Ligand 1a Research Articles

Decoy receptor 3 protects non-obese diabetic mice from autoimmune diabetes by regulating dendritic cell maturation and function

Decoy receptor 3 (DcR3), a member of the tumor necrosis factor receptor superfamily, regulates immune responses through competing with receptors of Fas ligand (FasL), LIGHT and TNF-like molecule 1A (TL1A). We have previously demonstrated that transgenic expression of DcR3 in a β cell-specific manner significantly protects non-obese diabetic (NOD) mice from autoimmune diabetes. In this study, we further investigated the systemic effect of DcR3 in regulating lymphocytes and dendritic cells in NOD mice. Our results demonstrated that both DcR3 plasmid and protein treatments significantly inhibited insulitis and diabetes. Lymphocytes from DcR3.Fc-treated mice revealed less proliferative potential and transferred ameliorated diabetes. By administration of DcR3.Fc in T1 and T2 double transgenic NOD mice expressing human Thy1 or murine Thy1.1 surface marker under IFN-γ or IL-4 promoter control respectively, we observed a remarkable reduction of Th1 and an increase of Th2 immune responses in vivo. Strikingly, in vitro polarization experiments exhibited that not only Th1 but also Th17 cell differentiation was significantly inhibited in splenocytes treated with DcR3.Fc protein. However, this phenomenon was only observed in splenocytes, not in purified CD4 + T cells, suggesting that DcR3-mediated inhibition of Th1 and Th17 differentiation is not T cell-autonomous and maybe through other cell types such as dendritic cells. Finally, our results demonstrated that DcR3 directly modulates the differentiation and maturation of dendritic cells and subsequently regulates the differentiation and effector function of T cells.

Synthesis, X-ray structures, electrochemical properties and cytotoxic effects of Co(II) complexes

1-Benzothiazol-2-yl-3,5-dimethyl-1 H-pyrazole ( 1a) and 1-benzothiazol-2-yl-5-(2-hydroxyphenyl)-3-methyl-1 H-pyrazole-4-carboxylic acid methyl ester ( 1b) were reacted with the hexahydrates of cobalt(II) chloride, cobalt(II) nitrate and cobalt(II) perchlorate to give the corresponding complexes 2a– 4a and 2b– 5b, respectively. Obtained compounds differ in coordination spheres of central atoms. The complex 2a includes a fivefold coordinated cobalt(II) ion, whereas 3a shows a distorted octahedral configuration around the cobalt(II) ion. All complexes were characterised by FTIR spectroscopy, MS and elemental analysis. The X-ray structures of 2a, 3a and 5b complexes were also solved. The cytotoxic properties of the ligand 1a and both series of Co(II) complexes were examined on human leukemia NALM-6 and HL-60 cells and melanoma WM-115 cells. The ligands, were found to have very low cytotoxicity. Complex 3b exhibited the highest cytotoxic activity with IC 50 values in the range of 6.9–17.1 μM for three examined cell lines.

TL1A in the inflammatory network in autoimmune diseases

Several lines of evidence both from experimental models and from clinical studies reveal that TNF-like ligand 1A (TL1A) and its interaction with death receptor 3 (DR3) is critically involved in the pathogenesis of rheumatoid arthritis and other autoimmune diseases.

TL1A induces the expression of TGF-β-inducible gene h3 (βig-h3) through PKC, PI3K, and ERK in THP-1 cells

βig-h3, an extracellular matrix protein involved in various biological processes including cellular growth, differentiation, adhesion, migration, and angiogenesis, has been shown to be elevated in various inflammatory processes. Death receptor 3 (DR3), a member of the TNF-receptor superfamily that is expressed on T cells and macrophages, is involved in the regulation of inflammatory processes through interaction with its cognate ligand, TNF-like ligand 1A (TL1A). In order to find out whether the TL1A-induced inflammatory activation of macrophages is associated with the up-regulation of βig-h3 expression, the human acute monocytic leukemia cell line (THP-1) was stimulated with either recombinant human TL1A- or DR3-specific monoclonal antibodies. Stimulation of DR3 up-regulated the intracellular levels as well as the secretion of βig-h3. Utilization of various inhibitors and Western blot analysis revealed that activation of protein kinase C (PKC), extracellular signal-regulated kinase (ERK), phosphoinositide kinase-3 (PI3K), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is required for TL1A-induced βig-h3 expression. PKC appears to be the upstream regulator of PI3K since the presence of PKC inhibitor blocked the phosphorylation of AKT without affecting ERK phosphorylation. On the other hand, suppression of either PI3K or ERK activity resulted in the suppression of IκB phosphorylation. These findings indicate that TL1A can regulate the inflammatory processes through modulation of the βig-h3 expression through two separate pathways, one through PKC and PI3K and the other through ERK, which culminates at NF-κB activation.

β-Amino Alcohol Derived β-Hydroxy- and β-(o-Diphenylphosphino)benzoyloxy(o-diphenylphosphino)benzamides: An Ester−Amide Ligand Structural Model for the Palladium-Catalyzed Allylic Alkylation Reaction

A commercially available collection of beta-amino alcohols have been converted to their corresponding beta-hydroxy- and beta-(o-diphenylphosphino)benzoyloxy(o-diphenylphosphino)benzamides 11a-f and 12a-f and have been employed in the Tsuji-Trost asymmetric alkylation reaction with 1,3-diphenylpropenyl acetate. With the exception of ligands 11b and 11f, the beta-hydroxybenzoyloxy(o-diphenylphosphino)benzamide ligands 11a-f primarily afforded the (R)-enantiomer of the product. In contrast, the bis(phosphine) ligands 12a-f consistently afforded the (S)-enantiomer. The best ligand (12c) was derived from cis-(1R,2S)-2-amino-1,2-diphenyl-1-ethanol, and when applied in the asymmetric allylic alkylation reaction, it yielded the product in an enantiomeric ratio of 97.8.22 favoring the (S)-enantiomer. A computational study was conducted on the conformation that this ligand might adopt in the palladium-catalyzed alkylation reaction as compared to that of the Trost ligand 1a.

Role of TL1A in the Pathogenesis of Rheumatoid Arthritis

TNF-like ligand 1A (TL1A), a member of the TNF superfamily, is the ligand of DR3 and DcR3. Several types of cells, such as endothelial cells, monocytes/macrophages, dendritic cells, and CD4 and CD8 T cells, are capable of producing this cytokine. In present study, we demonstrated that TL1A aggravated collagen-induced arthritis in mice. It increased collagen-induced arthritis penetrance and clinical scores as well as the severity of the pathological findings. TL1A administration led to the occurrence of multiple enlarged germinal centers in the spleen, and it boosted serum anti-collagen Ab titers in vivo. In vitro, TL1A augmented TNF-alpha production by T cells upon TCR ligation, and it greatly enhanced Th17 differentiation and IL-17 production. We further showed that human rheumatoid arthritis (RA) synovial fluids had elevated TL1A titers, and human chrondrocytes and synovial fibroblasts were capable of secreting TL1A upon TNF-alpha or IL-1beta stimulation. Taken together, these data suggest that TL1A secretion in lymphoid organs might contribute to RA initiation by promoting autoantibody production, and TL1A secretion stimulated by inflammatory cytokines in RA joints might be a part of a vicious circle that aggravates RA pathogenesis.

Effects of dietary glycine supplementation and fish meal on inflammatory responses in broiler chicks

1. The effect of dietary protein source and glycine (Gly) supplementation on inflammatory responses was investigated using broiler chicks. Birds (7 d of age) were fed on a maize–soybean meal based (CS) diet with or without 20 g fish meal (FM)/kg and/or 10 g Gly/kg for 14 d. 2. Inflammatory responses were assessed by determining changes in the plasma concentrations of nitrate plus nitrite (NO x ), caeruloplasmin (Cer) and α-1 acid glycoprotein (AGP), and changes in the expression of mRNA encoding substances related to the inflammatory response, such as interleukin (IL)-1 β and −6, tumour necrosis factor like ligand (TL)1A, inducible nitrite synthase (iNOS), interferon(IFN)-γ, following lipopolysaccharide (LPS) injection. 3. IL-1 β and TL1A mRNA expression in chicks fed on the FM diet was higher than in chicks fed on the CS diet. 4. Supplementing the CS diet with Gly resulted in smaller increases in the plasma concentrations of NO x , Cer and AGP after LPS injection than were observed for chicks fed on the CS diet alone. In addition, 2 h after LPS challenge the expression of encoding inflammatory response-related substances was lower in the spleens of those chicks fed on the Gly-supplemented diet than in those fed the CS diet. 5. Supplementation of the FM diet with Gly reduced the plasma AGP concentration and IL-1 β and TL1A expression. 6. These results suggest that modulation of inflammatory responses by dietary Gly supplementation is affected by dietary composition; Gly supplementation has different effects on the cytokine responses dependent on the diet.

Cyclometalation of 6-Phenyl-2,2′-Bipyridine and Iridium: Synthesis, Characterization, and Reactivity Studies

Heating the potential tridentate 6-(4-R-phenyl)-2,2′-bipyridine ligand 1a (R = H), and derivatives 1b (R = CMe3) and 1c (R = OH), with IrCl3 hydrate in 2-methoxyethanol or acetone/H2O gave the unexpected bidentate cyclometalated NC dinuclear complexes [Ir(NC)Cl2(C5H5N)]2 (2a−cPy), as the major product. Altering the ligand/metal ratio from 1:1 to 2:1 produced a mixture of bis-cyclometalated complexes, Ir(NNC)(NC)Cl (3a,b), with tridentate and bidentate binding modes. Using discrete IrI synthons, such as Ir(dmso)3Cl or [Ir(cyclooctene)2Cl]2, gave a complicated mixture of products. However, when [Ir(C2H4)2Cl]2 was used, then the desired tridentate cyclometalated Ir(NNC) complex Ir(NNC)Et(C2H4)Cl (4) was synthesized cleanly. The dinuclear complex 2a-Py was converted to the corresponding mononuclear dichloride complexes Ir(NC)(NN)Cl2 (5a) upon refluxing with 4,4′-di-tert-butylbipyridine in N,N-dimethylacetamide (DMA). Treatment of 5a with ZnMe2 gives Ir(NC)(NNtBu)MeCl (6a). Abstraction of the chloride with AgOTF yields Ir(NC)(NNtBu)MeOTf (7a). Complex 7a undergoes stoichiometric CH activation with arenes and shows catalytic activity for the H/D exchange between benzene and (trifluoro)acetic acids.

Functionalised Tris(pyrazolyl)methane Ligands and Re(CO)3 Complexes Thereof

AbstractThe synthesis of new tripodal nitrogen ligands derived from tris(pyrazolyl)methane (TpmR, R = H, tBu, Ph in 3‐position) is described. After deprotonation of the parent tris(pyrazolyl)methane TpmR, the carbanion reacts readily with ethylene oxide to yield the 3,3,3‐tris(3′‐substituted pyrazolyl)propanol ligands[(3‐Rpz)3CCH2CH2OH, R = H, tBu, Ph, 1a–c]. These ligands can be easily derivatised at the alcohol function. Microwave‐assisted reactions of these ligands and [Re(CO)5Br] yields the complex [(1a)Re(CO)3]Br (4) in the case of ligand 1a, whereas in the case of the substituted ligands 1b and 1c degradation was observed. The degradation products are identified as [(HpzR)2Re(CO)3Br] [R = tBu (7b), Ph (7c)]. These complexes were also prepared directly from [Re(CO)5Br] and the corresponding pyrazoles by microwave‐assisted synthesis. The Re(CO)3 complexes 4 and [(1a)Re(CO)3]OTf (5) are water‐soluble. The structures of 5·H2O and [{(pz)3CCH2CH3}Re(CO)3]OTf·1.5H2O·1/2CH3CN (6·1.5H2O·1/2CH3CN) as well as the structure of 7b have been elucidated by X‐ray crystallography.

Flexible, Bowl-Shaped N-Heterocyclic Carbene Ligands: Substrate Specificity in Iridium-Catalyzed Ketone Hydrosilylation

A series of benzimidazolium chlorides was synthesized as precursors to N-heterocyclic carbene ligands, with N-substituents varying in size from 3,5-xylyl (1a) to first-generation dendritic 3,5-bis(3,5-di-tert-butylphenyl)phenyl (1b), to the second-generation 3,5-bis[3,5-bis(3,5-di-tert-butylphenyl)phenyl]phenyl (1c). The dendritic side groups of 1b and 1c form a flexible, bowl-like cavity. Iridium complexes of 1a−c were synthesized and were shown to be catalytically active for the hydrosilylation of aryl methyl ketones. The dendritic ligands 1b and 1c effect a moderate level of substrate specificity in the competitive hydrosilylation of ketones of varying size. In the competitive hydrosilylation of acetophenone versus 3-(3,5-di-tert-butylphenyl)acetophenone, acetophenone is consumed approximately 3.7 times more quickly using the second-generation ligand 1c. Using the control ligand 1a, this ratio is 1.8.

Dietary supplementation of glycine modulates inflammatory response indicators in broiler chickens

Three experiments were conducted to investigate the effect of dietary glycine (Gly) supplementation on inflammatory responses in broiler chicks fed a basal diet using maize and soybean meal as the primary ingredients. Inflammation-related processes following lipopolysaccharide (LPS) injection were examined by analysing plasma concentrations of nitrate plus nitrite (NOx) and ceruloplasmin (Cer) in experiments 1 and 2, or expression of several genes in the spleen and liver including IL-1 beta and -6, TNF-like ligand (TL)1A, inducible NO synthase, interferon (IFN)-gamma and toll-like receptor (TLR) 4 were examined in experiment 3. Growth performance was also determined following immunological stimulation by both LPS and Sephadex injection in experiment 2. In experiment 1, birds fed a diet supplemented with Gly at 10 or 20 g/kg showed lower responses in plasma NOx and Cer than birds fed the diet supplemented with Gly at 0 or 40 g/kg. In experiment 2, a similar effect of Gly supplementation at 10 g/kg on plasma NOx and Cer was observed when chicks were fed either an isonitrogenous diet with Gly or glutamic acid (Glu). Gly-supplemented diet-fed birds showed better growth performance than Glu-supplemented diet-fed birds. The splenic expression of inflammatory response-related genes in birds fed a diet supplemented with Gly at 10 g/kg diet was lower than that of birds fed the basal diet in experiment 3. These results suggest that dietary Gly supplementation modulates the inflammatory response partly through changes in the expression of pro-inflammatory cytokines such as IL-1, IL-6, IFN-gamma and TL1A.

Role of Chicken TL1A on Inflammatory Responses and Partial Characterization of Its Receptor

The role of chicken TNF-like ligand 1A (ChTL1A) on inflammation and its receptor candidates was investigated to further understand its function as a proinflammatory cytokine. ChTL1A decreased the viability of CHO-K1 cells transfected with chicken TNFR2 or decoy receptor 3 and bound to TNFR2 and decoy receptor 3. ChTL1A was detected in chicken blood samples taken 4 h after LPS injection. Increased mRNA for inflammatory response-related factors such as IL-1beta, IL-6, ChTL1A, IFN-gamma, inducible NO synthase, and cyclooxygenase 2 were found in spleen samples following LPS injection. Ceruloplasmin and alpha(1) acid glycoprotein (as positive acute phase proteins) were increased in chicken plasma 12 h after ChTL1A injection. The injection of anti-ChTL1A Ab was able to prevent typical increases in plasma nitrite plus nitrate, ceruloplasmin, and alpha(1) acid glycoprotein concentrations following LPS injection. These results indicate that ChTL1A is a proinflammatory cytokine in chickens, animals that do not have TNF-alpha and lymphotoxin alpha orthologous genes, and that its proinflammatory action is, at least in part, expressed through binding to TNFR2.

Rate and Mechanism of the Oxidative Addition of Aryl Halides to Palladium(0) Complexes Generated in Situ from a Pd(0)−Triolefinic Macrocyclic Complex and Phosphines

The rate and mechanism of the oxidative addition of aryl halides (PhI, PhBr) to Pd(0) complexes generated in situ upon addition of phosphines (PPh3, PnBu3, dppf) to the macrocyclic triolefinic complex Pd0(1a) have been investigated in THF or DMF. The macrocyclic ligand 1a is known to allow a good recycling of the catalyst in catalytic reactions. It is established that the ligand 1a affects the kinetics of oxidative addition, as monitored by electrochemical techniques. As far as PPh3 is concerned, a reactivity order with PhI has been established in THF, Pd0(PPh3)4 > {Pd0(1a) + 4 PPh3}, as a consequence of an equilibrium between Pd0(1a) and Pd0(PPh3)3 which decreases the concentration of Pd0(PPh3)3 and consequently that of the reactive Pd0(PPh3)2. As expected, {Pd0(1a) + 2 PPh3} is more reactive than {Pd0(1a) + 4 PPh3}. In contrast to PPh3, the addition of n equivalents of PnBu3 to Pd0(1a) in DMF leads to the formation of Pd0(η2-1a)(PnBu3)2 and Pd0(PnBu3)3 (n > 2), characterized by 31P NMR. At equal phosphi...

Ir-Catalyzed Regio- and Enantioselective Friedel–Crafts-Type Allylic Alkylation of Indoles

Highly regio- and enantioselective Ir-catalyzed Friedel-Crafts type allylic alkylation of indoles have been realized using [Ir(COD)Cl]2/phosphoramidite ligand 1a, affording the branched products with up to >97/3 branched-linear ratio and 92% ee.

N-(o-Aminophenyl)-2-oxy-4-methoxybenzophenoneimine – Si-chelation by a tridentate ONN ligand system versus benzimidazoline formation

Reaction of 2-hydroxy-4-methoxybenzophenone (o-HO-p-MeO–C6H3–C(Ph)=O) with o-phenylenediamine (o-H2N–C6H4–NH2) yielded the tridentate chelating ligand 1a (N-(o-aminophenyl)-2-oxy-4-methoxybenzophenoneimine, o-HO-p-MeO–C6H3–C(Ph)=N-(o-C6H4)–NH2). Ligand 1a reacts with diphenyldichlorosilane in the presence of triethylamine to yield the pentacoordinate silicon compound 2a (Ph2Si[o-O-p-MeO–C6H3–C(Ph)=N-(o-C6H4)–NH]). N-acetylation of 1a yields 1b, the reaction of which with Ph2SiCl2 surprisingly yields a silylated benzimidazoline 3.

Ir-Catalyzed Regio- and Enantioselective Decarboxylative Allylic Alkylations

[Ir(COD)Cl]2/phosphoramidite ligand 1a was found to be an efficient catalytic system for the highly regio- and enantioselective decarboxylative alkylation of gamma-substituted allyl beta-ketocarboxylates, affording the branched products with up to >99/1 branched-linear ratio and 96% ee.

Synthesis of a Donor Molecule with Metal Coordination Sites toward Multifunctional Complexes

Abstract We have synthesized a donor-type ligand 1a–1f containing a 1,3-dithiol ring as the donor site and an N,N,N-tridentate ligand for metal complexation. In the crystal phase, the planar 1a molecules stack along the b axis in the “head-to-tail” fashion. The FeII complex 2 shows typical paramagnetic behavior.

Palladium(II)–allyl complexes containing chiral N-donor ferrocenyl ligands

A study of the reactivity of enantiopure ferrocenylimine ( S C )-[FcCH N–CH(Me)(Ph)] {Fc = (η 5-C 5H 5)Fe{(η 5-C 5H 4)–} ( 1a) with palladium(II)–allyl complexes [Pd(η 3-1R 1,3R 2-C 3H 3)(μ-Cl)] 2 {R 1 = H and R 2 = H ( 2), Ph ( 3) or R 1 = R 2 = Ph ( 4)} is reported. Treatment of 1a with 2 or 3 {in a molar ratio Pd(II): 1a = 1} in CH 2Cl 2 at 298 K produced [Pd(η 3-3R 2-C 3H 4){FcCH N–CH(Me)(Ph)}Cl] {R 2 = H ( 5a) or Ph ( 6a)}. When the reaction was carried out under identical experimental conditions using complex 4 as starting material no evidence for the formation of [Pd(η 3-1,3-Ph 2-C 3H 3){FcCH N–CH(Me)(Ph)}Cl] ( 7a) was found. Additional studies on the reactivity of ( S C )-[FcCH N–CH(R 3)(CH 2OH)] {R 3 = Me ( 1b) or CHMe 2 ( 1c)} with complex 4 showed the importance of the bulk of the substituents on the palladium(II) allyl–complex ( 2– 4) or on the ferrocenylimines ( 1) in this type of reaction. The crystal structure of 5a showed that: (a) the ferrocenylimine adopts an anti-( E) conformation and behaves as an N-donor ligand, (b) the chloride is in a cis-arrangement to the nitrogen and (c) the allyl group binds to the palladium(II) in a η 3-fashion. Solution NMR studies of 5a and 6a and [Pd(η 3-1,3-Ph 2-C 3H 3){FcCH N–CH(Me)(CH 2OH)}Cl] ( 7b) revealed the coexistence of several isomers in solution. The stoichiometric reaction between 6a and sodium diethyl 2-methylmalonate reveals that the formation of the achiral linear trans-( E) isomer of Ph–CH CH–CH 2Nu ( 8) was preferred over the branched derivative ( 9). A comparative study of the potential utility of ligand 1a, complex 5a and the amine ( S C )-H 2N–CH(Me)(Ph) ( 11) as catalysts in the allylic alkylation of ( E)-3-phenyl-2-propenyl ( cinnamyl) acetate with the nucleophile diethyl 2-methylmalonate (Nu −) is reported.

Heterodimetallic Palladium(II) Complexes with Bidentate (N,S) or Terdentate (C,N,S)- Ferrocenyl Ligands. The Effect of the Ligand Donor Atoms on the Regioselectivity of the Allylic Alkylation of Cinnamyl Acetate

The synthesis and characterization of [Pd(η3-1-R1-C3H4){FcCHN−(C6H4−2SMe)}][PF6] {R1 = H (2a) or Ph (3a)} are described. A comparative study of the catalytic activity of (a) the mixtures containing [Pd(η3-C3H5)(μ-Cl)]2 and its parent ligand (1a) or H2N−C6H4−2SMe (4) and (b) the palladacycles [Pd{[(η5-C5H3)−CHN−(C6H4−2SMe)]Fe(η5-C5H5)}Cl] (5a), [Pd{(2-CH2-4,6-Me2C6H2)−CHN−(C6H4−2SMe)}Cl] (5b) in the allylic alkylation of (E)-3-phenyl-2-propenyl (cinnamyl) acetate with sodium diethyl 2-methylmalonate is also reported.

New bis(fluoro-ponytailed) bipyridine ligands for Pd-catalyzed Heck reactions under fluorous biphasic catalysis condition

Three highly fluorinated bipyridine derivatives (4,4′-bis(R fCH 2OCH 2)-2,2′-bpy) {R f=HCF 2(CF 2) 7 ( 1a), n-C 8F 17 ( 1b), n-C 10F 21 ( 1c)} have been synthesized using 4,4′-bis(BrCH 2)-2,2′-bpy and the corresponding fluorinated alkoxides. The fluorine contents of ligands 1a– c are 58.3, 59.8, and 62.3%, respectively. Despite its high fluorine content, the ligand 1a with a –CF 2H polar terminal group is more soluble in organic solvents. The ligand 1b is a white solid and is still moderately soluble in CH 2Cl 2. The ligand 1c has a high fluorophilicity, the partition ratio being 42:1 for the n-C 8F 18/CH 2Cl 2 system. The reaction of ligands 1a– c with [PdCl 2(CH 3CN) 2] results in the novel Pd complexes [PdCl 2(4,4′-bis-(R fCH 2OCH 2)-2,2′-bpy)] where R f=HCF 2(CF 2) 7 ( 2a), n-C 8F 17 ( 2b), n-C 10F 21 ( 2c), respectively. The Pd complex 2b is a pale yellow solid, and has been tested unsatisfactorily for FBC. Insoluble in organic solvents, the Pd complex 2c dissolves only in fluorinated solvents, for instance FC77, which is mainly n-C 8F 18. The novel Pd complex 2c has been tested as a catalyst in Heck reactions under a fluorous biphasic catalysis condition. It was found that the Pd complex 2c, after an easy separation, keeps its catalytic activity (>90% yield), even after seven runs. The TGA studies indicate that the Pd complexes 2a– c are stable up to 330 °C.