Towards the Core Structure of Strychnos Alkaloids Using Samarium Diiodide‐Induced Reactions of Indole Derivatives

This report describes the development of a first and second generation approach towards the synthesis of the ABCEG pentacyclic core structure of Strychnos alkaloids. First, we discuss a sequential approach applying a series of functional group transformations to prepare suitable precursors for cyclization reactions. These include attempts of samarium diiodide‐induced cyclizations or a Barbier‐type reaction of a transient lithium organyl, which successfully led to a tetracyclic key building block earlier used for the synthesis of strychnine. Secondly, we account our first steps towards the development of an atom‐economical samarium diiodide‐induced cascade reaction using “dimeric” indolyl ketones as cyclization precursors. In this context, we discuss plausible mechanisms for the samarium diiodide‐induced cascade reaction as well as transformations of the obtained tetracyclic dihydroindoline derivatives.     

A General Way,From L-Ascorbic And D-Isoascorbic Acids,To Homochiral α-Hydroxy, α,β-Dihydroxy And α,β-Epoxy-Aldehydes,Useful Building Blocks For The Synthesis Of Linear Oxygenated Fatty Acids Metabolites

Abstract

Enantiomerically pure α-hydroxy, α,β-dihydroxy and α,β-epoxyaldehydes, useful building blocks for the synthesis of acyclic oxygenated fatty acids metabolites, were synthetized via epoxybutanediol acetonide starting from the commercially available L-ascorbic and D-isoascorbic acids.     

Convective director structures upon continuous rotation of nematic side group polymers

Abstract

We present the first study of convective director structures in nematic side group polymers. A thin liquid crystal cell (10–500 μm) was continuously rotated about an axis perpendicular to the field of a 7T NMR magnet. The director behaviour was followed by deuteron NMR as well as by polarization microscopy. While by optical studies the development of periodic director structures can be directly monitored, the analysis of the NMR lineshape gives detailed information about the director distribution in these structures. The development of the structures depends sensitively on the rotation frequency and is discussed in terms of non-linear amplification of long wavelength director fluctuations due to the coupling between director rotation and viscous flow of the nematic.     

Synthesis of helix 69 of Escherichia coli 23S rRNA containing its natural modified nucleosides,m(3)Psi and Psi

The synthesis of 3-methylpseudouridine (m(3)Psi) phosphoramidite, 5'-O-[benzhydryloxybis(trimethylsilyloxy)silyl]-2'-O-[bis(2-acetoxyethoxy)methyl]-3-methylpseudouridine-3'-(methyl-N,N-diisopropyl)phosphoramidite, is reported. Selective pivaloyloxymethyl protection of the Psi N1 followed by methylation at N3 was used to generate the naturally occurring pseudouridine analogue. The m(3)Psi phosphoramidite was used in combination with pseudouridine (Psi) and standard base phosphoramidites to synthesize a 19-nucleotide RNA representing helix 69 of Escherichia coli 23S ribosomal RNA (rRNA) (residues 1906-1924), containing a single m(3)Psi at position 1915 and two Psi's at positions 1911 and 1917. Our synthesis of the fully modified helix 69 RNA demonstrates the ability to make milligram quantities of RNA that can be used for further high-resolution structure studies. Site-selective introduction of the methyl group at the N3 position of pseudouridine at position 1915 causes a slight increase in the thermodynamic stability of the RNA hairpin relative to pseudouridine; RNAs containing either uridine or 3-methyluridine at position 1915 have similar stability. One-dimensional imino proton NMR and circular dichroism spectra of the modified RNAs reveal that the methyl group does not cause any substantial changes in the RNA hairpin structure.     

Measuring intracellular calcium fluxes in high throughput mode

The measurement of intracellular calcium fluxes in real time is widely applied within the pharmaceutical industry to measure the activation of G-protein coupled receptors (GPCRhyp;s), either for pharmacological characterisation or to screen for new surrogate ligands. Initially restricted to G(q) coupled GPCRs, the introduction of promiscuous and chimeric G-proteins has further widened the application of these assays. The development of new calcium sensitive dyes and assays has provided sensitive, homogeneous assays which can be readily applied to high throughput screening (HTS). In this paper we describe the full automation of this assay type using a fluorometric imaging plate reader (FLIPR ) integrated into a Beckman/Sagian system to establish a simple robotic system that is well suited for the current medium throughput screening in this area of lead discovery. Using a recently completed HTS we discuss important determinants for FLIPR based screening, highlight some limitations of the current approach, and look at the requirements for future automated systems capable of keeping up with expanding compound files.     

Radical cyclization cascade involving ynamides: an original access to nitrogen-containing heterocycles

A radical cascade involving a 5-exo-dig cyclization followed by a 6-endo-trig radical trapping transforms ynamides into heterogeneous polycyclic compounds in good yields. This leads interestingly to the formation of isoindols, isoindolinones, and pyridoisoindolones. [reaction: see text]     

Synthesis of 15N-enriched pseudouridine derivatives

[reaction: see text]. A procedure for the chemical synthesis of [3-15N]-labeled pseudouridine and a methylated derivative was developed. A suitably protected pseudouridine precursor was nitrated at N3 followed by treatment with 15NH4Cl to afford the 15N-labeled product in six steps with a 20% yield. This methodology will allow for the production of RNAs with [3-15N]pseudouridine and [3-15N-methyl]pseudouridine at specific locations.     

Die elektrochemische Reduktion von CSSe und CSe2 in Dimethylformamid: Heterocyclische 1,2-Dichalkogenolate und ihre Koordinationschemie

Electrochemical Reduction of CSSe and CSe₂ in Dimethylformamide: Heterocyclic 1,2-Dichalcogenolates and their Coordination Chemistry Starting from carbon diselenide or carbon selenidesulfide the electrochemical preparation (electrosynthesis) of heterocyclic dichalcogenolates C₃X₅^2? (X = Se: dsis; X = S/Se: C₃S_xSe_y^2?) is outlined. The 1,2-dichalcogenolate compounds were isolated and characterized as dibenzoyl derivatives. Bis- or tris-chelates of general type A_m[M(C₃X₅)_n] (with A = Bu₄N⁺, Ph₄As⁺; M = Zn^II, Pt^II, Pd^II, Ni^III, Cu^III, Au^III, In^III; X = Se, S/Se; m = 1, 2, 3; n = 2, 3, respectively) are available directly from methanolic solutions of the dibenzoylates after hydrolytic cleavage of the latter with sodium methanolate. In addition bis-chelates Bu₄N[Ni(C₃X₅)₂] (X = Se, S/Se) have been characterized by cyclovoltammetry and epr spectroscopy and compared with the corresponding all-sulfur ligand compound Bu₄N[Ni(dmit)₂] (X = S). Arguments are given for the fact that the allselenium ligand dsis (X = Se) yields the Cu^III or Ni^III chelate at once whereas with dmit using identical conditions the metal(II) compounds are formed.     

Digital Microfluidics and Magnetic Bead-Based Intact Proteoform Elution for Quantitative Top-down Nanoproteomics of Single C. elegans Nematodes

While most nanoproteomics approaches for the analysis of low-input samples are based on bottom-up proteomics workflows, top-down approaches enabling proteoform characterization are still underrepresented. Using mammalian cell proteomes, we established a facile one-pot sample preparation protocol based on protein aggregation on magnetic beads and intact proteoform elution using 40 % formic acid. Performed on a digital microfluidics device, the workflow enabled sensitive analyses of single Caenorhabditis elegans nematodes, thereby increasing the number of proteoform identifications compared to in-tube sample preparation by 46 %. Label-free quantification of single nematodes grown under different conditions allowed to identify changes in the abundance of proteoforms not distinguishable by bottom-up proteomics. The presented workflow will facilitate proteoform-directed analysis on samples of limited availability.     

Glyphosate–Exonuclease Interactions: Reduced Enzymatic Activity as a Route to Glyphosate Biosensing

N-phosphonomethyle-glycine (glyphosate) is the most widely used pesticide worldwide due to its effectiveness in killing weeds at a moderate cost, bringing significant economic benefits. However, owing to its massive use, glyphosate and its residues contaminate surface waters. On site, fast monitoring of contamination is therefore urgently needed to alert local authorities and raise population awareness. Here the hindrance of the activity of two enzymes, the exonuclease I (Exo I) and the T5 exonuclease (T5 Exo) by glyphosate, is reported. These two enzymes digest oligonucleotides into shorter sequences, down to single nucleotides. The presence of glyphosate in the reaction medium hampers the activity of both enzymes, slowing down enzymatic digestion. It is shown by fluorescence spectroscopy that the inhibition of ExoI enzymatic activity is specific to glyphosate, paving the way for the development of a biosensor to detect this pollutant in drinking water at suitable detection limits, i.e., 0.6 nm .