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The conjugate addition of Ni(II) complexes of glycine Schiff base to α,ß-unsaturated aldehydes catalyzed by (S)-2-(diphenyl(trimethylsilyloxy)methyl)pyrrolidine afforded adducts in excellent yields with up to 49:1 dr and 95% ee. This method enables the construction of two adjacent chiral centers in one step, and offers an alternative route to chiral α-amino acid derivatives.

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Poly(methyl methacrylate) (PMMA) bone cements have a long and successful history of use for implant fixation, but suffer from a relatively low fracture and fatigue resistance which can result in failure of the cement and the implant. Fiber or particulate reinforcement has been used to improve mechanical properties, but typically at the expense of the pre-cured cement viscosity, which is critical for successful integration with peri-implant bone tissue. Therefore, the objective of this study was to investigate the effects of zirconia fiber reinforcement on the fatigue life of acrylic bone cements while maintaining a relatively low pre-cured cement viscosity. Sintered straight or variable diameter fibers (VDFs) were added to a PMMA cement and tested in fully reversed uniaxial fatigue until failure. The mean fatigue life of cements reinforced with 15 and 20 vol% straight zirconia fibers was significantly increased by approximately 40-fold, on average, compared to a commercial benchmark (Osteobond) and cements reinforced with 0-10 vol% straight zirconia fibers. The mean fatigue life of a cement reinforced with 10 vol% VDFs was an order of magnitude greater than the same cement reinforced with 10 vol% straight fibers. The time-dependent viscosity of cements reinforced with 10 and 15 vol% straight fibers was comparable to the commercial benchmark during curing. Therefore, the addition of relatively small amounts of straight and variable diameter zirconia fibers was able to substantially improve the fatigue resistance of acrylic bone cement while exhibiting similar handling characteristics compared to current commercial products.

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The anisotropic elastic constants of human cortical bone were predicted using a specimen-specific micromechanical model that accounted for structural parameters across multiple length scales. At the nano-scale, the elastic constants of the mineralized collagen fibril were estimated from measured volume fractions of the constituent phases, namely apatite crystals and Type I collagen. The elastic constants of the extracellular matrix (ECM) were predicted using the measured orientation distribution function (ODF) for the apatite crystals to average the contribution of misoriented mineralized collagen fibrils. Finally, the elastic constants of cortical bone tissue were determined by accounting for the measured volume fraction of Haversian porosity within the ECM. Model predictions using the measured apatite crystal ODF were not statistically different from experimental measurements for both the magnitude and anisotropy of elastic constants. In contrast, model predictions using common idealized assumptions of perfectly aligned or randomly oriented apatite crystals were significantly different from the experimental measurements. A sensitivity analysis indicated that the apatite crystal volume fraction and ODF were the most influential structural parameters affecting model predictions of the magnitude and anisotropy, respectively, of elastic constants.

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Fibers can be used to improve the mechanical properties of bone cement for the long-term stability of hip prostheses. However, debonding of the fibers from the matrix due to the poor fiber/matrix interface is a major failure mechanism for such fiber reinforced bone cements. In this study, a novel fiber (variable diameter fibers or VDFs) technology for reinforced bone cement was studied to overcome the interface problem of short-fiber composites. These fibers change their diameters along their length to improve the fiber/matrix interfacial bond by the mechanical interlock between the VDFs and the matrix. A novel composite made from novel ceramic VDFs incorporated in PMMA matrix was developed. Both static and fatigue tests were carried out on the composites. Conventional straight fiber (CSF) reinforced bone cement was also tested for comparison purposes. Results demonstrated that both the stiffness and the fatigue life of VDF reinforced bone cement are significantly improved (P < 0.05) compared with the unreinforced bone cement. VDF contents of 10% by volume increased the fatigue life over unreinforced bone cement by up to 100-fold. Also, the fatigue life and modulus of toughness of VDF reinforced cement were significantly greater than those of CSF reinforced cement (P < 0.05 and P < 0.001, respectively). Scanning electron microscopy (SEM) micrographs revealed that VDFs can bridge the matrix cracks effectively and pullout of VDFs results in much more extensive matrix damage than pullout of CSFs increasing the resistance to fatigue. Therefore, VDF reinforced cement was significantly tougher, having a greater energy dissipation capacity than CSF reinforced cement. VDFs added to bone cement could potentially avoid implant loosening due to the mantle fracture of bone cement and delay the need for revision surgery.

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The title compound, C(14)H(20)O(2), crystallizes with homochiral chains of mol-ecules hydrogen bonded together along the b axis. Adjacent chains in the ab plane contain mol-ecules of the same chirality, leading to a chiral segregation of the mol-ecules into layers.

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Polyetheretherketone (PEEK) was reinforced with 0-50 vol% hydroxyapatite (HA) whiskers using a novel powder processing and compression molding technique which enabled uniform mixing at high whisker content. Texture analysis showed that viscous flow during compression molding produced a preferred orientation of whiskers along the specimen tensile axis. Consequently, the elastic modulus or ultimate tensile strength of HA-whisker-reinforced PEEK was able to be tailored to mimic human cortical bone. PEEK reinforced with 40 and 50 vol% HA whiskers exhibited elastic moduli of 17 and 23 GPa, respectively. Elastic constants were measured using ultrasonic wave propagation and revealed an orthotropic anisotropy also similar to that measured in human cortical bone. PEEK reinforced with 10 and 20 vol% HA whiskers exhibited an ultimate tensile strength of 90 and 75 MPa, respectively. Tensile specimen fracture surfaces showed evidence of brittle failure in both reinforced and un-reinforced PEEK. Whisker pullout was observed with PEEK adhered to HA whiskers, suggesting a relatively strong interface between the PEEK matrix and HA whisker reinforcements.

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The hepatotoxicity of bromobenzene (BB) derives from its reactive metabolites (epoxides and quinones), which arylate cellular proteins. Application of proteomic methods to liver proteins from rats treated with a hepatotoxic dose of [14C]-BB has identified more than 40 target proteins, but no adducted peptides have yet been observed. Because such proteins are known to contain bromophenyl- and bromodihydroxyphenyl derivatives of cysteine, histidine, and lysine, the failure to observe modified peptides has been attributed to the low level of total covalent binding and to the "dilution" effect of multiple metabolites reacting at multiple sites on multiple proteins. In this work glutathione S-transferase (GST), a well-known and abundant BB-target protein, was isolated from liver cytosol of rats treated with 14C-BB by use of a glutathione (GSH)-agarose affinity column and further resolved by reverse-phase high-performance liquid chromatography (HPLC) into subunits M1, M2, A1, A2 and A3. The subunits were identified by a combination of sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), whole-molecule mass spectrometry, and peptide mass mapping and found to contain radioactivity corresponding to 0.01-0.05 adduct per molecule of protein. Examination of tryptic digests of these subunits by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) and electrospray ionization mass spectrometry (ESI-MS) failed to reveal any apparent adducted peptides despite observed sequence coverages up to 87%. However, use of HPLC-linear ion-trap quadrupole Fourier transform mass spectrometry (LTQ-FTMS) to search for predicted modified tryptic peptides revealed peaks corresponding, with a high degree of mass accuracy, to a bromobenzoquinone adduct of peptide 89-119 in both GSTA1 and A2. The identity of these adducts and their location at Cys-111 was confirmed by tandem mass spectrometry (MS-MS). No evidence for the presence of any putative BB-adducts in GST M1, M2, or A3 was obtained. This work highlights the challenges involved in the unambiguous identification of reactive metabolite adducts formed in vivo.

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[structure: see text] A short and enantioselective synthesis of cis-fused 5-oxofuro[2,3-b]furans, being found in many spongiane diterpenoid natural products, is reported starting from inexpensive methyl 2-furoate. Moreover, the acid-catalyzed rearrangement of the furo[2,3-b]furan framework A to B is observed for some derivatives, suggesting a simple connection between natural products differing in the absolute configuration of the 3a,6a ring junction.

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The cytotoxicity of many small organic compounds often apparently derives from their metabolic activation and covalent binding to cellular proteins. It is therefore of considerable interest to be able to determine, for a given protoxin, which metabolites modify which proteins at which sites. Our laboratory has identified more than 45 target proteins for bromobenzene metabolites in liver by peptide mass mapping after two-dimensional electrophoresis. Through all of this work, we have never observed a bromine-containing peptide. We therefore generated model adducted proteins by carbodiimide coupling of Nalpha-acetyl-Ntau-(p-bromophenyl)-L-histidine (1) and Nalpha-acetyl-Nepsilon-(p-bromophenyl)-L-lysine (2) to bovine pancreatic ribonuclease A. For the adducts, RNase-(1)n and RNase-(2)n, mass spectrometry indicated that n = 0-2 and 0-6, respectively. RNase-(2)n was submitted to in-gel and in-solution digestion with trypsin, and the digests were analyzed by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) and liquid chromatgraphy electrospray ionization MS (LC/ESI-MS) and tandem MS (MS/MS). Sequence coverages observed ranged from 67% with only three modified lysines observed using in-gel digestion and MALDI-TOF analysis, to 100% coverage with all 10 lysines observed in both modified and unmodified form using in-solution digestion and LC/ESI-MS. In the mass spectra of all modified peptides up to 2000 Da, the bromine isotope pattern was obvious by visual inspection; for peptides up to 3600 Da, the isotopic signature could be recognized by visual comparison to simulated spectra. The presence of Br-containing adducts was confirmed by MS/MS analysis of selected peptides. The selection of peaks for MS/MS analysis was significantly facilitated by visual recognition of the bromine isotope pattern, even at signal-to-noise ratios of 10 (or lower in favorable cases). These results indicate that stable isotope labeling may have considerable potential for detecting and locating protein adducts of reactive metabolites.

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N(tau)-Aryl-histidine derivatives were synthesized using a modified one-step Cu-catalyzed coupling of aryl halides and N-acetylhistidine methyl ester. The latter is much less reactive than imidazole toward aryl halides. p-Chloroiodobenzene coupled with iodine displacement only, whereas m- and p-bromoiodobenzene both gave mixtures of bromo- and iodophenyl products.

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Twenty two analogues of SB-203207 have been prepared by total synthesis, and evaluated as inhibitors of a range of tRNA synthetases. Changes to the bicyclic core, removing either the terminal amino substituent or the sulfonyl group from the side chain, and altering either the carbon skeleton or stereochemistry of the isoleucine residue, decreases the potency of inhibition of isoleucyl tRNA synthetase. Substituting the isoleucine residue with other amino acids produces inhibitors of the corresponding synthetases. In particular, a methionine derivative is 50-100 times more potent against methionyl tRNA synthetase than against any of the corresponding isoleucyl, leucyl, valyl, alanyl and prolyl synthetases.

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