Differential inhibition of postnatal brain,spinal cord and body growth by a growth hormone antagonist

Background  

Growth hormone (GH) plays an incompletely understood role in the development of the central nervous system (CNS). In this study, we use transgenic mice expressing a growth hormone antagonist (GHA) to explore the role of GH in regulating postnatal brain, spinal cord and body growth into adulthood. The GHA transgene encodes a protein that inhibits the binding of GH to its receptor, specifically antagonizing the trophic effects of endogenous GH.     

Microfluidic platform for combinatorial synthesis in picolitre droplets

This paper presents a droplet-based microfluidic platform for miniaturized combinatorial synthesis. As a proof of concept, a library of small molecules for early stage drug screening was produced. We present an efficient strategy for producing a 7 × 3 library of potential thrombin inhibitors that can be utilized for other combinatorial synthesis applications. Picolitre droplets containing the first type of reagent (reagents A(1), A(2), …, A(m)) were formed individually in identical microfluidic chips and then stored off chip with the aid of stabilizing surfactants. These droplets were then mixed to form a library of droplets containing reagents A(1-m), each individually compartmentalized, which was reinjected into a second microfluidic chip and combinatorially fused with picolitre droplets containing the second reagent (reagents B(1), B(2), …, B(n)) that were formed on chip. The concept was demonstrated with a three-component Ugi-type reaction involving an amine (reagents A(1-3)), an aldehyde (reagents B(1-7)), and an isocyanide (held constant), to synthesize a library of small molecules with potential thrombin inhibitory activity. Our technique produced 10(6) droplets of each reaction at a rate of 2.3 kHz. Each droplet had a reaction volume of 3.1 pL, at least six orders of magnitude lower than conventional techniques. The droplets can then be divided into aliquots for different downstream screening applications. In addition to medicinal chemistry applications, this combinatorial droplet-based approach holds great potential for other applications that involve sampling large areas of chemical parameter space with minimal reagent consumption; such an approach could be beneficial when optimizing reaction conditions or performing combinatorial reactions aimed at producing novel materials.     

Fusion around the barrier for 7Li+12C

Fusion cross-sections for the ⁷Li + ¹²C reaction have been measured at energies above the Coulomb barrier by the direct detection of evaporation residues. The heavy evaporation residues with energies below 3 MeV could not be separated out from the α-particles in the spectrum and hence their contribution was estimated using statistical model calculations. The present work indicates that suppression of fusion cross-sections due to the breakup of ⁷Li may not be significant for ⁷Li + ¹²C reaction at energies around the barrier.     

Chemoselective reactions of amidines: selective formation of iminopyrimidine regioisomers

The dramatic effect of base on the chemoselectivity of the reaction of amidines with substituted 3-phenyl-2-propynylnitriles is demonstrated. Amidine 1 can be added to cyanoalkyne 2 to give iminopyrimidine isomer 3 with high selectivity. The addition of 2 equiv of NaHMDS completely reverses the selectivity of the reaction, yielding isomer 4 almost exclusively. This method has been used to prepare a variety of substituted 4-iminopyrimidines.     

Determination of stability constants for metal-ligand complexes using the voltammetric oxidation wave of the anion/ligand and the DeFord and Hume formalism

The voltammetric oxidation peaks for anions and other ligands that react at the Hg electrode can be used for the determination of stability constants of metal-ligand complexes using the DeFord and Hume formalism. Metal-ligand complexes with known stability constants that span the range of logbeta=2.9-5.9 were determined using the oxidation wave of the ligand as metal was varied. For the larger stability constants, it was possible to titrate concentrations of metal to ligand that are smaller than the ligand concentration and obtain reliable data (beta(j)C(x)(j) approaches 1 in this case) indicating that an excess of titrant is not required to obtain reliable beta values. Data reduction with different versions of the Solver tool (included with Microsoft Excel) is discussed and blind use of these programs without knowledge of the physical chemistry of the system is discouraged. The use of Solver gives beta values that are in agreement with previous work that used (non)linear regression to evaluate each F(n)(X) versus [X] function.     

Total synthesis of (-)-hennoxazole A

An enantioselective, convergent total synthesis of the antiviral marine natural product (-)-hennoxazole A is completed in 14 steps (longest linear sequence) from commercially available 4-methyloxazole-2-carboxylic acid. Synthesis of the C(1)-C(15) pyran/bisoxazole fragment takes advantage of an aldol-like coupling between a dimethyl acetal and an N-acetylthiazolidinethione for the direct, stereoselective installation of the C(8)-methoxy-bearing stereocenter. A one-pot acetoacetate acylation/decarboxylation/cyclodehydration of another elaborate thiazolidinethione allows for rapid assembly of the pyran-based ring system. Synthesis of the C(15)-C(25) skipped triene side chain fragment makes use of a [2,3]-Wittig-Still rearrangement for efficient installation of the trisubstituted Z-double bond. Key late-stage coupling of the two fragments is effected by deprotonation of the methyl group on the bisoxazole system using lithium diethylamide, followed by alkylation with an allylic bromide side chain segment to form the C(15)-C(16) bond.     

Detection of human and rodent 5-HT3B receptor subunits by anti-peptide polyclonal antibodies

Background  

The 5-HT₃ receptor is a member of a neurotransmitter-gated ion channel family which includes nicotinic acetylcholine, GABA_A, and glycine receptors. While antibodies specific for the 5-HT_3A receptor subunit are plentiful, and have revealed a wealth of structural and functional information, few antisera exist for the detection of 5-HT_3B receptor subunits. Here we describe the generation and characterisation of a rabbit polyclonal antiserum that specifically recognises 5-HT_3B receptor subunits     

Dibenzyl Structuresin a Macromolecular Chain. III. Dibenzyldiisocyanates Reactivity

The reactivity of the 2,2′-, 2,4′-, 4,4′-dibenzyldiisocyanate (2,2′-, 2,4′-, 4,4′-DBDI) with n-butanol in benzene has been studied. The concentrations of all species were monitored by using high performance liquid chromatography (HPLC). The reactivity of 4,4′-DBDI is similar to that of 4,4′-diphenylmethanediisocyanate (4,4′-MDI). Very strong intramolecular catalytic effects were noticed in the case of 2,2′-DBDI, probably due to the variable molecular geometry. These effects are responsible for the whole reaction pattern. The 2,4′-DBDI NCO ortho and para groups reactivities are different and comparable to that of 2,4-toluylenediisocyanate (2,4-TDI).     

Total synthesis of (-)-hennoxazole A

An enantioselective, convergent, total synthesis of the antiviral marine natural product (-)-hennoxazole A has been completed in 17 steps, longest linear sequence, from serine methyl ester and in 9 steps from an achiral bisoxazole intermediate. Elaboration of a thiazolidinethione allowed for rapid assembly of the pyran-based ring system. Key late-stage coupling was effected by deprotonation of the bisoxazole methyl group, followed by alkylation with an allylic bromide side chain segment. [structure: see text]