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Botulinum neurotoxins (BoNTs) are zinc endopeptidases that block release of the neurotransmitter acetylcholine in neuromuscular synapses through cleavage of soluble N-ethylmaleimide-sensitive fusion (NSF) attachment protein receptor (SNARE) proteins, which promote fusion of synaptic vesicles to the plasma membrane. We designed and tested a BoNT-derived targeted secretion inhibitor (TSI) targeting pituitary somatotroph cells to suppress growth hormone (GH) secretion and treat acromegaly. This recombinant protein, called SXN101742, contains a modified GH-releasing hormone (GHRH) domain and the endopeptidase domain of botulinum toxin serotype D (GHRH-LHN/D, where HN/D indicates endopeptidase and translocation domain type D). In vitro, SXN101742 targeted the GHRH receptor and depleted a SNARE protein involved in GH exocytosis, vesicle-associated membrane protein 2 (VAMP2). In vivo, administering SXN101742 to growing rats produced a dose-dependent inhibition of GH synthesis, storage, and secretion. Consequently, hepatic IGF1 production and resultant circulating IGF1 levels were reduced. Accordingly, body weight, body length, organ weight, and bone mass acquisition were all decreased, reflecting the biological impact of SXN101742 on the GH/IGF1 axis. An inactivating 2-amino acid substitution within the zinc coordination site of the endopeptidase domain completely abolished SXN101742 inhibitory actions on GH and IGF1. Thus, genetically reengineered BoNTs can be targeted to nonneural cells to selectively inhibit hormone secretion, representing a new approach to treating hormonal excess.

An improved procedure for the preparation of ethyl 2-diazomalonyl chloride was developed which involves the reaction of ethyl diazoacetate with triphosgene. Using this diazo acid chloride, it was possible to prepare a variety of diazoamides from substituted amines. The rhodium(II)-catalyzed decomposition of these diazoamides was studied in order to probe the chemoselectivity of the carbenoid intermediates in intramolecular insertion reactions. Rhodium(II) acetate decomposition of N-benzyl-2-diazo-N-phenylmalonamic acid ethyl ester resulted in intramolecular C-H insertion to give ethyl 1,4-diphenyl-2-oxoazetidine-3-carboxylate. By changing the catalyst ligand to trifluoroacetamide, β-lactam formation was completely suppressed in favor of the aromatic C-H insertion which produces an oxindole as the only detectable product. The competition between aliphatic and aromatic carbon-hydrogen insertion of 2-diazo-N-isobutyl-N-phenylmalonamic acid ethyl ester provides another example of ligand effectiveness in controlling chemoselectivity in dirhodium (II)-catalyzed metal carbene reactions. Thus, treatment of the N-isobutyldiazoanilide with rhodium(II) acetate results in exclusive aliphatic C-H insertion giving 4,4-dimethyl-2-oxo-1-phenylpyrrolidine-3-carboxylic acid ethyl ester, while the perfluorobutyramide ligand promotes oxindole formation by aromatic C-H insertion. Several other rhodium(II)-catalyzed reactions were studied and were studied and were found to be highly catalyst dependent, rhodium (II) perfluorocarboxamides promoting aromatic C-H insertion, and hence oxindole formation, over O-H insertion, cyclization onto adjacent triple bonds, or cyclization to generate 1,3-dipolar intermediates

Model studies towards the total synthesis of the cytotoxic marine natural product diazonamide A are described. The approach uses rhodium(I1) catalysed reactions of diazocarbonyl compounds in 4 key steps; the construction of the oxazole rings by the rhodium(I1) catalysed addition of diazocarbonyl compounds to nitriles, and of the indole and benzofuran tinits by rhodium(l1) mediated intramolecular aromatic C-H insertion reaction\. Recently the isolation of a number of oxazole containing natural products, particularly from marine sources, has caused a renewed interest in the chemistry of oxazoles. Naturally occurring oxazoles range in structure from relatively simple 2,s-substituted derivatives such as pimprinine (4.v.) to more complex bis-oxazoles such as the diazonamides. The diazonamides, exemplified by diazonamide A, isolated from the ascidan Diazona chinensis,( 1) show potent anticancer activity, and their unique his-oxazolylindole structure coupled to a dihydrobenzofuran makes them attractive targets for synthesis. We now report the results of model studies towards diazonamide A, using rhodium(1l) catnlysed reactions of diazocarbonyl conipounds in 4 key steps, viz. the construction of the oxazole rings by the rhodiuni(l1) catalysed addition of diazocarbonyl compounds to nitriles, arid of the indole and benzofuran units by rhodium(1l) mediated intramolecular aromatic C-H insertion reactions.

Beef longissimus dorsi muscle samples matured over a 21 day period were analysed using three different analytical techniques; (1)H NMR, GC-MS and HPLC. The data from the three experimental techniques were correlated with each other to determine if the results were statistically similar to each other. From our analysis we determined that the metabolites measured using (1)H NMR were statistically similar to the compounds quantified using the chromatography techniques (p0.001). In addition, using PCA, we were able to show that different metabolites, measured using the various analytical techniques produced very similar scores and loadings plots for all the analysis and extraction techniques undertaken across the 21 day time domain. Using a combination of these three different techniques provides a unique and holistic insight into the biochemistry behind the conversion of muscle to meat which would not be possible using any single technique alone.

Many small oilfields in poorly sorted and highly non-uniform unconsolidated formations with high fines content cannot be developed economically using the preferred sand control method, gravel pack. ‘J’ Field in Malaysia is a small oilfield with marginal economics that was developed successfully using stand-alone screen (SAS), a cost-effective open hole (OH) sand control method. Deployment of SAS in ‘J’ Field does not meet the industry-accepted criteria for sand control methods but provided the operator adequate sand control while fulfilling its economic needs. Recent advances in OH sandface completion technologies such as multi-layer mesh screens, inflow control devices (ICDs), and zonal isolation using swellable packers provided improved performance and reliability of recent SAS installations. This project marks a few firsts in sand control screen technology: World's first installation of multi-layer mesh screenMulti-layer mesh screen is the current state-of-the-art in premium mesh screen technology. It uses several layers of woven metal mesh filters of gradually decreasing micron rating and diffusion-bonded together, which creates a filter that provides better plugging resistance and solids retention capacity.Malaysia's first installation of tube-type ICDICDs are passive flow control devices that are used in OH horizontal (Hz) wells to delay the onset of water breakthrough and minimize its effect by balancing inflow from toe to heel or between high-perm and low-perm zones. ICDs are integrated with sand control screens for use in unconsolidated formations. Swellable packers are used in ICD completions to provide compartmentalization. This paper highlights the recent success of utilization of these cost-effective OH sandface completion technologies in the development of ‘J’ Field.

Physiological secretion of bile acids has previously been linked to the regulation of blood glucose. GLP-1 is an intestinal peptide hormone with important glucose-lowering actions, such as stimulation of insulin secretion and inhibition of glucagon secretion. In this investigation, we assessed the ability of several bile acid compounds to secrete GLP-1in vitroin STC-1 cells. Bile acids stimulated GLP-1 secretion from 3.3- to 6.2-fold but some were associated with cytolytic effects. Glycocholic and taurocholic acids were selected forin vivostudies in normal and GLP-1R-/-mice. Oral glucose tolerance tests revealed that glycocholic acid did not affect glucose excursions. However, taurocholic acid reduced glucose excursions by 40% in normal mice and by 27% in GLP-1R-/-mice, and plasma GLP-1 concentrations were significantly elevated 30 min post-gavage. Additional studies used incretin receptor antagonists to probe involvement of GLP-1 and GIP in taurocholic acid-induced glucose lowering. The findings suggest that bile acids partially aid glucose regulation by physiologically enhancing nutrient-induced GLP-1 secretion. However, GLP-1 secretion appears to be only part of the glucose-lowering mechanism and our studies indicate that the other major incretin GIP is not involved.

A new chiral proton sponge has been prepared, and the reasons for its unusually high basicity elucidated by a quantum chemical study.

Alkenylthiazolines undergo a highly diastereoselective novel dimerisation when treated with trichloroacetyl chloride or with trifluoroacetic anhydride.

As part of the second stage development of a mature oil field offshore Malaysia, deeper reservoirs in Field S were identified from four different blocks. In order for the wells to be economically viable, up to eleven (11) sands were planned to be completed. This proved to be challenging due to the high differential pressures between reservoirs, highly depleted zones above the target sands, and pressure and reserve uncertainties of the target sands. This paper covers design, planning, and execution of the well completion for four (4) infill wells where the differential pressure between zones was predicted to be up to 1,700 psi (Pounds per Square Inch). Some of the zones were highly depleted, and the most depleted zone was 0.216 psi/ft (Pounds per Square Inch per Foot). Even with the lowest brine weight of 8.5 ppg (Pounds per Gallon), the over balance was about 1,800 psi. The completion was designed to maximize the number of sands in each well (eleven (11) sands with six (6) zones) to gain maximum production, while at the same time the short string needs selectivity. One of the challenges was the production casing design could not be larger than 7". To facilitate selectivity on the short string, the upper completion was designed with a Y-block. To avoid significant losses from high overbalance and differential pressures, stage-by-stage perforation was planned. However, the challenge was to achieve the required under balance across all the zones since there was no stimulation planned. Both static and dynamic under balance perforation techniques were used for perforation. With all the upfront planning and design, the well completion operation was successfully executed with less than 1% Non Productive Time (NPT) recorded, which was an excellent achievement considering the complexity of the completion design and operation. In conclusion, the post-analysis showed the production rate target was successfully attained - indicating the formation damage was minimal even though the wells were drilled and completed with more than 1,000 psi overbalance.

Phthalans 1-3 have been converted into oxonane-3,8-diones 7-9 by a 3-step sequence involving Birch reduction, hydrogenation and oxidative cleavage; the 2-ethyl-9-pentyl derivative 9 has been deoxygenated to give obtusan 12. The method was extended to the preparation of azonane 15 from isoindoline.

Model studies towards the total synthesis of the cytotoxic marine natural product diazonamide A are described. The approach uses rhodium(I1) catalysed reactions of diazocarbonyl compounds in 4 key steps; the construction of the oxazole rings by the rhodium(I1) catalysed addition of diazocarbonyl compounds to nitriles, and of the indole and benzofuran tinits by rhodium(l1) mediated intramolecular aromatic C-H insertion reaction\. Recently the isolation of a number of oxazole containing natural products, particularly from marine sources, has caused a renewed interest in the chemistry of oxazoles. Naturally occurring oxazoles range in structure from relatively simple 2,s-substituted derivatives such as pimprinine (4.v.) to more complex bis-oxazoles such as the diazonamides. The diazonamides, exemplified by diazonamide A, isolated from the ascidan Diazona chinensis,( 1) show potent anticancer activity, and their unique his-oxazolylindole structure coupled to a dihydrobenzofuran makes them attractive targets for synthesis. We now report the results of model studies towards diazonamide A, using rhodium(1l) catnlysed reactions of diazocarbonyl conipounds in 4 key steps, viz. the construction of the oxazole rings by the rhodiuni(l1) catalysed addition of diazocarbonyl compounds to nitriles, arid of the indole and benzofuran units by rhodium(1l) mediated intramolecular aromatic C-H insertion reactions.

An improved procedure for the preparation of ethyl 2-diazomalonyl chloride was developed which involves the reaction of ethyl diazoacetate with triphosgene. Using this diazo acid chloride, it was possible to prepare a variety of diazoamides from substituted amines. The rhodium(II)-catalyzed decomposition of these diazoamides was studied in order to probe the chemoselectivity of the carbenoid intermediates in intramolecular insertion reactions. Rhodium(II) acetate decomposition of N-benzyl-2-diazo-N-phenylmalonamic acid ethyl ester resulted in intramolecular C-H insertion to give ethyl 1,4-diphenyl-2-oxoazetidine-3-carboxylate. By changing the catalyst ligand to trifluoroacetamide, β-lactam formation was completely suppressed in favor of the aromatic C-H insertion which produces an oxindole as the only detectable product. The competition between aliphatic and aromatic carbon-hydrogen insertion of 2-diazo-N-isobutyl-N-phenylmalonamic acid ethyl ester provides another example of ligand effectiveness in controlling chemoselectivity in dirhodium (II)-catalyzed metal carbene reactions. Thus, treatment of the N-isobutyldiazoanilide with rhodium(II) acetate results in exclusive aliphatic C-H insertion giving 4,4-dimethyl-2-oxo-1-phenylpyrrolidine-3-carboxylic acid ethyl ester, while the perfluorobutyramide ligand promotes oxindole formation by aromatic C-H insertion. Several other rhodium(II)-catalyzed reactions were studied and were studied and were found to be highly catalyst dependent, rhodium (II) perfluorocarboxamides promoting aromatic C-H insertion, and hence oxindole formation, over O-H insertion, cyclization onto adjacent triple bonds, or cyclization to generate 1,3-dipolar intermediates

Oxonanes can be readily prepared from phthalans by a 3-step procedure involving Birch reduction, selective hydrogenation and oxidation. 2-Ethyl-9-pentyloxonane-3,8-dione has been deoxygenated to give obtusan. The method has been applied to the synthesis of an azonane.

Chiral 2-alkenyloxazolines and 2-alkenylthiazolines react with isocyanates and ketenes to give formal hetero-Diels-Alder adducts with complete diastereocontrol. In each case an electron-rich double bond in the adduct is prone to a second addition of the heterocumulene. In the case of the oxazoline adducts the second addition is faster than the first, while with thiazolines the second addition is slower so that a different heterocumulene can be incorporated.

Alkenyldihydrooxazoles undergo a highly diastereoselective formal aza-Diels–Alder reaction with aryl and arenesulfonyl isocyanates to give oxazolo[3,2-c]pyrimidines. Depending on the substitution pattern of the alkenyldihydrooxazole, these compounds may then undergo addition of a second equivalent of the isocyanate to give either tetrahydrooxazolo[3,2-c]pyrimidine-8-carboxamides or octahydroazeto[2,3-d]oxazolo[3,2-c]pyrimidines. The second addition is sensitive to steric and electronic factors, and can be prevented in some cases.

Diastereomerically pure oxazolo[3,2-c]pyrimidines can be readily prepared by the reaction of alkenyloxazolines with isocyanates. The mechanism of this transformation has been investigated computationally. These compounds undergo epimerisation upon prolonged heating, a reaction which is consistent with the proposed stepwise mechanism. Hydrolysis reactions of these compounds have been investigated.

During aerial refueling operations, the receiver aircraft should hold position within a "refueling box" to maintain the boom-receptacle connection while the tanker aircraft ies in a racetrack maneuver. Prior research work shows, especially in turns, signicant diculty resides in meeting y-deviation requirements, i.e., to stay within the box in the lateral direction. This observation indicates tanker motion as "the biggest disturbance" in turn. The nonlinear equations of motion for receiver aircraft used in this work are developed in terms of position and orientation states relative to the tanker. Linearization results in a set of equations with tanker motion clearly quantied as disturbance. The linearized state-space equation has an additional term with a disturbance matrix representing how tanker motion aects the relative motion. In this paper, a disturbance rejection method, based on these linearized equations, is employed to develop a new control law to reduce the eect of the tanker turning maneuver on the station-keeping performance of the receiver. This would lead to proactive (feed-forward) control action in addition to reactive (feedback) control. Practical implementation of this approach will require the communication of tanker states (velocity, attitude, angular rates, etc.) to the receiver controller.

Fifteen examples are presented showing that various modes of cyclization (5-endo, 5-exo, 6-endo, 6-exo, and 7-endo) can be used for the desymmetrization of cyclohexa-1,4-dienes. All take place with complete diastereocontrol and good yield.

This chapter reviews the synthesis and reactions of heterocyclic compounds consisting of a 6-5 fused system with three heteroatoms in the six-membered ring and one in the five-membered ring. A wide range of compounds of this type have been reported between 1995 and 2007. The most prominent group of compounds are ribose derivatives in which the 3-hydroxy and 4-hydroxymethyl groups are tethered with phosphorus, sulfur, or silicon. Coverage of the cyclic phosphate derivatives is restricted to structural studies. Various isomers of thieno-thiadiazines have been studied due to their psychotropic and potassium channel activity. The synthesis and reactions of other compounds containing the requisite ring sizes and heteroatoms are also reviewed.

The chemistry of alkylidenepyrrolidines is reviewed, including the full range of methods for the synthesis and a discussion of their reactivity and applications in heterocyclic chemistry.

The reactions of alkylidenepyrrolidine esters with isocyanates generally favour C-acylation, except in the case of benzyl isocyanate. Reactions with alkyl isocyanates are slow, and require forcing conditions. Reactions with isothiocyanates give exclusively the C-acylated products.

Methods for the formation of diazo compounds, hydrazones, and imines substituted with a heteroatom at nitrogen are reviewed. For formation of hydrazones, reaction of a carbonyl compound with a hydrazine remains the most popular method, although there has been a significant increase in the reports of functionalization of hydrazones, both at the hydrazone carbon and the α-carbon. Most of these methods are asymmetric reactions of proline-derived hydrazones. Other methods for the formation of hydrazones have been used only occasionally, and include reduction of diazo compounds and conjugate addition to azo compounds. Metallated imines are prepared by a variety of methods, depending on the choice of metal. N-Lithiated imines are generally prepared by addition of organolithium reagents to nitriles, although these compounds are seldom isolated. N-Silylimines are most conveniently prepared by addition of a bis-silylamine to a carbonyl compound. These two classes of substituted imines have been used to prepare a range of other heteroatom-substituted imines by substitution of either lithium or silicon. Diazo compounds are most commonly prepared by diazo transfer to a methylene group flanked by one or more electron-withdrawing groups. Sulfonyl azides are widely used to achieve this transformation, although a range of reagents and other modifications have been used in individual cases. In recent years, the versatility of the diazo group has been demonstrated by a number of new reactions, which feature elaboration of diazo compounds either at the diazo-carbon or elsewhere. Less commonly, oxidation of hydrazones and Bamford–Stevens reaction of sulfonylhydrazones have been used to prepare diazo compounds. A hydrogen atom on a diazo-carbon is readily removed, and this chemistry has also been used to access a range of compounds bearing heteroatoms at the diazo carbon.

The Lewis-acid promoted cyclisation reactions of N-arylcinnamamides have been investigated. With aluminium ­chloride a range of products were obtained, while much more se­lective cyclisation reactions were observed with bismuth chloride.

A range of simple derivatives of 2-methyl-3-oxoheptane-1,7-dicarboxylic acid have been prepared by Birch reduction/methylation of 2,6-dimethoxybenzoic acid derivatives followed by solvolysis.

Application of a diastereoselective three-component coupling to the bicyclic core of the batzelladine alkaloids is described. The synthesis features the elaboration of glutamic acid by use of Eschenmoser sulfide contraction. An earlier approach is also included, which shows some limitations of dithiane chemistry when applied to the particular compounds required for this target.

An improved synthesis of the 1,1′,2,2′,3,3′,4,4′-octahydro-1,1′-biisoquinoline ring system is described. The reactivity of this system has been investigated, including the unusually high basicity of the parent compound and its N,N′-dimethyl derivative. The resolution of the parent compound has been achieved for the first time, along with the development of a straightforward method for assaying its enantiomeric purity.