A class of small molecules that inhibit TNFalpha-induced survival and death pathways via prevention of interactions between TNFalphaRI, TRADD, and RIP1

Small-molecule library screening to find compounds that inhibit TNFalpha-induced, but not interleukin 1beta (IL-1beta)-induced, intercellular adhesion molecule 1 (ICAM-1) expression in lung epithelial cells identified a class of triazoloquinoxalines. These compounds not only inhibited the TNFalpha-induced nuclear factor kappaB (NFkappaB) survival pathway but also blocked death-pathway activation. Such dual activity makes them unique against other known NFkappaB-pathway inhibitors that inhibit only a subset of TNFalpha signals leading to increased TNFalpha-induced cytotoxicity. Interestingly, these compounds inhibited association of TNFalpha receptor (TNFalphaR) I with TNFalphaR-associated death domain protein (TRADD) and receptor interacting protein 1 (RIP1), the initial intracellular signaling event following TNFalpha stimulation. Further study showed that they blocked ligand-dependent internalization of the TNFalpha-TNFalphaR complex, thereby inhibiting most of the TNFalpha-induced cellular responses. Thus, compounds with a triazoloquinoxaline scaffold could be a valuable tool to investigate small molecule-based anti-TNFalpha therapies.     

Syntheses, characterization, and dioxygen reactivities of Cu(I) complexes with cis,cis-1,3,5-triaminocyclohexane derivatives: a Cu(III)2O2 intermediate exhibiting higher C-H activation

Six Cu(I) complexes with cis,cis-1,3,5-triaminocyclohexane derivatives (R3CY, R = Et, iBu, and Bn), [Cu(MeCN)(Et3CY)]SbF6 (1), [Cu(MeCN)(iBu3CY)]SbF6 (2), [Cu(MeCN)(Bn3CY)]SbF6 (3), [Cu(CO)(Et3CY)]SbF6 (4), [Cu(CO)(iBu3CY)]SbF6 (5), and [Cu(CO)(Bn3CY)]SbF6 (6), were prepared to probe the ability of copper complexes to effectively catalyze oxygenation reactions. The complexes were characterized by elemental analysis, electrochemical and X-ray structure analyses, electronic absorption spectroscopy, IR spectroscopy, 1H NMR spectroscopy, and ESI mass spectrometry. The crystal structures of 1-3 and 6 and the CO stretching vibrations (nuCO) of 4-6 demonstrate that the ability of R3CY to donate electron density to the Cu(I) atom is stronger than that of the previously reported ligands, 1,4,7-triazacyclononane (R3TACN) and 1,4,7-triazacyclodecane (R3TACD). Reactions of complexes 1-3 with dioxygen in THF or CH2Cl2 at -105 to -80 degrees C yield bis(mu-oxo)dicopper(III) complexes 7-9 as intermediates as confirmed by electronic absorption spectroscopy and resonance Raman spectroscopy. The Cu-O stretching vibrations, nu(Cu-O) for 7 (16O2: 553, 581 cm-1and 18O2: 547 cm-1) and 8 (16O2: 571 cm-1 and 18O2: 544 cm-1), are observed in a lower energy region than previously reported for bis(micro-oxo) complexes. The decomposition rates of complexes 7-9 in THF at -90 degrees C are 2.78 x 10-4 for 7, 8.04 x 10-4 for 8, and 3.80 x 10-4 s-1 for 9. The decomposition rates of 7 and 8 in CH2Cl2 were 5.62 x 10-4 and 1.62 x 10-3 s-1, respectively, and the thermal stabilities of 7-9 in CH2Cl2 are lower than the values measured for the complexes in THF. The decomposition reactions obeyed first-order kinetics, and the H/D isotope experiments for 8 and 9 indicate that the N-dealkylation reaction is the rate-determining step in the decomposition processes. On the other hand, the decomposition reaction of 7 in THF results in the oxidation of THF (acting as an exogenous substrate) to give 2-hydroxy tetrahydrofuran and gamma-butyrolactone as oxidation products. Detailed investigation of the N-dealkylation reaction for 8 by kinetic experiments using N-H/D at -90 degrees C showed a kinetic isotope effect of 1.25, indicating that a weak electrostatic interaction between the N-H hydrogen and mu-oxo oxygen contributes to the major effect on the rate-determining step of N-dealkylation. X-ray crystal structures of the bis(micro-hydroxo)dicopper(II) complexes, [Cu2(OH)2(Et3CY)2](CF3SO3)2 (10), [Cu2(OH)2(iBu3CY)2](CF3SO3)2 (11), and [Cu2(OH)2(Bn3CY)2](ClO4)2 (12), which have independently been prepared as the final products of bis(micro-oxo)dicopper(III) intermediates, suggest that an effective interaction between N-H and mu-oxo in the Cu(III)2(micro-O)2 core may enhance the oxidation ability of the metal-oxo species.     

Revised structures of gambiriins A1, A2, B1, and B2, chalcane-flavan dimers from gambir (Uncaria gambir extract)

Gambir, the aqueous extract from Uncaria gambir (Rubiaceae), has been used as an astringent medicine in Asian countries. Investigation of the constituents in the extract led to the isolation of four chalcane-flavan dimers, gambiriin A1 (6), A2 (7), B1 (8), and B2 (9), in addition to (+)-catechin (1), (+)-epicatechin (2), and dimeric proanthocyanidins, procyanidin B1 (3), procyanidin B3 (4), and gambiriin C (5). The spectroscopic and chemical data obtained in the present study indicated that their previously proposed structures 6a, 7a, 8a, and 9a should be revised to 6, 7, 8, and 9, respectively.     

Solution properties of perfluorinated anionic surfactants with divalent counterion of separate electric charges

Novel surfactants of perfluorinated double long-chain salts with divalent counterion of separate electric charge, 1,1-(1,omega-alkanediyl)bispyridinium diperfluorononanoate (CnBP(FC9)2, n = 2, 4, 6, 8) were newly synthesized. Their solution properties were investigated by surface tension measurement over the temperature range from 298.2 to 313.2 K, where magnesium diperfluorononanoate (Mg(FC9)2) was employed as a reference surfactant with divalent counterion of concentrated electric charge. From change of surface tension with concentration, the critical micelle concentration (CMC), surface excess (Gamma), apparent molecular surface area (A), and -log(concentration to reduce surface tension of water by 20 mN m-1) (pC20) were determined. The CMC values of CnBP(FC9)2 decreased with increasing charge separation and with increasing temperature, where the values of CnBP(FC9)2 were much smaller than those of Mg(FC9)2. In addition, the pC20 values of the former were also much larger than those of the latter. These results indicate a strong influence of the extent of charge separation or the spacer length of the counterions upon surface activity of the fluorinated surfactants. The surface excess or the corresponding apparent molecular surface area monotonously changed with the spacer length (n < or = 6), whereas the behavior for n = 8 was much different from the other CnBP(FC9)2 due to conformational change in the in-between alkanediyl chain. The entropy changes (Deltas) for the surface adsorption or condensation were found to be mostly negative for CnBP(FC9)2, where the changes approached zero with an increase in the charge separation. On the other hand, the changes for Mg(FC9)2 were positive over the whole concentration below the CMC. In addition, Brewster angle microscopy indicated no condensation of the present surfactants just at the air/solution interface.     

苯并10芳杂环化合物的合成

近年来符合休克尔规则的,经典的6π芳香环以外的大环或多环芳香族化合物的合成及其应用的开发曰益受到人们的重视^[1,2]。本文简要介绍含有三氟甲基及三氟乙酰基的苯并10π-芳杂环化合物的合成及其结构的确定。此类化合物目前文献中尚未见报导。     

Synthesis of conjugated polymers with azobenzene moieties in the main chain

Poly(phenylenevinylene)‐based conjugated polymers with azobenzene groups in the main chains were prepared by the Pd‐catalyzed coupling polymerization of divinylarenes with dihaloarenes. The Pd‐catalyzed coupling polymerization of 4,4′‐divinylazobenzene with dihaloarenes such as 1,3‐dibromobenzene, 1,4‐dibromo‐2,5‐dihexylbenzene, 4,4′‐dibromoazobenzene, and 4,4′‐diiodoazobenzene resulted in polymers with poor solubility. In contrast, soluble polymers containing azobenzene moieties in the main chains were attainable from divinylbenzenes with 4,4′‐dihaloazobenzenes if either or both of the monomers possessed hexyl groups on the aromatic rings. The number‐average molecular weight of the polymer exceeded 10,000 under optimized conditions, and the polymer showed a remarkably redshifted absorption in the visible region (456 nm). ¹H NMR and IR spectra supported that the polymers having only trans‐geometry for the double bonds. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 1057–1063, 2000     

Preparation of core‐shell polystyrene‐polyimide particles by dispersion polymerization of styrene using poly(amic acid) as a stabilizer

Dispersion polymerization of styrene (S) and vinylbenzyltrimethylammonium chloride (VBA) was conducted in an ethanol‐water medium using an aromatic poly(amic acid) (PAA) as the stabilizer. When equimolar amounts of VBA and the carboxylic acid of PAA were used, monodisperse particles with high PAA content were obtained quantitatively. The imidization of PAA on the particles proceeded with acetic anhydride and N,N‐dimethylaminopyridine to form core‐shell PS‐polyimide particles.     

Photochemical behavior of poly(ethylacryloylacetate) and poly(acryloylacetone) films

Films of poly(ethylacryloylacetate) (PEAA) and poly(acryloylacetone) (PAA) were subjected to UV irradiation (λ = 254 nm) at room temperature. The photoinduced structure transfer from cis-enol onto a diketo forms has been investigated. The structure transfer caused by UV light was found to be slower than for the corresponding process in solution. The spectral investigations (UV, IR) showed reversible process of photoketonization. The results were analyzed in terms of the model for the participation of the trans-enol form in the process of the ketonization. Based on the results obtained, some general conclusions were made about the organization of the units in the polymer chain. © 1997 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 35: 3683–3688, 1997     

Polymerization of N-carbazolylacetylene by various transition metal catalysts and polymer properties

N-Carbazolylacetylene (CzA) was polymerized in the presence of various transition metal catalysts including WCl₆, MoCl₅, [Rh(NBD)Cl]₂, and Fe(acac)₃ to give polymers in good yields. The polymers produced with W catalysts were dark purple solids and soluble in organic solvents such as toluene, chloroform, etc. The highest weight-average molecular weight of poly(CzA) reached about 4 × 10⁴. In the UV–visible spectrum in CHCl₃, poly(CzA) exhibited an absorption maximum around 550 nm (ε_max = 4.0 × 10³ M⁻¹ cm⁻¹) and the cutoff wavelength was 740 nm, showing a large red shift compared with that of poly(phenylacetylene) [poly(PA)]. Poly(CzA) began to lose weight in TGA under air at 310°C, being thermally more stable than poly(PA) and poly[3-(N-carbazolyl)-1-propyne]. Poly(CzA) showed a third-order susceptibility of 18 × 10⁻¹² esu, which was 2 orders larger than that of poly(PA). © 1998 John Wiley & Sons, Inc. J. Polym. Sci. A Polym. Chem. 36: 2489–2492, 1998