Stereodivergent Biocatalytic Formal Reduction of α-Angelica Lactone to (R)- and (S)-γ-Valerolactone in a One-Pot Cascade

The formal asymmetric and stereodivergent enzymatic reduction of α-angelica lactone to both enantiomers of γ-valerolactone was achieved in a one-pot cascade by uniting the promiscuous stereoselective isomerization activity of Old Yellow Enzymes with their native reductase activity. In addition to running the cascade with one enzyme for each catalytic step, a bifunctional isomerase-reductase biocatalyst was designed by fusing two Old Yellow Enzymes, thereby generating an unprecedented case of an artificial enzyme catalyzing the reduction of nonactivated C=C bonds to access (R)-valerolactone in overall 41 % conversion and up to 91 % ee. The enzyme BfOYE4 could be used as single biocatalyst for both steps and delivered (S)-valerolactone in up to 84 % ee and 41 % overall conversion. The reducing equivalents were provided by a nicotinamide recycling system based on formate and formate dehydrogenase, added in a second step. This enzymatic system provides an asymmetric route to valuable chiral building blocks from an abundant bio-based chemical.     

Are Phosphatidylcholine and Lysophosphatidylcholine Body Levels Potentially Reliable Biomarkers in Obesity? A Review of Human Studies

Phosphatidylcholines (PCs) are the major components of biological membranes in animals and are a class of phospholipids that incorporate choline as a headgroup. Lysophosphatidylcholines (LPCs) are a class of lipid biomolecules derived from the cleavage of PCs, and are the main components of oxidized low-density lipoproteins (oxLDLs) that are involved in the pathogenesis of atherosclerosis. Since obesity is associated with a state of chronic low-grade inflammation, one can anticipate that the lipidomic profile changes in this context and both PCs and LPCs are gaining attention as hypothetically reliable biomarkers of obesity. Thus, a literature search is performed on PubMed, Latin American and Caribbean Health Science Literature (LILACS), and Excerpta Medica DataBASE (Embase) to obtain the findings of population studies to clarify this hypothesis. The search strategy resulted in a total of 2403 reports and 21 studies were included according to the eligibility criteria. Controversial data on the associations of PCs and LPCs with body mass index (BMI) and body fat parameters have been identified. There is an inverse relationship between BMI and most species of PCs, and a majority of studies exhibited negative associations between BMI and LPCs. Other findings regarding the differences between PCs and LPCs in obesity are presented, and the associated uncertainties are discussed in detail.     

Concentration of biologically active polyamines in rabbit meat, liver and kidney after slaughter and their changes during meat storage and cooking

The concentration of putrescine (PUT), spermidine (SPD) and spermine (SPM) was determined in chilled meat and kidneys of 18 rabbits and in liver of 12 animals 24 h after slaughter. Very low PUT concentrations were detected only in kidneys. Mean SPD levels were 2.2, 2.2, 61.7 and 32.7 mg kg^− 1 in saddle, leg, liver and kidneys, respectively. The respective SPM concentrations were 14.7, 8.0, 115 and 88.4 mg kg^− 1. SPD and SPM losses of about one third of the initial levels were apparent in saddles stored at − 18 °C for 8 months. Losses of both polyamines of about 15-20% of the initial concentrations were found in saddles stored aerobically at + 2 °C for up to 9 days. Stewing of saddles caused significant SPD and SPM losses of about 20-25%, while upon roasting and pan-roasting without oil a decrease of about 50% of the initial concentration was observed.     

Sequestration of zinc from zinc oxide nanoparticles and life cycle effects in the sediment dweller amphipod Corophium volutator

We studied the effects of ZnO nanoparticles [ZnO NPs, primary particle size 35 ± 10 nm (circular diameter, TEM)], bulk [160 ± 81 nm (circular diameter, TEM)], and Zn ions (from ZnCl(2)) on mortality, growth, and reproductive endpoints in the sediment dwelling marine amphipod Corophium volutator over a complete lifecycle (100 days). ZnO NPs were characterized by size, aggregation, morphology, dissolution, and surface properties. ZnO NPs underwent aggregation and partial dissolution in the seawater exposure medium, resulting in a size distribution that ranged in size from discrete nanoparticles to the largest aggregate of several micrometers. Exposure via water to all forms of zinc in the range of 0.2-1.0 mg L(-1) delayed growth and affected the reproductive outcome of the exposed populations. STEM-EDX analysis was used to characterize insoluble zinc precipitates (sphaerites) of high sulfur content, which accumulated in the hepatopancreas following exposures. The elemental composition of the sphaerites did not differ for ZnO NP, Zn(2+), and bulk ZnO exposed organisms. These results provide an illustration of the comparable toxicity of Zn in bulk, soluble, and nanoscale forms on critical lifecycle parameters in a sediment dwelling organism.     

Discovery of 5′′‐Chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064): A Selective Orexin 2 Receptor Antagonist (2‐SORA) for the Treatment of Insomnia

The field of small‐molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof‐of‐concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX₁R and OX₂R), termed dual orexin receptor antagonists (DORAs), affording late‐stage development candidates including Merck’s suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX₁R or OX₂R alone has been hampered by the dearth of suitable subtype‐selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2‐SORA) series to afford a potent, orally bioavailable 2‐SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5‐disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P‐glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2‐SORA clinical candidate, 5′′‐chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064), in mouse, rat, dog, and rhesus sleep models.     

Synthesis and Properties of Fumaric Copolymers as Potential Bitumen Modifiers

New copolymers of dioctyl fumarate (DOF) and styrene (S) were synthetized by radical polymerization and used to modify bitumen. The poly(dioctyl fumarate-co-styrene) copolymers, PFS, were characterized by ¹H-NMR and FTIR spectroscopies and size exclusion chromatography (SEC) in order to determine their monomer composition and weight average molecular weights, respectively. The polymer-bitumen blending conditions were optimized and the samples analyzed by different methodologies. Fluorescence microscopy, rotational viscosity and differential scanning calorimetry (DSC) were used to study the morphological changes of blends during their manufacturing and the rheological and thermal behavior, respectively. All modified bitumen (MB) exhibited higher viscosity than the based bitumen (BB) under studied conditions and this effect was more evident for the MB containing the higher molecular weight polymer. The addition of polymers to BB enhances the bitumen viscosity and thus increased the energy required for the flowing (activation energy calculated by Arrhenius equation). Thermal and morphological analysis showed that all MB exhibited good polymer- bitumen compatibility, which could be consider as a good starting point for a potential applications of this new material in road engineering.     

Shape effects of filaments versus spherical particles in flow and drug delivery

Interaction of spherical particles with cells and within animals has been studied extensively, but the effects of shape have received little attention. Here we use highly stable, polymer micelle assemblies known as filomicelles to compare the transport and trafficking of flexible filaments with spheres of similar chemistry. In rodents, filomicelles persisted in the circulation up to one week after intravenous injection. This is about ten times longer than their spherical counterparts and is more persistent than any known synthetic nanoparticle. Under fluid flow conditions, spheres and short filomicelles are taken up by cells more readily than longer filaments because the latter are extended by the flow. Preliminary results further demonstrate that filomicelles can effectively deliver the anticancer drug paclitaxel and shrink human-derived tumours in mice. Although these findings show that long-circulating vehicles need not be nanospheres, they also lend insight into possible shape effects of natural filamentous viruses.