Novel proresolving aspirin-triggered DHA pathway

Endogenous mechanisms in the resolution of acute inflammation are of interest because excessive inflammation underlies many pathologic abnormalities. We report an aspirin-triggered DHA metabolome that biosynthesizes a potent product in inflammatory exudates and human leukocytes, namely aspirin-triggered Neuroprotectin D1/Protectin D1 [AT-(NPD1/PD1)]. The complete stereochemistry of AT-(NPD1/PD1) proved to be 10R,17R-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. The chirality of hydroxyl groups and geometry of the conjugated triene system essential for bioactivity were established by matching biological materials with stereochemically pure isomers prepared by organic synthesis. AT-(NPD1/PD1) reduced neutrophil (PMN) recruitment in murine peritonitis in a dose-dependent fashion whereby neither a Δ(15)-trans-isomer nor DHA was effective. With human cells, AT-(NPD1/PD1) decreased transendothelial PMN migration as well as enhanced efferocytosis of apoptotic human PMN by macrophages. These results indicate that AT-(NPD1/PD1) is a potent anti-inflammatory proresolving molecule.     

Molecular recognition probes of solvation thermodynamics in solvent mixtures

High-throughput UV-Vis experiments using four molecular recognition-based probes, made by the combination of two hydrogen bond acceptors, tri-n-butylphosphine oxide and N,N'-bis(2-ethylhexyl)acetamide, and two hydrogen bond donors, 4-phenylazophenol and 4-nitrophenol, were performed. The association constants for the 1 : 1 H-bond interaction involved in each probe system were measured in mixtures of a polar and non-polar solvent, di-n-hexyl ether and n-octane, respectively. Similar behaviour was observed for all four systems. When the concentration of the polar solvent was low, the association constant was identical to that observed in pure n-octane. However, once the concentration of the polar solvent exceeded a threshold, the association constant decreased linearly with the concentration of di-n-hexyl ether. Selective solvation in mixtures can be understood based on the competition between the multiple competing equilibria in the system. In this case, solvation thermodynamics are dominated by competition of the ether for solvation of H-bond donors. For the more polar solute, 4-nitrophenol, the selective solvation starts at lower concentrations of the polar solvent compared with the less polar solute, 4-phenylazophenol. Thus the speciation and hence the properties of systems containing multiple solutes and multiple solvents can be estimated from the H-bond properties and the concentrations of the individual functional groups.     

A sulfone-based strategy for the preparation of 2,4-disubstituted furan derivatives

2,4-Disubstituted furans are prepared by treating 2,3-dibromo-1-phenylsulfonyl-1-propene (DBP, 2) with 1,3-diketones under basic conditions. The furan-forming step involves a deacetylation, and the selectivity of this process depends upon the steric demand of the R group. The substituent in position 4 is elaborated by reaction of sulfonyl carbanions with alkyl halides, acyl halides, and aldehydes. Oxidative or reductive desulfonylation produces the 2,4-disubstituted furans in 60-92% yield. This strategy has been used to prepare rabdoketone A (12) and the naturally occurring nematotoxic furoic acid 13.     

Organometallic reactivity: the role of metal-ligand bond energies from a computational perspective

The association and dissociation of ligands plays a vital role in determining the reactivity of organometallic catalysts. Computational studies with density functional theory often fail to reproduce experimental metal-ligand bond energies, but recently functionals which better capture dispersion effects have been developed. Here we explore their application and discuss future challenges for computational studies of organometallic catalysis.     

The role of molecular modeling in confined systems: impact and prospects

Molecular modeling at the electronic and atomistic levels plays an important and complementary role to experimental studies of confinement effects. Theory and atomistic simulation can provide fundamental understanding, determine the limits of well known macroscopic laws such as Kelvin's equation, provide predictions for systems that are difficult to study via experiment (e.g. adsorption of highly toxic gases), and can be used to gain detailed molecular level information that may not be accessible in the laboratory (e.g. the local structure and composition of confined phases). We describe the most important and useful methods that are based firmly on quantum mechanics and statistical mechanics, including ab intio and classical density functional theories, and Monte Carlo and molecular dynamics simulation. We discuss their strengths and limitations. We then describe examples of applications of these methods to adsorption and equilibrium properties, including testing the Kelvin equation, determination of pore size distributions and capillary phenomena. Applications to self and transport diffusion, including single-file and anomalous diffusion, and viscous flow in nanoporous materials are described. The use of these methods to understand confinement effects on chemical reactions in heterogeneous media is treated, including effects on reaction equilibria, rates and mechanism. Finally we discuss the current status of molecular modeling in this area, and the outlook and future research needs for the next few years. The treatment is suitable for the general technical reader.     

Triacylglycerol profiling of microalgae strains for biofuel feedstock by liquid chromatography-high-resolution mass spectrometry

Biofuels from photosynthetic microalgae are quickly gaining interest as a viable carbon-neutral energy source. Typically, characterization of algal feedstock involves breaking down triacylglycerols (TAG) and other intact lipids, followed by derivatization of the fatty acids to fatty acid methyl esters prior to analysis by gas chromatography (GC). However, knowledge of the intact lipid profile could offer significant advantages for discovery stage biofuel research such as the selection of an algal strain or the optimization of growth and extraction conditions. Herein, lipid extracts from microalgae were directly analyzed by ultra-high pressure liquid chromatography–mass spectrometry (UHPLC-MS) using a benchtop Orbitrap mass spectrometer. Phospholipids, glycolipids, and TAGs were analyzed in the same chromatographic run, using a combination of accurate mass and diagnostic fragment ions for identification. Using this approach, greater than 100 unique TAGs were identified over the six algal strains studied and TAG profiles were obtained to assess their potential for biofuel applications. Under the growth conditions employed, Botryococcus braunii and Scenedesmus obliquus yielded the most comprehensive TAG profile with a high abundance of TAGs containing oleic acid.     

Expanding Lipidome Coverage Using LC-MS/MS Data-Dependent Acquisition with Automated Exclusion List Generation

Untargeted omics analyses aim to comprehensively characterize biomolecules within a biological system. Changes in the presence or quantity of these biomolecules can indicate important biological perturbations, such as those caused by disease. With current technological advancements, the entire genome can now be sequenced; however, in the burgeoning fields of lipidomics, only a subset of lipids can be identified. The recent emergence of high resolution tandem mass spectrometry (HR-MS/MS), in combination with ultra-high performance liquid chromatography, has resulted in an increased coverage of the lipidome. Nevertheless, identifications from MS/MS are generally limited by the number of precursors that can be selected for fragmentation during chromatographic elution. Therefore, we developed the software IE-Omics to automate iterative exclusion (IE), where selected precursors using data-dependent topN analyses are excluded in sequential injections. In each sequential injection, unique precursors are fragmented until HR-MS/MS spectra of all ions above a user-defined intensity threshold are acquired. IE-Omics was applied to lipidomic analyses in Red Cross plasma and substantia nigra tissue. Coverage of the lipidome was drastically improved using IE. When applying IE-Omics to Red Cross plasma and substantia nigra lipid extracts in positive ion mode, 69% and 40% more molecular identifications were obtained, respectively. In addition, applying IE-Omics to a lipidomics workflow increased the coverage of trace species, including odd-chained and short-chained diacylglycerides and oxidized lipid species. By increasing the coverage of the lipidome, applying IE to a lipidomics workflow increases the probability of finding biomarkers and provides additional information for determining etiology of disease.

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Controlling chemoselectivity in vinyl and allylic C-X bond activation with palladium catalysis: a pK(a)-based electronic switch

It has been demonstrated that the same Pd catalyst can be used to effect allylic substitution or vinylic cross-coupling reactions selectively and interchangeably on polyfunctionalized olefin building blocks despite the differences in reaction mechanism. This was achieved by altering the pK(a) of the conjugate acid of the allylic leaving group while keeping the vinyl coupling partner constant. In the case of 2,3-dibromo-1-propene, Pd-catalyzed allylic ionization with malonate nucleophile proceeded selectively and quantitatively in the presence of the Suzuki reaction components necessary for cross-coupling. Conversely, the bromide of 2-bromo-1-(4-ethylphenoxy)-2-propene could be cross-coupled selectively without activation of the allylic phenoxy substituent. In both reactions, the same catalyst could then be used to complete the sequence, which typically involved heating as the trigger to promote the second, more reluctant reaction. Mechanistic considerations as well as synthetic applications demonstrating the value of this interchangeable catalyzed sequence are presented.     

Amplification of a cyclic mixed-metalloporphyrin tetramer from a dynamic combinatorial library through orthogonal metal coordination

A cyclic porphyrin tetramer, consisting of two bis-phosphine substituted zinc(II) porphyrin units and two Rh(III)TPP units, is selected and amplified virtually quantitatively from a dynamic combinatorial library using 4,4'-bipy as a scaffold and using orthogonal binding modes.     

Highly Functionalized Cyclopentane Derivatives by Tandem Michael Addition/Radical Cyclization/Oxygenation Reactions

Densely functionalized cyclopentane derivatives with up to four consecutive stereocenters are assembled by a tandem Michael addition/single‐electron transfer oxidation/radical cyclization/oxygenation strategy mediated by ferrocenium hexafluorophosphate, a recyclable, less toxic single‐electron transfer oxidant. Ester enolates were coupled with α‐benzylidene and α‐alkylidene β‐dicarbonyl compounds with switchable diastereoselectivity. This pivotal steering element subsequently controls the diastereoselectivity of the radical cyclization step. The substitution pattern of the radical cyclization acceptor enables a switch of the cyclization mode from a 5‐exo pattern for terminally substituted olefin units to a 6‐endo mode for internally substituted acceptors. The oxidative anionic/radical strategy also allows efficient termination by oxygenation with the free radical 2,2,6,6‐tetramethyl‐1‐piperidinoxyl, and two C?C bonds and one C?O bond are thus formed in the sequence. A stereochemical model is proposed that accounts for all of the experimental results and allows the prediction of the stereochemical outcome. Further transformations of the synthesized cyclopentanes are reported.