Extrusion – back to the future: Using an established technique to reform automated chemical synthesis

• Deborah E. Crawford

Beilstein J. Org. Chem. 2017, 13, 65–75, doi:10.3762/bjoc.13.9

• ]. This work highlights another advantage of extrusion in that the barrel can have separate heating zones (some also provide cooling), allowing the temperatures to be varied along the production line. In addition, due to the low free volume of the extruder barrel, but the high throughput rates achievable

Computational methods in drug discovery

• Sumudu P. Leelananda and
• Steffen Lindert

Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

• methods are discussed. Advances in virtual high-throughput screening, protein structure prediction methods, protein–ligand docking, pharmacophore modeling and QSAR techniques are reviewed. Keywords: ADME; computer-aided drug design; docking; free energy; high-throughput screening; LBDD; lead optimization

• the consumer market. Approximately 75% of the cost is due to failures that happen along the drug discovery and design pipeline [1]. Nowadays with faster high-throughput screening (HTS) experiments, which can assay thousands of molecules with robotic automation, human labor associated with screening of

• it possible to use structure-based tools such as virtual high-throughput screening and direct docking methods on targets and possible drug molecules. The affinity of molecules to targets can be evaluated by computing various estimates of binding free energies. Further filtering and optimization of

Opportunities and challenges for direct C–H functionalization of piperazines

• Zhishi Ye,
• Kristen E. Gettys and
• Mingji Dai

Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70

• versatile method to functionalize amines, particularly saturated N-heterocycles [62][63][64][65][66]. However, photoredox catalysis for direct α-C–H functionalization of piperazines is very limited and only a few examples have been reported by MacMillan and co-workers (Figure 15) [63][65][66]. Using a high

• -throughput and automated workflow platform, they have discovered a photoredox-catalyzed C–H arylation of N-arylamines with 1,4-dicyanobenzene (88) to produce pharmaceutically important benzylic amines. This reaction works well with piperazine substrate 87 to synthesize the α-arylated piperazine 89 in 95

Enabling technologies and green processes in cyclodextrin chemistry

• Giancarlo Cravotto,
• Marina Caporaso,
• Laszlo Jicsinszky and
• Katia Martina

Beilstein J. Org. Chem. 2016, 12, 278–294, doi:10.3762/bjoc.12.30

• . Besides batch reactors, in the last decade these techniques have been adapted to flow systems, which provide greater efficiency, flexibility and lower energy consumption, or in high-throughput applications. Our experience in process intensification and innovative reactors took advantage from flow

Learning from the unexpected in life and DNA self-assembly

• Jennifer M. Heemstra

Beilstein J. Org. Chem. 2015, 11, 2713–2720, doi:10.3762/bjoc.11.292

• demonstrated that we could use our split aptamer ligation method to measure the concentration of a small-molecule target, but doing so required analysis via gel electrophoresis. Thus, we sought to create an assay that would be capable of the high throughput needed for clinical diagnostics applications, and we

• potential to provide throughput on the order of 105–106 samples per day [18]. We envisioned that aptamers could serve as powerful recognition elements for fluorescence-based high-throughput enantiopurity measurement, and the first key element to our approach was the concept of reciprocal chiral substrate

Profluorescent substrates for the screening of olefin metathesis catalysts

• Raphael Reuter and
• Thomas R. Ward

Beilstein J. Org. Chem. 2015, 11, 1886–1892, doi:10.3762/bjoc.11.203

• have been prepared and tailored towards specific applications [12]. With the ultimate aim of identifying new olefin metathesis catalysts using high-throughput screening, we set out to develop and evaluate olefinic substrates amenable to a 96-well plate screening format. Results and Discussion A quick

Active site diversification of P450cam with indole generates catalysts for benzylic oxidation reactions

• Paul P. Kelly,
• Anja Eichler,
• Susanne Herter,
• David C. Kranz,
• Nicholas J. Turner and
• Sabine L. Flitsch

Beilstein J. Org. Chem. 2015, 11, 1713–1720, doi:10.3762/bjoc.11.186

• high; (iii) each substrate might result in many different oxidation products. Here, we describe how such issues can be overcome by (i) using surrogate high-throughput screening (HTS) protocols that can deal with a large number of mutants; (ii) identification of active mutant libraries; (iii

Effects of RAMEA-complexed polyunsaturated fatty acids on the response of human dendritic cells to inflammatory signals

• Éva Rajnavölgyi,
• Renáta Laczik,
• Viktor Kun,
• Lajos Szente and
• Éva Fenyvesi

Beilstein J. Org. Chem. 2014, 10, 3152–3160, doi:10.3762/bjoc.10.332

• information to other cell types lead to the notion that different subtypes and subsets of DC are central regulators of both innate and adaptive immunity and thus they can also be harnessed for vaccine development [33] and also for immunotherapeutic interventions [34]. By using high throughput approaches we

The search for new amphiphiles: synthesis of a modular, high-throughput library

• George C. Feast,
• Thomas Lepitre,
• Xavier Mulet,
• Charlotte E. Conn,
• Oliver E. Hutt,
• G. Paul Savage and
• Calum J. Drummond

Beilstein J. Org. Chem. 2014, 10, 1578–1588, doi:10.3762/bjoc.10.163

• organic amphiphilic compounds was synthesised consisting of glucose, galactose, lactose, xylose and mannose head groups and double and triple-chain hydrophobic tails. A modular, high-throughput approach was developed, whereby head and tail components were conjugated using the copper-catalysed azide–alkyne

• amphiphiles has been underexplored, generally due to technical difficulties in the synthesis and handling of such compounds [13]. Thus, a new method combining high-throughput synthesis and liquid-crystalline phase characterisation may open new territory in the field of amphiphile discovery. Furthermore

• was the first amphiphile library synthesised in this manner. In a follow-up study, this protocol was applied to produce amphiphiles with single-chained saturated, unsaturated, and branched tails with sugar head groups [30]. This library of amphiphiles was analysed by high-throughput synchrotron small

Molecular recognition of surface-immobilized carbohydrates by a synthetic lectin

• Melanie Rauschenberg,
• Eva-Corrina Fritz,
• Christian Schulz,
• Tobias Kaufmann and
• Bart Jan Ravoo

Beilstein J. Org. Chem. 2014, 10, 1354–1364, doi:10.3762/bjoc.10.138

• sequencing, automated synthesis and high-throughput microarray screening are lacking in glycobiology [5]. However, during the last decade, these methods have also been adapted to carbohydrates [6][7][8]. Carbohydrate microarrays on chips proved to be a particularly useful tool in glycomics [9][10][11] since

• their description in 2002 by several groups [12][13][14][15][16][17]. Microarrays normally consist of carbohydrates immobilized in an ordered and well defined format on a flat surface. The arrays can be considered as minimal models of cell surfaces that are compatible with high-throughput analysis

A one-pot synthesis of 3-trifluoromethyl-2-isoxazolines from trifluoromethyl aldoxime

• Raoni S. B. Gonçalves,
• Michael Dos Santos,
• Guillaume Bernadat,
• Danièle Bonnet-Delpon and
• Benoit Crousse

Beilstein J. Org. Chem. 2013, 9, 2387–2394, doi:10.3762/bjoc.9.275

• inhibitors [17][18][19][20][21]. Another powerful area, yet a somewhat less utilised role for fluorine is as a tag for 19F NMR that offers several analytical advantages including speed, sensitivity and selectivity [22][23]. Fluorinated molecules have served as valuable 19F NMR probes in high-throughput

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

• , combinatorial chemistry techniques have been used to generate large compound libraries in the hope that high-throughput screenings would identify new structures worthy of further development [21]. Unfortunately, these efforts have not resulted in a net increase in the number of new pyridine containing drug

Synthesis and characterization of novel bioactive 1,2,4-oxadiazole natural product analogs bearing the N-phenylmaleimide and N-phenylsuccinimide moieties

• Catalin V. Maftei,
• Elena Fodor,
• Peter G. Jones,
• M. Heiko Franz,
• Gerhard Kelter,
• Heiner Fiebig and
• Ion Neda

Beilstein J. Org. Chem. 2013, 9, 2202–2215, doi:10.3762/bjoc.9.259

• inducers represents an attractive approach for the discovery of new anticancer agents. 1,2,4-oxadiazole A (Figure 2) was found to act as an apoptosis agent by a high-throughput screening (HTS) assay [8]. A series of 1,2,4-oxadiazole-5-carboxamides B have been synthesized and tested as inhibitors of the

Flow synthesis of phenylserine using threonine aldolase immobilized on Eupergit support

• Jagdish D. Tibhe,
• Hui Fu,
• Timothy Noël,
• Qi Wang,
• Jan Meuldijk and
• Volker Hessel

Beilstein J. Org. Chem. 2013, 9, 2168–2179, doi:10.3762/bjoc.9.254

• scale [26]. Similarly these reactors can provide high throughput opportunities, reduced reaction time with high conversion efficiency and high productivity per unit reaction volume for biocatalysis in fine chemistry [27]. These advantages have been demonstrated for reactions such as hydrolysis and

Flow synthesis of a versatile fructosamine mimic and quenching studies of a fructose transport probe

• Matthew B. Plutschack,
• D. Tyler McQuade,
• Giulio Valenti and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2013, 9, 2022–2027, doi:10.3762/bjoc.9.238

• . Performing this step in flow enables a ~64-fold throughput enhancement relative to batch. The flow process enables the synthesis to be accomplished three times faster than the comparable batch route. The high throughput enabled the production of larger quantities of the fluorescent fructose transport probe

• groups present on 3. When 1 M solutions of sodium bicarbonate are used instead of saturated sodium bicarbonate, the resulting TLCs indicate the formation of more byproducts and the lower isolated yields of NBDM (<20%) also support this hypothesis. We are confident that a completely continuous high

• -throughput process to 3 could be realized with improvements in continuous extraction techniques. That being said, the semi-continuous approach we have defined here results in significant improvements compared to the original batch conditions. Many fluorophores and biologically relevant tags have been

Synthesis of mucin-type O-glycan probes as aminopropyl glycosides

• David Benito-Alifonso,
• Rachel A. Jones,
• Anh-Tuan Tran,
• Hannah Woodward,
• Nichola Smith and
• M. Carmen Galan

Beilstein J. Org. Chem. 2013, 9, 1867–1872, doi:10.3762/bjoc.9.218

• structural diversity and present a significant challenge for synthesis [7][8]. The efficient preparation of structurally defined oligosaccharide fragments of this class, in sufficient purity and amounts and ready to be immobilized into carbohydrate arrays for high-throughput biological analysis is crucial to

• compounds 1–7 were produced functionalized with an amine linker ready to be incorporated onto glycoarray platforms for high throughput biological screening [31]. Structure of mucin-type oligosaccharide fragments synthesized. Synthesis of glycan targets 2–4. Synthesis of disaccharide targets 5 and 6

ML212: A small-molecule probe for investigating fluconazole resistance mechanisms in Candida albicans

• Willmen Youngsaye,
• Cathy L. Hartland,
• Barbara J. Morgan,
• Amal Ting,
• Partha P. Nag,
• Benjamin Vincent,
• Carrie A. Mosher,
• Joshua A. Bittker,
• Sivaraman Dandapani,
• Michelle Palmer,
• Luke Whitesell,
• Susan Lindquist,
• Stuart L. Schreiber and
• Benito Munoz

Beilstein J. Org. Chem. 2013, 9, 1501–1507, doi:10.3762/bjoc.9.171

• frontline treatments. This, in turn, affords critical lead-time towards the development of novel antimicrobial drugs. The National Institutes of Health Molecular Libraries and Probe Production Centers Network (NIH-MLPCN) recently performed a high-throughput screening (HTS) campaign to search for potential

• against diverse mechanisms of fluconazole resistance, including biofilm formation, drug-target mutations, and efflux-pump amplification. Conclusion High-throughput screening of 300,000 compounds from the NIH’s MLSMR collection identified several substances that potentiate the effect of fluconazole in

Controlled synthesis of poly(3-hexylthiophene) in continuous flow

• Helga Seyler,
• Jegadesan Subbiah,
• David J. Jones,
• Andrew B. Holmes and
• Wallace W. H. Wong

Beilstein J. Org. Chem. 2013, 9, 1492–1500, doi:10.3762/bjoc.9.170

• ). As our current flow setup is limited by the size of the coil reactors, we anticipate that larger coil reactor volumes would ensure high-throughput production of high-molecular-weight P3HT in continuous flow. In our studies, stainless-steel tube reactors were also examined for the synthesis of P3HT

Enhancement of efficiency in organic photovoltaic devices containing self-complementary hydrogen-bonding domains

• Rohan J. Kumar,
• Jegadesan Subbiah and
• Andrew B. Holmes

Beilstein J. Org. Chem. 2013, 9, 1102–1110, doi:10.3762/bjoc.9.122

• a variety of solvents and the domain size controlled through the judicious choice of solvent. This will be advantageous for use in high-throughput production methods, ultimately lowering the cost and energy for the manufacture of organic photovoltaic devices. Conclusion A self-complementary hydrogen

Design and synthesis of tag-free photoprobes for the identification of the molecular target for CCG-1423, a novel inhibitor of the Rho/MKL1/SRF signaling pathway

• Jessica L. Bell,
• Andrew J. Haak,
• Susan M. Wade,
• Yihan Sun,
• Richard R. Neubig and
• Scott D. Larsen

Beilstein J. Org. Chem. 2013, 9, 966–973, doi:10.3762/bjoc.9.111

• that inhibit gene expression mediated by this Rho/MKL1/SRF signaling pathway [8]. The lead CCG-1423 (1, Figure 1) was identified in a cell-based high-throughput screen as an inhibitor of expression of a luciferase reporter gene driven by the serum response element promoter (SRE-Luc) [9]. Analysis of

Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway

• Paul M. Hershberger,
• Satyamaheshwar Peddibhotla,
• E. Hampton Sessions,
• Daniela B. Divlianska,
• Ricardo G. Correa,
• Anthony B. Pinkerton,
• John C. Reed and
• Gregory P. Roth

Beilstein J. Org. Chem. 2013, 9, 900–907, doi:10.3762/bjoc.9.103

• academic pilot-scale (MLSCN) screening effort for exploring potential new therapeutic targets stemming from the human genome project. After initial successes in high-throughput chemical screening (HTS), efforts in medicinal chemistry and exploratory pharmacology were added in order to leverage and advance

• . Importantly, none of the probes showed evidence of cytotoxicity in immortalized human hepatocyctes (Fa2N-4 cells) and in the NCI-60 cell line cytotoxicity panel with 10 and 50 μM test concentrations [36]. Conclusion The high-throughput screening of cell-based phenotypic and specific NOD1 protein-based assay

Utilizing the σ-complex stability for quantifying reactivity in nucleophilic substitution of aromatic fluorides

• Magnus Liljenberg,
• Tore Brinck,
• Tobias Rein and
• Mats Svensson

Beilstein J. Org. Chem. 2013, 9, 791–799, doi:10.3762/bjoc.9.90

• allowing a high throughput and robustness. The main interest, and also the original reason for this work, was to investigate whether it is possible to develop a predictive reactivity model that could combine high throughput with a quantitative or semiquantitative accuracy. Predictive reactivity models In

Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

• Allison S. Limpert,
• Margrith E. Mattmann and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2013, 9, 717–732, doi:10.3762/bjoc.9.82

• come from animal studies demonstrating that the reduction of SOD1 protein levels in motor neurons causes these cells to become resistant to ALS-induced cellular death [23]. In order to identify small molecules that downregulate the transcription of SOD1, Murakami et al. [24] developed a high-throughput

• reduce phosphorylation of the transcription factor Nrf2, a known activator of cellular stress genes as well as an upregulator of SOD1 transcription [24]. A similar high-throughput screen was performed by Wright et al. [25], who assayed 30,000 small molecules for SOD1 transcriptional repression by

• incubation with the selected compounds, the SOD1 G85R YFP cells were imaged using a high throughput fluorescent microscopy system and analyzed for the number of SOD1 aggregates per cell [28]. This screening strategy, combined with chemoinformatic methodologies used to cluster structurally similar compounds

From bead to flask: Synthesis of a complex β-amido-amide for probe-development studies

• Kevin S. Martin,
• Cristian Soldi,
• Kellan N. Candee,
• Hiromi I. Wettersten,
• Robert H. Weiss and
• Jared T. Shaw

Beilstein J. Org. Chem. 2013, 9, 260–264, doi:10.3762/bjoc.9.31

• step involves the use of a β-amino acid-forming three-component reaction (3CR), the scope of which defines its role in the synthetic strategy. Keywords: β-amino acid; benzimidazole; multicomponent reaction; Introduction Library syntheses and high-throughput screening can often be combined to enable

Asymmetric synthesis of host-directed inhibitors of myxoviruses

• Terry W. Moore,
• Kasinath Sana,
• Dan Yan,
• Pahk Thepchatri,
• John M. Ndungu,
• Manohar T. Saindane,
• Mark A. Lockwood,
• Michael G. Natchus,
• Dennis C. Liotta,
• Richard K. Plemper,
• James P. Snyder and
• Aiming Sun

Beilstein J. Org. Chem. 2013, 9, 197–203, doi:10.3762/bjoc.9.23

• University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA 10.3762/bjoc.9.23 Abstract High-throughput screening (HTS) previously identified benzimidazole 1 (JMN3-003) as a compound with broad antiviral activity against different influenza viruses and paramyxovirus strains. In pursuit of a lead

• principle, less susceptibility to the development of resistance. Using high-throughput screening, in combination with counter-screening for detecting a broadened viral target spectrum that extends to other pathogens of the myxovirus families, our research group has been successful in identifying small