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The ‘β-silyl effect’ of ground-state chemistry has been found to be operative in excited-state systems as well, where it exerts just as remarkable of an effect on the yields and selectivity of the intermolecular arene-olefin photocyclization reaction. Benzyl-trimethylsilane has been found to undergo intermolecular arene-olefin photocyclization with alicyclic hydrocarbon alkenes to provide 2,6- META-adducts with yields of 65-90% in a regio- and stereo-selective manner. Particularly encouraging are the reactions with cyclohexene and with CIS-cyclooctene, as both of these substrates give anomalous results with many arenes, but fall perfectly in line when coupling with benzyltrimethylsilane. These data augur well for the use of β-silyl directing groups in more complex photocyclization reactions. The ability of a C-Si sp 3 bond to stabilize an incipient positive charge in the β-position by hyperconjugation apparently also allows it to stabilize a transiently electron-deficient excited state, in the same way that an electron-donating group (e.g., a methyl or a methoxy group) has been observed to direct the regiochemistry of the arene-olefin photocyclization reaction. To fully characterize the photoadducts, they have been elaborated via radical addition of substituted thiophenols to crystalline compounds and X-ray crystal structures obtained.

This paper outlines research exploring differences in approach to outsourcing and offshoring by multinational corporations. In particular, a comparison is drawn between German and UK headquartered organizations in the airline and engineering sectors. A novel conceptual framework is developed; and the initial findings from two case studies are that German organizations are less inclined to outsource (in both sectors) preferring to retain control as a wholly owned business offshore. The UK businesses were less risk adverse and seemed to be more flexible and agile in their sourcing policies – using competitors when there is a sound business case. The relationships’ with trade unions / works council was also found to be very different, with reluctance by management in Germany to progress radical initiatives. A favorable economy in Germany has also created an environment in which overseas expansion could take place without a loss of jobs at home

UK and German headquartered engineering multinational corporations (MNCs) are compared with a focus on their outsourcing and offshoring initiatives. A novel conceptual framework is developed that uses differing varieties of capitalism (VoC) to compare and contrast a series of criteria. Underlying theory is taken from the resource based view (RBV) of the firm and global production networks (GPNs). The findings from a comparative case study were that in the UK, lower labour costs and reorganising the value chain were key reasons to outsource and offshore. The UK business was less risk adverse and seemed more flexible and agile in its sourcing policies. The German organisation was less inclined to outsource preferring to retain control of a wholly owned offshore business unit. A further difference was that management in Germany were reluctant to progress radical initiatives with the works council. There was little evidence of re-shoring

This paper outlines research by a doctoral candidate exploring differences in approach to outsourcing and offshoring by multinational corporations. In particular, a comparison is drawn between German and UK headquartered organizations in the airline / transport and also the engineering sectors. A novel conceptual framework is developed that uses differing varieties of capitalism (VoC) to compare and contrast a series of criteria. Underlying theory that is drawn from the resource based view (RBV) of the firm and global production networks (GPNs) are also considered. The initial findings from two case studies are that German organizations are less inclined to outsource (in both sectors) preferring to retain control as a wholly owned business offshore. The UK businesses were less risk adverse and seemed to be more flexible and agile in their sourcing policies being prepared to outsource, offshore and partner or acquire as appropriate, even using competitors when there is a sound business case. The relationships’ with trade unions / works council was also found to be very different, with reluctance by management in Germany to progress radical initiatives. A favorable economy in Germany has also created an environment in which overseas expansion could take place without a significant loss of jobs at home. Further research is required to better understand when the driving force to restructure and grow is to lower labour or total costs, seek market entry to support customer needs or a combination

The C-terminal α-amide moiety of most peptide hormones arises by the posttranslational cleavage of a glycine-extended precursor in a reaction catalyzed by bifunctional peptidylglycine α-amidating monooxygenase (PAM). Glutathione and the S -alkylated glutathiones have a C-terminal glycine and are, thus, potential substrates for PAM. The addition of PAM to glutathione, a series of S -alkylated glutathiones, and leukotriene C 4 results in the consumption of O 2 and the production of the corresponding amidated peptide and glyoxylate. This reaction proceeds in two steps with the intermediate formation of a C-terminal α-hydroxyglycine-extended peptide. Amidated glutathione (γGlu-Cys-amide) is a relatively poor substrate for glutathione S -transferase with a V / K value that is 1.3% of that for glutathione. Peptide substrates containing a penultimate hydrophobic or sulfur-containing amino acid exhibit the highest ( V / K ) app values for PAM-catalyzed amidation. The S -alkylated glutathiones incorporate both features in the penultimate position with S -decylglutathione having the highest ( V / K ) app of the substrates described in this report.

Phosphonic/phosphinic acid analogs have been studied for inhibitory and ligand activity in farnesyl pyrophosphate synthase, prostaglandin, and other GPCR's.

Phosphonic acid derivatives of prostaglandins F 1α and F 2α were prepared through Arbuzov reaction of 2-decarboxy-2-iodoprostaglandin intermediates. The intermediate iodo compounds, which are potentially valuable for the synthesis of other analogs, were obtained from the parent prostaglandins by Barton's modification of the Hunsdiecker reaction.

Summary Background Disorders, such as age spots, melasma and hyperpigmentation at sites of actinic damage, emanate from the augmentation of an increased amount of epidermal melanin. Objectives The ineptness of current therapies in treating these conditions, as well as high cytotoxicity, mutagenicity, poor skin penetration and low stability of skin-depigmenting formulations led us to investigate new compounds that meet the medical requirements for depigmentation agents. We have shown previously that the tyrosinase inhibitor deoxyArbutin (dA) is a more effective and less toxic skin lightener than hydroquinone (HQ). Methods The efficacy and reversibility of dA and its derivatives on inhibiting tyrosine hydroxylase and DOPAoxidase was assessed using standard assays. Results dA and its second-generation derivatives inhibit tyrosine hydroxylase and DOPAoxidase activities of tyrosinase dose dependently thereby inhibiting melanin synthesis in intact melanocytes, when used at concentrations that retain 95% cell viability in culture. This depigmenting effect was completely reversible when the compounds were removed. Tyrosinase inhibition was also observed in vitro when tested using human and purified mushroom tyrosinase, establishing that they are direct enzyme inhibitors. Lineweaver–Burk reciprocal plot analysis using mushroom tyrosinase illustrated that dA and its derivatives are more robust competitive inhibitors than HQ, when tyrosine is used as substrate. Conclusions Thus, dA and its second-generation derivatives, which inhibit melanogenesis at safe concentrations by specifically acting on the tyrosinase enzyme at a post-translational level, are promising agents to ameliorate hyperpigmented lesions or lighten skin.

A series of prostaglandins selective for the human FP receptor have been synthesized and evaluated as potential therapeutics for the treatment of osteoporosis. The compounds proved to be potent (nanomolar binding affinity) and selective (>100x) ligands for the human FP receptor in vitro, and increased bone volume in the ovariectomized rat in vivo.

A series of prostaglandins selective for the human FP receptor have been synthesized and evaluated as potential therapeutics for the treatment of osteoporosis. The compounds proved to be potent (nanomolar binding affinity) and selective (>100x) ligands for the human FP receptor in vitro, and increased bone volume in the ovariectomized rat in vivo.

A series of novel C(1) alkylphosphinic acid analogues of the prostaglandin-F family have been evaluated at the eight human prostaglandin receptors for potential use in the treatment of osteoporosis. Using molecular modeling as a tool for structure-based drug design, we have discovered that the phosphinic acid moiety (P(O)(OH)R) behaves as an isostere for the C(1) carboxylic acid in the human prostaglandin FP binding assay in vitro and possesses enhanced hFP receptor selectivity when compared to the parent carboxylic acid. When evaluated in vivo, the methyl phosphinic acid analogue (4b) produced a bone anabolic response in rats, returning bone mineral volume (BMV) [corrected], to intact levels in the distal femur in the ovariectomized rat (OVX) model. These results suggest that prostaglandins of this class may be useful agents in the treatment of diseases associated with bone loss.

Bifunctional peptidylglycine alpha-amidating monooxygenase (PAM) catalyzes the copper-, ascorbate-, and O2-dependent cleavage of C-terminal glycine-extended peptides, N-acylglycines, and the bile acid glycine conjugates to the corresponding amides and glyoxylate. Two known metabolites of aspirin, salicyluric acid and gentisuric acid, are also substrates for PAM, leading to the formation of salicylamide and gentisamide. The time course for O2 consumption and glyoxylate production indicates that salicylurate amidation is a two-step reaction. Salicylurate is first converted to N-salicyl-alpha-hydroxyglycine, which is ultimately dealkylated to salicylamide and glyoxylate. The enzymatically generated salicylamide and N-salicyl-alpha-hydroxyglycine were characterized by mass spectrometry and two-dimensional 1H-13C heteronuclear multiple quantum coherence NMR.

A novel class of saturated prostaglandin F2alpha sulfonamide analogs have been synthesized and evaluated in the human FP receptor binding assay for potential use in the treatment of osteoporosis. These compounds have been modified at the C1 carboxylic acid moiety and at the C16-C20 region of the prostaglandin. Based on the structure-activity relationships, it was found that at C1, the aryl sulfonamide analogs possessed greater affinity for the hFP receptor when compared to alkyl sulfonamides. When the sulfonamide was introduced into the C16-C20 region (omega chain) of the prostaglandin, a significant reduction in binding was observed. These results are discussed within the framework of a proposed model for the human FP receptor.

The in vitro evaluation of a series of saturated prostaglandins revealed that compounds with omega chain aromatic rings retain nanomolar potency for the human prostaglandin F receptor (hFP receptor), exemplified by compound 8. In contrast, the double bonds are required for activity in the series with an acyclic omega chain as in PGF2α.

A short reversed-phase HPLC column and a tandem mass spectrometer were used to develop a stable-isotope-dilution assay for the rapid and sensitive analysis of fluprostenol, a prostaglandin analog, in rat plasma. A Waters Symmetry ODS column (2.1×10 mm) afforded rapid isocratic elution of fluprostenol ( t R =40 s) but still provided a relatively large k ′ value of 4. The use of tandem mass spectrometry allowed the interference-free detection of fluprostenol under the rapid elution conditions, with a limit of quantitation of 25 pg ml −1 fluprostenol, using 0.2 ml plasma sample volumes. The method was linear over three orders of magnitude, yielded accurate and precise results and allowed the pharmacokinetic profile of fluprostenol to be defined following intravenous administration in rats.