Nosyl (2-Nitrobenzenesulfonyl) Annulation Strategy toward Winding Vine-Shaped Bithiophenes.

Winding vine-shaped bithiophene was synthesized through the nosyl (2-nitrobenzenesulfonyl) cyclization protocol. The reaction of bithiophene bearing bromomethyl groups at the 3,3'-positions with nosylated 1,2-ethylenediamine in the presence of potassium carbonate afforded the annulated product in excellent yield. The obtained bithiophene was found to contain a 10-membered ring, which was confirmed by X-ray analysis. The related nosyldiamine bearing a tri- or tetramethylene group also reacted in a similar manner, affording an 11- or 12-membered macrocycle, respectively.

A nitrogenase cluster model [Fe8S6O] with an oxygen unsymmetrically bridging two proto-Fe4S3 cubes: relevancy to the substrate binding mode of the FeMo cofactor.

An oxygen-encapsulated iron sulfido cluster, [(DmpS)Fe(4)S(3)O][(DmpS)Fe(4)S(3)](µ-SDmp)(2)(µ-OCPh(3)) (2; Dmp = 2,6-(mesityl)(2)C(6)H(3)), has been synthesized by the reaction of the preformed dinuclear iron thiolate/alkoxide [(Ph(3)CO)Fe](2)(µ-SDmp)(2) (1) with (1/8)S(8) and (1/4)H(2)O in toluene. In the [Fe(8)S(6)O] core, the oxygen atom bridges unsymmetrically two incomplete Fe(4)S(3) cubes, and two coordinatively unsaturated iron atoms are weakly bound to mesityl rings. Relevance of the cluster structure of 2 to the nitrogenase FeMo cofactor and its substrate binding mode is discussed.

Non-centrosymmetric coordination polymer with a highly hindered octahedral copper center bridged by mandelate.

A novel chiral coordination polymer, [Cu(C(6)H(5)CH(OH)COO)(µ-C(6)H(5)CH(OH)COO)] (1-L and 1-D), was synthesized through a reaction of copper acetate with L-mandelic acid at room temperature. Although previously reported copper mandelate prepared by hydrothermal reaction was a centrosymmetric coordination polymer because of the racemization of mandelic acid, the current coordination polymer shows noncentrosymmetry and a completely different structure from that previously reported. The X-ray crystallography for 1-L revealed that the copper center of the compound showed a highly distorted octahedral structure bridged by a chiral mandelate ligand in the unusual coordination mode to construct a one-dimensional (1D) zigzag chain structure. These 1D chains interdigitated each other to give a layered structure as a result of the formation of multiple aromatic interactions and hydrogen bonds between hydroxyl and carboxylate moieties at mandelate ligands. The coordination polymer 1-L belongs to the noncentrosymmetric space group of C2 to show piezoelectric properties and second harmonic generation (SHG) activity.

Synthesis of coordinatively unsaturated mesityliron thiolate complexes and their reactions with elemental sulfur.

The reactions of Fe(2)Mes(4) (1; Mes = mesityl) with bulky thiols, namely, HSDmp (Dmp = 2,6-dimesitylphenyl), HSDxp (Dxp = 2,6-dixylylphenyl), and HSBtip [Btip = 2,6-(2,4,6-(i)Pr(3)C(6)H(2))(2)C(6)H(3)], provided a series of iron(II) mesityl complexes bearing bulky thiolate ligands. These iron complexes are the thiolate-bridged dinuclear complexes Fe(2)Mes(2)(mu-SAr)(mu-Mes) (2a, Ar = Dmp; 2b, Ar = Dxp), the 1,2-dimethoxyethane (DME) adducts (DME)Fe(SAr)(Mes) (3a, Ar = Dmp; 3b, Ar = Dxp), the mixed-valence Fe(I)-Fe(II) dinuclear complexes (Mes)Fe(mu-SAr)(mu-S Ar) Fe (4a, Ar = Dmp; 4b, Ar = Dxp), and a low-coordinate mononuclear complex (B tipS) Fe(Mes) (5). An [Fe(8)S(7)] cluster [Fe(4)S(3)(SDmp)](2)(mu-SDmp)(2)(mu-SMes)(mu(6)-S) (6), the core structure of which is topologically relevant to that of the FeMo-cofactor of nitrogenase, was obtained from the reaction of 3a or 4a with S(8). The mu-SMes ligand in 6 is formed via insertion of a sulfur atom into the Fe-C(Mes) bond. The formation of cluster 6 from 3a or 4a demonstrates that organoiron complexes are applicable as precursors for iron-sulfur clusters.

Cellobiose Prevents the Development of Dextran Sulfate Sodium (DSS)-Induced Experimental Colitis.

Cellobiose is produced from cellulose using specific bacterial enzymes, and is hydrolyzed into glucose by the enzymes cellobiosidase and cellulase. In this study, we examined the effects of cellobiose on colonic mucosal damage in a dextran sulfate sodium (DSS) colitis model. BALB/c mice were divided into two groups. In the first group, the mice were fed 3.5% DSS mixed with normal chow. In the second group, the mice were fed 3.5% DSS plus 6.0 or 9.0% (weight/weight) cellobiose mixed with normal chow. The development of colitis was assessed on day 21. Mucosal cytokine expression was analyzed by RT-PCR. Body weight loss was significantly attenuated in the 9.0% cellobiose-fed DSS mice as compared to the DSS mice. Colonic weight/length ratio, a maker of tissue edema, was significantly higher in the DSS mice than in the 9.0% cellobiose-fed DSS mice. The disease activity index and histological colitis score were also significantly higher in the DSS mice than in the 9.0% cellobiose-fed DSS mice. Mucosal mRNA expression for IL-1beta, TNF-alpha, IL-17 and IP-10 were markedly reduced in the 9.0% cellobiose-fed DSS mice. In conclusion, a preventive effect of cellobiose against DSS colitis suggests its clinical use for inflammatory bowel diseases patients.

Inhibitory effects of short-chain fatty acids on matrix metalloproteinase secretion from human colonic subepithelial myofibroblasts.

BACKGROUND AND AIMS: Short-chain fatty acids (SCFAs), such as acetate, propionate and butyrate, are the major by-product of bacterial fermentation of dietary fiber in the colon. In this report, we investigated how SCFAs modulate matrix metalloproteinase (MMP) secretion from human colonic subepithelial myofibroblasts (SEMFs). MATERIALS AND METHODS: SEMFs were identified by expression of alpha-smooth muscle actin and vimentin. Cytokine-induced MMP-1 and MMP-3 levels were determined by enzyme-linked immunosorbent assay. Cytokine-induced MMP mRNA expression was analyzed by RT-PCR and real-time PCR methods. RESULTS: Acetate had no effect on MMP secretion. Propionate and butyrate significantly attenuated IL-1 beta- and TNF-alpha-induced MMP-1 and MMP-3 secretion. Similar responses were also observed at the mRNA levels. Propionate and butyrate did not modulate IL-1 beta- and TNF-alpha-induced activation of mitogen-activated protein kinases (MAPKs), which play a crucial role in MMP induction. Trichostatin A, a histone-deacetylase inhibitor, reduced IL-1 beta-induced MMP-1 and MMP-3 mRNA expression, and suppressed TNF-alpha-induced MMP-3 mRNA expression. CONCLUSION: SCFAs play an anti-inflammatory role through suppression of MMP secretion in the colon. Inhibitory effects of SCFAs on MMP secretion might be associated with their action of histone hyperacetylation.

Monitoring 6-thioguanine nucleotide concentrations in Japanese patients with inflammatory bowel disease.

BACKGROUND AND AIM: There have been no reports on 6-thioguanine nucleotide (6-TGN) concentrations in Japanese patients with inflammatory bowel disease (IBD) undergoing azathioprine (AZA) or 6-mercaptopurine (6-MP) therapy. The aim of this study was to assess 6-TGN concentrations in Japanese IBD patients. METHODS: Eighty-three patients with Crohn's disease (n = 42) and ulcerative colitis (n = 41) were enrolled. In 69 patients, AZA was prescribed at 50 mg/day, and seven patients were given 75 (n = 5) or 100 mg/day (n = 2). 6-MP was administered at 30 mg/day (n = 7). The 6-TGN concentrations were then assayed by high-performance liquid chromatography. RESULTS: The mean 6-TGN concentrations of the entire study population (n = 83) were 277.9 +/- 179.8 pmol/8 x 10(8) red blood cells (RBC). The mean 6-TGN concentrations in those patients with active disease (n = 38) and those in remission (n = 45) were 232.9 +/- 159.7(mean +/- SD) and 342.8 +/- 184.6 pmol/8 x 10(8) RBC, respectively (P < 0.05). The odds ratio of being in remission and having a 6-TGN value >235 pmol/8 x 10(8) RBC was 2.6 (95% CI 1.05-6.2). A significant inverse correlation was found between the white blood cell (WBC) counts and 6-TGN concentrations (r = -0.301, P < 0.05, n = 83); the mean WBC counts of the active patients (6780 +/- 2412) were significantly higher than the patients in clinical remission (5468 +/- 1920, P < 0.05). Three patients with severe leukopenia and 10 patients with high 6-TGN concentrations had no thiopurine S-methyl transferase mutations. CONCLUSION: The 6-TGN concentrations in Japanese patients with IBD on low-dose AZA and 6-MP therapy were comparable to those reported from Western countries. The monitoring of 6-TGN concentrations may be helpful for developing a therapeutic strategy for Japanese IBD patients.

Interleukin-31 stimulates production of inflammatory mediators from human colonic subepithelial myofibroblasts.

Interleukin (IL)-31 is mainly produced by CD4+ T cells, in particular T cells skewed toward a Th2 phenotype. Here we report for the first time that IL-31 stimulates secretion of proinflammatory cytokines, chemokines and matrix metalloproteinases (MMPs) from human colonic subepithelial myofibroblasts (SEMFs). The effects of IL-31 were investigated by cDNA microarrays, enzyme-linked immunosorbent assay, and real-time PCR. IL-31 effectively induced chemokines [IL-8, GRO-alpha (growth-related oncogene-alpha), MCP-3 (monocyte chemoattractant protein-3), CXCL3, CCL13 and CCL15], proinflammatory cytokines (IL-6, IL-16 and IL-32) and matrix metalloproteinases (MMP-1, MMP-3, MMP-25 and MMP-7). IL-31 dose-dependently induced secretion of IL-6, IL-8, GRO-alpha, MCP-3, MMP-1 and MMP-3. The effects of IL-31 were comparable to the effects of IL-17A. IL-31 and IL-17A showed additive effects on IL-6, IL-8, GRO-alpha, MCP-3, MMP-1 and MMP-3 secretion. In conclusion, we demonstrated that IL-31 is a potent inducer of proinflammatory mediators in human colonic SEMFs. IL-31 may function as a proinflammatory cytokine derived from Th2 cells.