Thermal expansion effects in a silo

We consider a vertical container filled with granular material and exposed to temperature cycles which induce changes in the pressure distribution. Our starting point is an elastic model for the grains leading to classical Janssen behaviour in isothermal conditions. We assume complete mobilisation of the wall frictions. The dynamics superposes static friction plus a viscous friction. After a T jump favouring an expansion, we predict that the resulting overpressures are relaxed only in a region (of size comparable to the Janssen screening length λ) near the top. When T returns to the initial value, we expect decohesion in a certain layer near the top (for rapid cooling). For slow cooling, we expect a smooth return to the original Janssen state. We also discuss a different, but related, effect: instead of changing the temperature, we switch off the gravity effects (on a small column) by suddenly rotating the column from vertical to horizontal. Here, a rarefaction wave should invade the whole column.     

Fluorophores for Excited-State Intramolecular Proton Transfer by an Yttrium Triflate Catalyzed Reaction of Isocyanides with Thiocarboxylic Acids

Discovery of new chemical reactivity of a given functional group can often result in innovative synthesis of important chemical entities that possess unprecedented properties. We designed and developed a one-step synthesis of 5-amino-4-carboxamidothiazoles 1 by an yttrium-triflate-catalyzed reaction of thiocarboxylic acids 2 with isocyanides 3 . In this reaction, both reactants 2 and 3 deviated from their normal reactivities because of metal coordination. The resulting heterocycles are novel prototypical structures for the double ESIPT process. Some of them were excited by visible light irradiation and emitted fluorescence at the NIR region with large Stokes shift, high quantum yield, and strong solvatochromism.     

Tools,techniques, organisation and culture of the CADD group at Sygnature Discovery

Computer-aided drug design encompasses a wide variety of tools and techniques, and can be implemented with a range of organisational structures and focus in different organisations. Here we outline the computational chemistry skills within Sygnature Discovery, along with the software and hardware at our disposal, and briefly discuss the methods that are not employed and why. The goal of the group is to provide support for design and analysis in order to improve the quality of compounds synthesised and reduce the timelines of drug discovery projects, and we reveal how this is achieved at Sygnature. Impact on medicinal chemistry is vital to demonstrating the value of computational chemistry, and we discuss the approaches taken to influence the list of compounds for synthesis, and how we recognise success. Finally we touch on some of the areas being developed within the team in order to provide further value to the projects and clients.     

Copper‐Catalyzed Reaction Cascade of Thiophenol Hydroxylation and S‐Arylation through Disulfide‐Directed C−H Activation

Copper‐catalyzed thiophenol C?H activation is described. Through an initial attempt to conduct C‐arylation with arylboronic acid, a rather surprising sequential C?H activation and S‐arylation was discovered. Mechanistic investigation revealed the disulfide intermediate as the key component in directing C?H oxidation. The overall reaction proceeded under mild conditions with molecular oxygen as the oxidant. Discovery of disulfide as the directing group provides a potential new direction for catalytic C?H functionalization under mild conditions.     

Nitrofuran antibiotic metabolites detected at parts per million concentrations in retina of pigs--a new matrix for enhanced monitoring of nitrofuran abuse

Nitrofuran metabolite residues AOZ, AMOZ, AHD and SEM were detected at parts per million concentrations in retina of pigs fed therapeutic doses of nitrofuran antibiotics. Discovery of this residue depot may allow widespread technology transfer to laboratories lacking LC-MS/MS thus improving global monitoring of these drugs.     

Enabling drug discovery project decisions with integrated computational chemistry and informatics

Computational chemistry/informatics scientists and software engineers in Genentech Small Molecule Drug Discovery collaborate with experimental scientists in a therapeutic project-centric environment. Our mission is to enable and improve pre-clinical drug discovery design and decisions. Our goal is to deliver timely data, analysis, and modeling to our therapeutic project teams using best-in-class software tools. We describe our strategy, the organization of our group, and our approaches to reach this goal. We conclude with a summary of the interdisciplinary skills required for computational scientists and recommendations for their training.     

Comparison of zirconia- and silica-based reversed stationary phases for separation of enkephalins

In this study, the separation of biologically active peptides on two zirconia-based phases, polybutadiene (PBD)-ZrO2 and polystyrene (PS)-ZrO2, and a silica-based phase C18 was compared. Basic differences in interactions on both types of phases led to quite different selectivity. The retention characteristics were investigated in detail using a variety of organic modifiers, buffers, and temperatures. These parameters affected retention, separation efficiency, resolution and symmetry of peaks. Separation systems consisting of Discovery PBD-Zr column and mobile phase composed of a mixture of acetonitrile and phosphate buffer, pH 2.0 (45:55, v/v) at 70 degrees C and Discovery PS-Zr with acetonitrile and phosphate buffer, pH 3.5 in the same (v/v) ratio at 40 degrees C were suitable for a good resolution of enkephalin related peptides. Mobile phase composed of acetonitrile and phosphate buffer, pH 5.0 (22:78, v/v) was appropriate for separation of enkephalins on Supelcosil C18 stationary phase.     

Determination of diclazuril in animal feed by liquid chromatography.

A method is described for the determination of diclazuril (Janssen Research Compound R64433; trademark Clinacox) in chicken feed at the mg kg(-1) level. Compound R062646, a structure analogous to diclazuril, was used as the interna standard. The drug was extracted from food with acidified methanol. Diclazuril was then isolated by means of solid-phase extraction with a cartridge containing a C18 phase. The eluate was evaporated and the residue redissolved in dimethylformamide. An aliquot was injected onto a reversed-phase high-performance liquid chromatographic column and the drug substance quantified at 280 nm by an ultraviolet detector. Extraction (absolute) recoveries of 85% for both internal standard and diclazuril were obtained. The method is suitable for diclazuril concentrations ranging from 0.1 to 1.5 mg kg(-1). Method validation data are presented.     

Off-line Coupling of Isotachophoresis and High Performance Liquid Chromatography for Determination of Flavonoids in Plant Extract

Summary The use of isotachophoretic sample pretreatment coupled with high performance liquid chromatography for the analysis of some flavonoids occurring in plant extracts of Hypericum perforatum and Crataegus sp. is described. The samples were extracted with methanol by means of sonication in low temperature. The optimal leading electrolyte was used 10 mM Cl^– as a leading ion in a buffer system at apparent pH^*=7.2 (adjusted by TRIS) and terminating electrolyte was 50 mM boric acid at apparent pH^*=8.2 (adjusted by barium hydroxide). The ITP electrolytes contained 20% (v/v) of methanol. To improve the sample pre-treatment, a pair of discrete ITP spacers defining the trapped constituents was used. Major components presented in the extracts were separated on a Discovery C18 and Discovery RP Amid C16 columns with a gradient mobile phase consisting of methanol, acetonitrile and diluted ortho-phosphoric acid. The quantification was performed by using external standards. The recoveries of the coupled ITP-HPLC analytical procedure were in the range of 91.2–95.6%.     

Journal of Computer-Aided Molecular Design incorporating Perspectives in Drug Discovery and Design

Instructions for authors

Journal of Computer-Aided Molecular Design incorporating Perspectives in Drug Discovery and Design     

Biomimetic Assembly Lines Producing Natural Product Analogs: Strategies from a Versatile Manifold to Skeletally Diverse Scaffolds

Biosynthetic assembly lines have evolved in nature, adopting divergent processes to produce a vast number of secondary metabolites. Inspired by these biogenetic processes, this account introduces recent investigations by my research group to formulate a synthetic strategy for establishing a biomimetic assembly line. With the aim not only to construct natural product‐relevant scaffolds within 5–7 steps, but also to systematically diversify skeletal and stereochemical properties and functional groups, divergent synthetic processes exploiting a versatile manifold have been developed. This approach allows for cost‐effective production of skeletally diverse and biologically active natural product analogs inaccessible by other means. Discovery of several lead candidates for a neglected tropical disease is a proof‐of‐concept of this synthetic approach.     

The design and synthesis of cyclic renin inhibitors

A prototype cyclic renin inhibitor was designed through a combined effort between Discovery and Computer Aided Molecular Design. Synthesis of the prototype structure provided compounds which showed weak inhibitory activity of the enzyme renin.     

Insights into the Retention Mechanisms on Perfluorohexylpropylsiloxane-Bonded (Fluophase-RP) and Octadecylsiloxane-Bonded (Betasil C18) Stationary Phases Based on the Same Silica Substrate in RP-LC

The solvation parameter model is used to elucidate the retention mechanism on a perfluorohexylpropylsiloxane-bonded (Fluophase RP) and octadecylsiloxane-bonded (Betasil C18) stationary phases based on the same silica substrate with acetonitrile–water and methanol–water mobile phase compositions. Dewetting affects the retention properties of Fluophase RP at mobile phase compositions containing less than 20% (v/v) acetonitrile or 40% (v/v) methanol. It results in a loss of retention due to an unfavorable change in the phase ratio as well as changes in specific intermolecular interactions. Steric repulsion reduces retention of bulky solutes on fully solvated Betasil C18 with methanol–water (but not acetonitrile–water) mobile phase compositions but is not important for Fluophase RP. The retention of weak bases is affected by ion-exchange interactions on Fluophase RP with acetonitrile–water, and to a lesser extent, methanol-water mobile phases but these are weak at best for Betasil C18. The system constants of the solvation parameter model and retention factor scatter plots are used to compare selectivity differences for Fluophase RP, Betasil C18 and a perfluorophenylpropylsiloxane-bonded silica stationary phase Discovery HS F5 for conditions where incomplete solvation, steric repulsion and ion-exchange do not significantly contribute to the retention mechanism. Lower retention on Fluophase RP results from weaker dispersion and/or higher cohesion moderated to different extents by polar interactions since solvated Fluophase RP is a stronger hydrogen-bond acid and more dipolar/polarizable than Betasil C18. Retention factors for acetonitrile–water mobile phases are highly correlated for Fluophase RP and Betasil C18 except for compounds with a large excess molar refraction and weak hydrogen-bonding capability. Selectivity differences are more significant for methanol–water mobile phases. Retention factors on Fluophase RP are strongly correlated with those on Discovery HSF5 for acetonitrile–water mobile phases while methanol–water mobile phases retention on Fluophase RP is a poor predictor of the retention order on Discovery HS F5.     

Liquid chromatographic-electrospray mass spectrometric determination (LC-ESI-MS) of phase II metabolites of flobufen in rat liver microsomes-Chiral discrimination

Glucuronidation of the non-steroidal anti-inflammatory chiral drug flobufen and its major metabolite M17203 has been implicated as an important mechanism of flobufen elimination. To characterize flobufen metabolism by O-glucuronidation, new liquid chromatographic method (LC) coupled with ESI-MS was developed to detect the conjugates of flobufen and its metabolites formed in vitro in rat liver microsomes. Discovery DSC-18 LT cartridge columns were utilized for solid phase extraction (SPE) and Discovery C18 column (150 mm x 2.1 mm, 5 microm particle size) was used for LC separation. Chiral inversion of flobufen and its metabolites enantiomers was checked by special 1-allyl-(5R,8S,10R)-terguride column (150 mm x 4.6 mm). O-Glucuronidation of the S-enantiomer displayed a typical Michaelis-Menten kinetics, whereas the R-enantiomer exhibited a substrate inhibition type of kinetics. The study of glucuronidation of M17203 led to kinetics with sigmoidal characteristics.     

Impact of normal-phase gradient elution in chiral chromatography: a novel,robust, efficient and rapid chiral screening procedure

Novel normal-phase gradient systems have been employed for fast high-throughput chiral analyses of Discovery compounds in our research laboratories in Eli Lilly and Company. In this report, we describe an automated screening approach based on gradient elution, in order to achieve accurate enantiomeric excess determinations, and chiral separations when needed, in the shortest possible timeframe. Baseline resolution of enantiomers has been obtained for over 85% of the samples so tested. For the remaining cases, complete enantioseparation by isocratic optimisation is generally achieved in a single shot. This technique has been proven to be robust and is now standard operating procedure at our analytical research laboratories.     

Molecular simulation of model sulfated polysaccharides of low molecular weight from Ganoderma lucidum and their interaction with human serum albumin

The extracellular polysaccharides from Ganoderma lucidum possess low molecular weight and are mainly composed of (1 → 3)/(1 → 6) linked-α-glucan and (1 → 3)/(1 → 6) linked-α-galactose. In the present study, conformations of the polysaccharides were simulated and investigated using Discovery studio 2.5. Their sulfated derivatives were also taken into account. The simulation was performed using CHARMM force field. The results show that the polysaccharides exist as random coil conformations, while the sulfated derivatives adopt more extensive and stiffer conformations in most cases. In addition, the molecular docking between polysaccharide and human serum albumin (HSA) was also investigated using ZDOCK module in Discovery studio 2.5. It is shown that the unmodified polysaccharide possesses higher affinity with HSA than the sulfated derivatives do due to its higher ZDOCK score.     

Antimicrobial screening of a historical collection of over 140 000 small molecules

Most of the chemical compound collection (currently about 200 000), assembled at the N. D. Zelinsky Institute of Organic Chemistry over the past 30 years, has been screened for antimicrobial activity against five ESKAPE pathogens and two fungi at the University of Queensland on a charitable basis. A total of 2517 active molecules (MIC ≤ 32 μg ml^–1) were found, of which about 10% are active at very low concentrations (MIC ≤ 1 μg ml^–1). Structures of 142 012 compounds and experimental data on their antimicrobial activity are publicly available through the demo version of the CheD software and the public database of the Community for Open Antimicrobial Drug Discovery.     

均相铬系催化剂的合成与催化α－烯烃聚合的进展

铬系多相催化剂已广泛应用于工业聚乙烯的生产中。近年来，探明多相铬催化 剂的本质，并进一步开发新一代铬系均相催化剂成为人们追求的热点。综述了近年 来有关均相铬催化剂的合成与催化α－烯烃的报道。