoprotective in various organs including the brain. It has also been shown that prostaglandin D2 (PGD2) and its spontaneous metabolite 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) are also cytoprotective. It is possible that these prostaglandins derived from circulating mononuclear cells may mediate the actions of 7beta-OH-EPIA. The aim of this study, therefore, was to ascertain the effect of 7beta-OH-EPIA (in the absence or presence of tumour necrosis factor-alpha (TNF-alpha)), a pro-inflammatory stimulus, on the biosynthesis of PGD2, PGE2 and 15d-PGJ2 from human mononuclear cells. Prostaglandins were measured by enzyme immunoassay (EIA). 7beta-OH-EPIA alone induced a concentration-dependant increase in the production of PGD2. TNF-alpha increased PGD2 levels which were enhanced by 7beta-OH-EPIA. 7beta-OH-EPIA increased 15d-PGJ2 levels both in the absence and presence of TNF-alpha. 7beta-OH-EPIA alone had no effect on PGE2 biosynthesis but suppressed TNF-alpha-induced PGE2 circa 50%. 7beta-OH-EPIA also increased the level of free arachidonic acid and radiolabelled prostaglandins in cells pre-incubated with radiolabelled arachidonic acid, indicating that the increase may occur via the enhanced release of substrate arachidonic acid. 7beta-OH-EPIA did not affect levels of the anti-inflammatory cytokine IL-10 indicating that this is an unlikely mechanism by which 7beta-OH-EPIA induces its actions but more likely exerts its effects via the production of cytoprotective prostaglandins.

Mechanistic variety in zirconium-catalyzed bond-forming reaction of arsines.

Triamidoamine-supported zirconium complexes have been demonstrated to catalyze a range of bond-forming events utilizing arsines. Three different mechanisms have been observed in these reactions. In the first mechanism, triamidoamine-supported zirconium complexes of the general type (N3N)ZrX (N3N =N(CH2CH2NSiMe3)33-; X = monoanionic ligand) catalyzed the dehydrogenative dimerization of diphenylarsine. Mechanistic analysis revealed that As-As bond formation proceeds via sigma-bond metathesis steps similar to the previously reported dehydrocoupling of phosphines by the same catalysts. In the second mechanism, sterically encumbered primary arsines appear to be dehydrocoupled via alpha elimination of an arsinidene fragment. Dehydrocoupling of dmpAsH2 (dmp = 2,6-dimesitylphenyl) to form (dmp)As = As(dmp) by (N3N)Zr-complexes appeared to proceed via elimination of dmpAs: from the arsenido intermediate, (N3N)ZrAsH(dmp). Further support for -arsinidene elimination came from the thermal decomposition of (N3N)ZrAsHMes (9) to (MesAs)4 (10), which obeyed first-order kinetics. In the third mechanism, the observation of stoichiometric insertion reactivity of the Zr-As bond with polar substrates, PhCH2NC, PhCN, (1-napthyl)NCS, and CS2, led to the development of intermolecular hydroarsination catalysis of terminal alkynes. Here, (N3N)ZrAsPh2 (2) catalyzed the addition of diphenylarsine to phenylacetylene and 1-hexyne to give the respective vinylarsine products. Arsenido complexes 2 and 9 and tetraarsine 10 have been structurally characterized.