Molecular basis of Celmer's rules: stereochemistry of catalysis by isolated ketoreductase domains from modular polyketide synthases

A system is reported for the recombinant expression of individual ketoreductase (KR) domains from modular polyketide synthases (PKSs) and scrutiny of their intrinsic specificity and stereospecificity toward surrogate diketide substrates. The eryKR(1) and the tylKR(1) domains, derived from the first extension module of the erythromycin PKS and the tylosin PKS, respectively, both catalyzed reduction of (2R, S)-2-methyl-3-oxopentanoic acid N-acetylcysteamine thioester, with complete stereoselectivity and stereospecificity, even though the substrate is not tethered to an acyl carrier protein or an intact PKS multienzyme. In contrast, and to varying degrees, the isolated enzymes eryKR(2), eryKR(5), and eryKR(6) exercised poorer control over substrate selection and the stereochemical course of ketoreduction. These data, together with modeling of diketide binding to KR(1) and KR(2), demonstrate the fine energetic balance between alternative modes of presentation of ketoacylthioester substrates to KR active sites.     

Quantification of a single aggregate inner porosity and pore accessibility using hard X-ray phase-contrast nanotomography

The 3D structure of three individual aggregates composed of 165 nm polystyrene primary particles is revealed nondestructively by hard X-ray phase-contrast synchrotron nanotomography. Three-dimensional image analysis allows us for the first time to obtain the complex inner porosity of the entire aggregate. It is demonstrated that despite their rather compact structure, characterized by a fractal dimension equal to 2.7, the produced aggregates are still porous, with porosity increasing with its size. Generated pores have diameters from 100 nm to 3 μm and are almost completely interconnected.     

Effect of Different Crosslinking Strategies on Physical Properties and Biocompatibility of Freestanding Multilayer Films Made of Alginate and Chitosan

Freestanding multilayer films prepared by layer‐by‐layer technique have attracted interest as promising materials for wound dressings. The goal is to fabricate freestanding films using chitosan (CHI) and alginate (ALG) including subsequent crosslinking to improve the mechanical properties of films while maintaining their biocompatibility. Three crosslinking strategies are investigated, namely use of calcium ions for crosslinking ALG, 1‐ethyl‐3‐(‐3‐dimethylaminopropyl) carbodiimide combined with N‐hydroxysuccinimide for crosslinking ALG with CHI, and Genipin for crosslinking chitosan inside the films. Different characteristics, such as surface morphology, wettability, swelling, roughness, and mechanical properties are investigated showing that films became thinner, exhibited rougher surfaces, had lower water uptake, and increased mechanical strength after crosslinking. Changes of wettability are moderate and dependent on the crosslinking method. In vitro cytotoxicity and cell attachment studies with human dermal fibroblasts show that freestanding CHI‐ALG films represent a poorly adhesive substratum for fibroblasts, while studies using incubation of plastic‐adherent fibroblast beneath floating films show no signs of cytotoxicity in a time frame of 7 days. Results from cell experiments combined with film characteristics after crosslinking, indicate that crosslinked freestanding films made of ALG and CHI may be interesting candidates for wound dressings.     

Julia-Kocienski Olefination in the Synthesis of Trisubstituted Alkenes: Recent Progress

Julia-Kocienski olefination, a coupling reaction between a carbonyl component and a sulfone partner, has emerged as a powerful synthetic tool in the preparation of several organic compounds. A number of interesting examples involving particularly the preparation of trisubstituted alkenes along with important observations regarding the stereoselectivity of those reactions have been recently reported. This reviewing work covers the literature for the period 2016–2022 and describes in a comprehensive way the progress and developments of Julia-Kocienski olefination application in the synthesis of trisubstituted alkenes which serve as precursors of natural products and their analogs as well of pharmaceutically interesting/biologically important compounds. Moreover, key methodology results dealing with the investigation of the optimum conditions and stereoselectivities and new modifications and approaches are discussed.     

Electronic,bonding, and optical properties of 1d [CuCN]n (n = 1–10) chains, 2d [CuCN]n (n = 2–10) nanorings,and 3d [Cun(CN)n]m (n = 4, m = 2, 3; n = 10, m = 2) tubes studied by DFT/TD‐DFT methods

The electronic, bonding, and photophysical properties of one‐dimensional [CuCN]_n (n = 1–10) chains, 2‐D [CuCN]_n (n = 2–10) nanorings, and 3‐D [Cu_n(CN)_n]_m (n = 4, m = 2, 3; n = 10, m = 2) tubes are investigated by means of a multitude of computational methodologies using density functional theory (DFT) and time‐dependent‐density‐functional theory (TD‐DFT) methods. The calculations revealed that the 2‐D [CuCN]_n (n = 2–10) nanorings are more stable than the respective 1‐D [CuCN]_n (n = 2–10) linear chains. The 2‐D [CuCN]_n (n = 2–10) nanorings are predicted to form 3‐D [Cu_n(CN)_n]_m (n = 4, m = 2, 3; n = 10, m = 2) tubes supported by weak stacking interactions, which are clearly visualized as broad regions in real space by the 3D plots of the reduced density gradient. The bonding mechanism in the 1‐D [CuCN]_n (n = 1–10) chains, 2‐D [CuCN]_n (n = 2–10) nanorings, and 3‐D [Cu_n(CN)_n]_m (n = 4, m = 2, 3; n = 10, m = 2) tubes are easily recognized by a multitude of electronic structure calculation approaches. Particular emphasis was given on the photophysical properties (absorption and emission spectra) of the [CuCN]_n chains, nanorings, and tubes which were simulated by TD‐DFT calculations. The absorption and emission bands in the simulated TD‐DFT absorption and emission spectra have thoroughly been analyzed and assignments of the contributing principal electronic transitions associated to individual excitations have been made. © 2015 Wiley Periodicals, Inc.     

Thermotropic biaxial nematic liquid crystals: spontaneous or field stabilized?

An intermediate nematic phase is proposed for the interpretation of recent experimental results on phase biaxiality in bent-core nematic liquid crystals. The phase is macroscopically uniaxial but has microscopic biaxial, and possibly polar, domains. Under the action of an electric field, the phase acquires macroscopic biaxial ordering resulting from the collective alignment of the domains. A phenomenological theory is developed for the molecular order in this phase and for its transitions to purely uniaxial and to spontaneously biaxial nematic phases.     

Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome

The role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 weeks. AM6545, the peripheral silent antagonist and AM4113, the central neutral antagonist were administered in the last 4 weeks. At the end of study, blood and urine samples were collected for biochemical analyses while the kidneys were excised for histopathological investigation and transforming growth factor beta 1 (TGFβ1) measurement. MetS was associated with deteriorated kidney function as indicated by the elevated proteinuria and albumin excretion rate. Both compounds equally inhibited the elevated proteinuria and albumin excretion rate while having no effect on creatinine clearance and blood pressure. In addition, AM6545 and AM4113 alleviated the observed swelling and inflammatory cells infiltration in different kidney structures. Moreover, AM6545 and AM4113 alleviated the observed histopathological alterations in kidney structure of MetS rats. MetS was associated with a ten-fold increase in urine uric acid while both compounds blocked this increase. Furthermore, AM6545 and AM4113 completely prevented the collagen deposition and the elevated expression of the TGFβ1 seen in MetS animals. In conclusion, AM6545 and AM4113, possess reno-protective effects by interfering with TGFβ1-mediated renal inflammation and fibrosis, via peripheral action.     

Dynamics of solvent-free grafted nanoparticles

The diffusivity and structural relaxation characteristics of oligomer-grafted nanoparticles have been investigated with simulations of a previously proposed coarse-grained model at atmospheric pressure. Solvent-free, polymer-grafted nanoparticles as well as grafted nanoparticles in a melt were compared to a reference system of bare (ungrafted) particles in a melt. Whereas longer chains lead to a larger hydrodynamic radius and lower relative diffusivity for grafted particles in a melt, bulk solvent-free nanoparticles with longer chains have higher relative diffusivities than their short chain counterparts. Solvent-free nanoparticles with short chains undergo a glass transition as indicated by a vanishing diffusivity, diverging structural relaxation time and the formation of body-centered-cubic-like order. Nanoparticles with longer chains exhibit a more gradual increase in the structural relaxation time with decreasing temperature and concomitantly increasing particle volume fraction. The diffusivity of the long chain nanoparticles exhibits a minimum at an intermediate temperature and volume fraction where the polymer brushes of neighboring particles overlap, but must stretch to fill the interparticle space.     

Synthesis and characterization of a compact tricyclic resorcinol from (+)- and (−)-3-pinanol

Resorcinol derivatives are important building blocks in the synthesis of natural products and pharmaceutical compounds including cannabinoids. Here we describe the synthesis and the structural characterization of a key resorcinol which carries a fully restricted bridged bicyclic group. We also report a potential mechanism for the acid catalyzed condensation of (+)- or (−)-3-pinanol with 2,6-dimethoxyphenol. The synthesized resorcinol facilitates the development of novel conformationally restricted cannabinoid analogs.