Synthesis of the Antimicrobial S‐Linked Glycopeptide,Glycocin F

The first total synthesis of glycocin F, a uniquely diglycosylated antimicrobial peptide bearing a rare S‐linked N‐acetylglucosamine (GlcNAc) moiety in addition to an O‐linked GlcNAc, has been accomplished using a native chemical ligation strategy. The synthetic and naturally occurring peptides were compared by HPLC, mass spectrometry, NMR and CD spectroscopy, and their stability towards chymotrypsin digestion and antimicrobial activity were measured. This is the first comprehensive structural and functional comparison of a naturally occurring glycocin with an active synthetic analogue.     

Vanadium(V) Oxo and Imido Calix[8]arene Complexes: Synthesis,Structural Studies,and Ethylene Homo/Copolymerisation Capability

Interaction of p‐tert‐butylcalix[8]areneH₈ (L⁸H₈) with [NaVO(OtBu)₄] (formed in situ from VOCl₃) afforded the complex [Na(NCMe)₅][(VO)₂L⁸H]?4 MeCN ( 1 ?4 MeCN). Increasing [NaVO(OtBu)₄] to 4 equiv led to [Na(NCMe)₆]₂[(Na(VO)₄L⁸)(Na(NCMe))₃]₂?10 MeCN ( 2 ?10 MeCN). With adventitious oxygen, reaction of 4 equiv of [VO(OtBu)₃] with L⁸H₈ afforded the alkali‐metal‐free complex [(VO)₄L⁸(μ³‐O)₂] ( 3 ); solvates 3 ?3 MeCN and 3 ?3 CH₂Cl₂ were isolated. For the lithium analogue, the order of addition had to be reversed such that lithium tert‐butoxide was added to L⁸H₈ and then treated with 2 equiv of VOCl₃; crystallisation afforded [(VO₂)₂Li₆[L⁸](thf)₂(OtBu)₂(Et₂O)₂]?Et₂O ( 4 ?Et₂O). Upon extraction into acetonitrile, [Li(NCMe)₄][(VO)₂L⁸H]?8 MeCN ( 5 ?8 MeCN) was formed. Use of the imido precursors [V(NtBu)(OtBu)₃] and [V(Np‐tolyl)(OtBu)₃] and L⁸H₈, afforded [tBuNH₃][{V(p‐tolylN)}₂L⁸H]?3 1/2 MeCN ( 6 ?3 1/2 MeCN). The molecular structures of 1 to 6 are reported. Complexes 1 , 3 , and 4 were screened as precatalysts for the polymerisation of ethylene in the presence of cocatalysts at various temperatures and for the copolymerisation of ethylene with propylene. Activities as high as 136 000 g (mmol(V) h)^?1 were sometimes achieved; higher molecular weight polymers could be obtained versus the benchmark [VO(OEt)Cl₂]. For copolymerisation, incorporation of propylene was 7.1–10.9 mol % (compare 10 mol % for [VO(OEt)Cl₂]), although catalytic activities were lower than [VO(OEt)Cl₂].     

Tobramycin and Nebramine as Pseudo‐oligosaccharide Scaffolds for the Development of Antimicrobial Cationic Amphiphiles

Antimicrobial cationic amphiphiles derived from aminoglycoside pseudo‐oligosaccharide antibiotics interfere with the structure and function of bacterial membranes and offer a promising direction for the development of novel antibiotics. Herein, we report the design and synthesis of cationic amphiphiles derived from the pseudo‐trisaccharide aminoglycoside tobramycin and its pseudo‐disaccharide segment nebramine. Antimicrobial activity, membrane selectivity, mode of action, and structure–activity relationships were studied. Several cationic amphiphiles showed marked antimicrobial activity, and one amphiphilic nebramine derivative proved effective against all of the tested strains of bacteria; furthermore, against several of the tested strains, this compound was well over an order of magnitude more potent than the parent antibiotic tobramycin, the membrane‐targeting antimicrobial peptide mixture gramicidin D, and the cationic lipopeptide polymyxin B, which are in clinical use.     

Three‐dimensional structure of cyclic antibiotic teicoplanin aglycone using NMR distance and dihedral angle restraints in a DMSO solvation model

The three‐dimensional solution conformation of teicoplanin aglycone was determined using NMR spectroscopy. A combination of NOE and dihedral angle restraints in a DMSO solvation model was used to calculate an ensemble of structures having a root mean square deviation of 0.17 Å. The structures were generated using systematic searches of conformational space for optimal satisfaction of distance and dihedral angle restraints. Comparison of the NMR‐derived structure of teicoplanin aglycone with the X‐ray structure of a teicoplanin aglycone analog revealed a common backbone conformation with deviation of two aromatic side chain substituents. Experimentally determined backbone ¹³C chemical shifts showed good agreement with those computed at the density functional level of theory, providing a cross validation of the backbone conformation. The flexible portion of the molecule was consistent with the region that changes conformation to accommodate protein binding. The results showed that a hydrogen‐bonded DMSO molecule in combination with NMR‐derived restraints together enabled calculation of structures that satisfied experimental data. Copyright © 2015 John Wiley & Sons, Ltd.     

Catalytic enantioselective synthesis of azacycloalkenes via intermolecular rhodium carbenoid C–H insertion/ring-closing metathesis sequence

Enantiomerically enriched cyclopropanes and products of C–H insertion reactions were obtained in excellent combined yields and enantioselectivities as a consequence of rhodium-catalyzed decomposition of vinyl diazoacetate in the presence of tert-butoxycarbonyl-(Boc)-protected amines as trapping agents. A series of enantiomerically enriched six- to eight-membered nitrogen-containing heterocycles were subsequently prepared via ring-closing metathesis of the dienes catalyzed by ruthenium benzylidene complex.     

A flow chemistry route to 2-phenyl-3-(1H-pyrrol-2-yl)propan-1-amines

The Knoevenagel condensation of pyrrole-2-carboxaldehyde (1) with a range of substituted benzyl nitriles (2a-e) afforded rapid access to a family of α,β-unsaturated nitriles (3a-e) in good yields (67-78%). Flow hydrogenation (ThalesNano H-cube™) at 60 °C, 50 bar H₂ pressure, 1.0 mL/min through a 10% Pd-C catalyst selectively, and quantitatively, hydrogenated the olefin double bond (4a-e). Use of a Raney Nickel catalyst at 70 °C, 70 bar H₂ pressure and flow rates of 0.5-1.0 mL/min afforded quantitative conversion into the corresponding saturated amines with the reduction of both the olefin and nitrile bonds (5a-e). The versatility of this approach was further exemplified by reaction of 5a and 5c with norcantharidin to afford acid amide norcantharidin analogues 7 and 8 as novel protein phosphatase 1 and 2A inhibitors.     

Probing small molecule binding to amyloid fibrils

Much effort has focussed in recent years on probing the interactions of small molecules with amyloid fibrils and other protein aggregates. Understanding and control of such interactions are important for the development of diagnostic and therapeutic strategies in situations where protein aggregation is associated with disease. In this perspective article we give an overview over the toolbox of biophysical methods for the study of such amyloid-small molecule interactions. We discuss in detail two recently developed techniques within this framework: linear dichroism, a promising extension of the more traditional spectroscopic techniques, and biosensing methods, where surface-bound amyloid fibrils are exposed to solutions of small molecules. Both techniques rely on the measurement of physical properties that are very directly linked to the binding of small molecules to amyloid aggregates and therefore provide an attractive route to probe these important interactions.     

Surfactant addition and alternating current electrophoretic oscillation during size fractionation of nanoparticles in channels with two or three different height segments

An array of parallel planar nanochannels containing two or three segments with varying inner heights was fabricated and used for size fractionation of inorganic and biological nanoparticles. A liquid suspension of the particles was simply drawn through the nanochannels via capillary action. Using fluorescently labeled 30 nm polyacrylonitrile beads, different trapping behaviors were compared using nanochannels with 200-45 nm and 208-54-30 nm height segments. Addition of sodium dodecyl sulfate (SDS) surfactant to the liquid suspension and application of an AC electric field were shown to aid in the prevention of channel clogging. After initial particle trapping at the segment interfaces, significant particle redistribution occurred when applying a sinusoidal 8V peak-to-peak oscillating voltage with a frequency of 150 Hz and DC offset of 4V. Using the 208-54-30 nm channels, 30 nm hepatitis B virus (HBV) capsids were divided into three fractions. When the AC electric field was applied to this trapped sample, all of the virus particles passed through the interfaces and accumulated at the channel ends.     

Optimization of preparative chromatographic separation of multiple rare earth elements

This work presents a method to optimize multi-product chromatographic systems with multiple objective functions. The system studied is a neodymium, samarium, europium, gadolinium mixture separated in an ion exchange chromatography step. A homogeneous Langmuir Mobile Phase Modified model is calibrated to fit the experiments, and then used to perform the optimization task. For the optimization a multi-objective Differential Evolution algorithm was used, with weighting based on relative value of the components to find optimal operation points along the Pareto front. The objectives of the Pareto front are weighted productivity and weighted yield with purity as an equality constraint. A prioritizing scheme based on relative values is applied for determining the pooling order. A simple rule of thumb for pooling strategy selection is presented. The multi-objective optimization gives a Pareto front which shows the rule of thumb, as a gap in one of the objective functions.