Abstract
Laboratory Automation and High-Throughput Chemistry
An Efficient Laboratory Automation Concept for Process Chemistry
In a concept article C. Bernlind and C. Urbaniczky outline a successful strategy for rolling out an automation concept on a broad basis to AstraZe-neca Process R&D laboratories. Examples of hardware and software are presented as well as a couple of examples related to process safety (Org. Process Res. Dev.
An Efficient Synthesis of a Cyclic Ether Key Intermediate for 9-Membered Masked Enediyne Using an Automated Synthesizer
Naturally occurring antibiotics containing 9-membered enediynes have received considerable attention for many years due to their potent DNA-cleaving activity. Despite the importance of the 9-membered enediynes, application of these molecules is limited by their difficult synthesis. T. Takahashi et al., report an improved process for the generation of a synthetic, masked 9-membered enediyne that uses an automated synthesizer for the production of a key synthetic intermediate (Org. Process Res. Dev.
Solid-Phase Organic Synthesis of Difluoroalkyl Entities Using a Novel Fluorinating Cleavage Strategy: Part I. Linker Development: Scope and Limitations
An efficient method to synthesize gem-difluorinated compounds on solid support has been developed by S. Bräse et al. The strategy is based on the design of a novel sulfur linker system that enables the release of target structures from the resin under simultaneous fluorination. Starting from an immobilized dithiol, coupling with an excess of aldehyde or ketone furnished dithianes. These can be further functionalized before release from the resin using the newly developed fluorinating cleavage conditions. Amide-forming reactions, palladium-catalyzed reactions (Heck, Suzuki, and Sonogashira couplings), reductions, alkylations, and olefinations are successfully explored on the linker. The difluorinated target substances are obtained in modest to excellent yields and in high purities (J. Comb. Chem.
Solid-Phase Organic Synthesis of Difluoroalkyl Entities Using a Novel Fluorinating Cleavage Strategy: Part 2. Synthesis of Three Small Gem-Difluorinated Compound Libraries Using a Dithiane Linker
Three small compound biaryl libraries featuring a novel fluorinating cleavage strategy for preparation of a difluoromethyl group have been assembled by S. Bräse et al. on solid supports. The average reaction yield per step is up to 96% in a synthetic sequence over five to six steps. Key features are Suzuki coupling reactions, transesterification with potassium cyanide, and amidation reaction with trimethyl aluminum on solid supports (J. Comb. Chem.
Rapid Discovery of Triazolobenzylidene-Thiazolopyrimidines (TBTP) as CDC25 Phosphatase Inhibitors by Parallel Click Chemistry and In Situ Screening
R. Duval et al. highlight the relevance of click chemistry for the rapid discovery of novel CDC25 phosphatase inhibitors in a parallel manner. Rational design of inactive azide precursors and use of alkynes as pharmacomodulating elements lead to the generation of an 87-member triazole library with good to quantitative yields and high purities. This permits the direct biological screening of reaction mixtures for bioactive cycloadducts, thus efficiently shortcutting the standard drug-discovery approach. From this strategy, novel micromolar inhibitors with an unprecedented triazolobenzy-lidene-thiazolopyrimidine skeleton are identified (J. Comb. Chem.
Microfluidic Chip Technology and Micro Reactor Technology
High-Throughput Reaction Optimization and Activity Screening of Ferrocene-Based Lewis Acid-Catalyst Complexes by using Continuous-flow Reaction Detection Mass Spectrometry
Optimizing synthetic conversions and assessing catalyst performance is tedious work. Martha et al. (Chem. Eur. J.,
High-Throughput Analytics
Desorption Electrospray Ionization Tandem Mass Spectrometry for Detection of 24 Carcinogenic Aromatic Amines in Textiles
Textiles are often tinged with azo dyes, the most used group of synthetic dyestuff. Some compounds of azo dyes may generate carcinogenic aromatic amines if they come in contact with the human body, skin, or oral cavity. This can be very risky to the human health and the environment. Therefore, rapid analytical methods for detection of these carcinogenic aromatic amines are of increasing importance for inline quality monitoring in the textile industry. Yang et al. have developed a high-throughput able technique using desorption electrospray ionization tandem MS (DESI-MS) for nondestructive analysis of textiles (Anal. Chem.
Single-Step LC/MS Method for the Simultaneous Determination of GC-Amenable Organochlorine and LC-Amenable Phenoxy Acidic Pesticides
For monitoring pesticide residues in water and food samples, gas chromatography (GC) and liquid chromatography (LC) in combination with MS are the most widely used analytical techniques. Organochlorine pesticides (OCPs) are persistent and nonbiodegradable pollutants. They are mostly analyzed with GC/MS because they are nonpolar and easily volatile compounds. Another kind of environmental pollutants are phenoxy acids. These are polar and poorly volatile substances. Thus, they are mostly analyzed with LC coupled to atmospheric pressure ionization MS (LC/API-MS). The analysis of pollutants of both substance classes in the same sample and in one step is an analytical challenge. Faminglini et al. present a single-step trace-level analysis of OCPs together with pesticides belonging to the class of phenoxy acids in river water samples (Anal. Chem.
Effective sample enrichment for all target analytes is realized with an off-line solid-phase extraction protocol. The following analysis is performed by nanoscale LC coupled to a mass spectrometer with a direct electron ionization interface (LC/direct-EI-MS). As target compounds seven pesticides of the class of phenoxy acids and 12 OCPs are investigated. The results, especially the method limits of detection in the range of 0.002—0.052 μg/L, are in accordance with European Union legislative requirements for drinking water. The method allows a rapid, effective, and sensitive single-step technique for a simultaneous analysis of OCPs and phenoxy acidic pesticides by LC/direct-EI-MS in drinking water.
Bioautomation and Screening
Cancer and Virus Leads by HTS, Chemical Design, and SEA Data Mining
A variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, and to accelerate the development of drug candidates. The Emory Chemical and Biology Discovery Center (ECBDC) has been an active participant in the National Institutes of Health's high-throughput screening (HTS) endeavor to identify potent small molecule probes for poorly studied proteins. Several of Emory's projects relate to cancer or viral infection. A. Sun et al. report three successful examples, including discovery of potent measles virus RNA-dependent RNA polymerase inhibitors, development of heat-shock protein 90 blockers and identification of angiogenesis inhibitors using transgenic Zebrafish as a HTS model (Curr. Top. Med. Chem.
Small-Molecule Modulators of the NF-κB Pathway Newly Identified by a Translocation-Based Cellular Assay
Nuclear factor-kappa B (NF-κB) is an important transcription factor. Aberrant regulation of the NF-κB pathway is frequently observed in a number of major ailments, such as cancer and inflammatory diseases. Hence, NF-κB modulators have been intensely pursued for their potential therapeutic applications. Recently, a variety of structurally and functionally novel small molecules, identified through high-throughput screens conducted within the Molecular Libraries Screening Center Network (MLSCN) of the National Institutes of Health Roadmap for Medical Research, have been added to the current list of NF-κB regulators. S.-X. Deng et al. discuss in a review the inhibitors and activators newly discovered by Columbia's Molecular Libraries Screening Center (MLSC) using a well-designed and stable cellular assay (Curr. Top. Med. Chem.
The Pilot Phase of the NIH Chemical Genomics Center
The National Institutes of Health Chemical Genomics Center (NCGC) was the inaugural center of the MLSCN. Along with the nine other research centers of the MLSCN, the NCGC was established with a primary goal of bringing industrial technology and experience to empower the scientific community with small molecule compounds for research use. C. J. Thomas and C. P. Austin et al. introduce the NCGC standard operating procedures with an overview of several of the lessons learned during the pilot phase and a review of several of the innovative discoveries reported during the pilot phase of the MLSCN (Cur. Top. Med. Chem.
A Case Study From the Chemistry Core of the Pittsburgh Molecular Library Screening Center: The Polo-Like Kinase Polo-Box Domain (Plkl-PBD)
The Polo-like kinase (Plk) family comprises four cell cycle serine/threonine kinases, Plkl-4. Among these, Plkl has been most thoroughly characterized; it contains a conserved kinase domain and a C-terminal docking site for S/ T-phosphorylated proteins (polo-box domain, PBD). Plks are deregulated in oncogenesis and therefore constitute a therapeutic target for cancer. P. Wipf et al. report a HTS campaign by the Pittsburgh Molecular Library Screening Center (PMLSC) using a fluorescence polarization assay with recombinant Plkl-PBD to monitor the inhibition of binding of an optimal phosphopeptide substrate motif with recombinant Plkl-PBD. Screening of 97,090 small molecule library samples led to 11 confirmed hits. The Pittsburgh MLSCN Chemistry Core selects one of the most structurally tractable hits, SID 861574, for chemical hit-to-probe development. A broad chemistry program is initiated that develops new strategies for 6-amino- and 6-hydroxy uracil synthesis and acylanilides and generates a total of 70 analogs. Out of 46 analogs tested, none, nor the resynthesized hit, show affinity to Plkl-PBD in the follow-up assays. In contrast, reassays of the original screening materials display activities similar to the original HTS assay. The authors conclude that an impurity in the commercial material leads to the positive screening artifact. This case study not only highlights the development of a synthesis of 6-position functionalized uracil analogs but also illustrates the importance of careful quality and compound stability monitoring of screening collections (Curr. Top. Med. Chem.
The Identification, Characterization, and Optimization of Small Molecule Probes of Cysteine Proteases: Experiences of the Penn Center for Molecular Discovery with Cathepsin B and Cathepsin L
During the pilot phase of the National Institutes of Health Molecular Library Screening Network, the Penn Center for Molecular Discovery focused on a series of projects aimed at HTS and the development of probes of a variety of protease targets. D. M. Huryn and A. B. Smith discuss their medicinal chemistry experience with cathepsin B and cathepsin L. The authors describe their approach for hit validation and characterization that led to an understanding of the nature of hits from the cathepsin B project (Curr. Top. Med. Chem.
Discovery and Development of a Potent and Highly Selective Small Molecule Muscarinic Acetylcholine Receptor Subtype I (mAChR I or MI) Antagonist In Vitro and In Vivo Probe
C. W. Lindsley et al. describe the discovery and development of the first highly selective, small molecule antagonist of the muscarinic acetylcholine receptor subtype I (mAChR1 or Ml). An Ml functional, cell-based, calcium-mobilization assay identifies three distinct chemical series with initial selectivity for Ml versus M4. An iterative parallel synthesis approach is used to optimize all three series in parallel, which leads to the development of novel microwave-assisted chemistry (Curr. Top. Med. Chem.
Discovery of Selective Probes and Antagonists for G Protein-Coupled Receptors FPR/FPRLI and GPR30
Recent technological advances in flow cytometry provide a versatile platform for HTS of compound libraries coupled with high-content biological testing and drug discovery. The G protein-coupled receptors (GPCRs) constitute the largest class of signaling molecules in the human genome with frequent roles in disease pathogenesis, yet many examples of orphan receptors with unknown ligands remain. The complex biology and potential for drug discovery within this class provide strong incentives for chemical biology approaches seeking to develop small molecule probes to facilitate elucidation of mechanistic pathways and enable specific manipulation of the activity of individual receptors.
J. B. Arterburn et al. have initiated small molecule probe development projects targeting two distinct families of GPCRs: the formylpeptide receptors (FPR/FPRLI) and G protein-coupled estrogen receptor (GPR30). In each case, the assay for compound screening involves the development of an appropriate small molecule fluorescent probe, and the flow cytometry platform provides inherently biological rich assays that enhance the process of identification and optimization of novel antagonists. The contributions of cheminfor-matics analysis tools, virtual screening, and synthetic chemistry in synergy with the biomolecular screening program yield valuable new chemical probes with high binding affinity, selectivity for the targeted receptor, and potent antagonist activity (Curr. Top. Med. Chem.
Protein A-Based Antibody Immobilization Onto Polymeric Microdevices for Enhanced Sensitivity of Enzyme-Linked Immunosorbent Assay
The ELISA technique uses the high specificity of antibodies against their antigens in microtiter plate format and has therefore wide distribution in such different fields as medical diagnostics, environmental analyses, and biochemical studies. Nevertheless, ELISA analyses, which are usually performed in 96-well microtiter plates, also have drawbacks. In particular, the requirement of large quantities of partially expensive reagents and their complicated handling lead to the development of miniaturized alternatives. The application of polymer-based microfluidic devices with passive adsorption of the antibodies seems to be one of the most promising possibilities to circumvent the mentioned problems. The passive adsorption on solid surfaces can lead to dramatic losses of antibody reactivity. To overcome this problem, the authors present a novel approach for the development of a Protein A-based ELISA microdevice. As polymer of the chip, poly-(methyl methacrylate) is used, activated with oxygen plasma and then coated with poly(ethyleneimine), an amine-containing polymer. Protein A is treated with tyrosinase, converting specifically tyrosine/histidine residues into O-quinones, which are highly reactive toward primary amines. Final coupling of the antibody to Protein A leads to the development of a novel ELISA chip with different advantages. Due to the usage of protein A as a spacer molecule, the specificity and the sensitivity of the antibody can be significantly enhanced. Furthermore, these improvements lead to a wider linear detection range and shorter assay times compared with previously applied methods and also to classical ELISAs. Taken altogether, the presented approach offers great potential for improving the performance of microfluidic ELISA devices and other biosensor applications based on immunoassays (Biotechnol. Bioeng.
Automation Systems
The End of the Babylonian Confusion
Today, automated systems are using a wide range of sensors and actuators, these systems usually use many different analog and digital interfaces, such as analog current- and voltage-interfaces, digital interfaces, such as RS232, RS422, and so on. The parallel use of different interfaces is a very important cost factor. Thorsten Schroeder describes a modern new interface, the IO-Link. This IO-Link Interface realizes a point-to-point communication on the last few meters between actuators or sensors to a controller- or fieldbus-system. It is a manufacturer-independent standard and is supported globally by more than 30 manufacturers. The system complements existing network topologies and thus is not in competition with existing field buses and is easily integrated into well-established systems. The system consists of an IO-Link-Master with one or more ports. Only one IO-Link-Device can be connected to each port, and these links are always made by a simple standard 3-wire cable. Besides the possibility to join a “real” IO-Link sensors and actuators, there is also the possibility to connect traditional sensors, thus the possibility of a smooth migration (elektro Autom.
The Long Perspective for Robotic Vision
This article depicts the development of vision in providing high-end integration of robotic handling systems in production lines in the last 20 years. After a short look into history, where vision systems were bulky, slow, costly, low in quality and performance (e.g., resolution and speed), and laborious to integrate (required careful lighting set-ups), it is stated that nowadays reliability, lower acquisition costs, and better advances in calibration and deployment has led to a wide spreading of vision systems. 1D applications are mainly used for object detection to select or reject a product, whereas 2D systems are seen as the next step toward vision in the human sense because they capture product images. Besides orientation and position recognition for an extending quality inspection and fault detection, 2D cameras allow for a variety of high-speed (120 cycle/min) pick and place solutions in medium- and high-volume production environments. However, the application of these technologies is restricted by the missing third dimension, which avoids for instance picking of piled parts and complex shapes or the severe differentiation between reflecting or inconspicuous objects and their backgrounds.
To overcome these hurdles, 3D stereoscopic vision is introduced first in this article. The quite complex and time consuming calibration and the necessity of a bespoke lighting solution are named as reasons for the application of a second technique based on laser triangulation. To build up a true 3D image, this technology requires the movement of either the object or the camera. If this is not feasible, a new 3D technology has to be applied and is introduced by the author. The so-called 3D area scan devices emit an array of laser (or similar) spots and analyze the reflected information. Because advanced technologies are always more expensive, it is stressed several times that manufacturers should look carefully at their requirements and how they can appropriately be achieved before committing themselves to one of the displayed vision systems. A modular approach by RTS Flexible Systems is introduced in this respect. The remainder of the article deals with the general advantages of vision technologies in automation lines compared with manual testing. The continuous defection detection instead of examining representative samples and the possibility to communicate the gathered information back down the line as a feedback to ensure production parameter adjustment if necessary are two considerable features.
The author ends with a demand. To take full advantage of the benefits of vision systems, system integrators and manufacturers should work together to make industries aware of possible solutions and optimize system development through application orientation (Assemb Autom.
Information Technology and Systems
Supporting Exploration Awareness in Information Visualization
When users want to continue an analysis performed in the past, done by themselves or by a collaborator, they need an overview of what has been done and found so far. Such an overview helps them gain a shared knowledge about each others’ analysis strategies and continue the analysis. The authors aim to support users in this process, and thereby support their exploration awareness. For this purpose, the article presents an information visualization framework with three linked processes: overview, search, and retrieve. The overview is a visual representation of the structure and key aspects of the exploration process. The search process covers keyword and similarity-based visualization retrieval mechanisms. Retrieve is a visual representation that provides an overview of the search results and helps users retrieve specific visualizations from the analysis.
First, a user's information interest model that captures key aspects of the exploration process is presented. The proposed model has three levels based on the users’ specification with data transformations (which data set must be shown) and visualization transformations (how it must be shown) to a visualization system through exploration actions. The authors select four aspects to describe exploration: visualization and data transformations, data dimensions specified through these, viewed objects (medium-interest objects), and selected objects (high-interest objects).
Exploration overview and keyword- and similarity-based search mechanisms are designed based on the key aspects of the information interest model. Users can get an overview of an exploration in two ways. The structure overview emphasizes the process and the key-aspect overview emphasizes the content. Users can perform keyword searches on all text that plays a role in visualization and data transformation, data aspects, and viewed and selected objects. The keywords are highlighted in the key-aspects overview as history. A further option is the search of similar states. The key aspects of one visualization state are compared with those of another. The similarity between states can be expressed in a single number. One common way to visualize similarity search results is through the ranked-list view. A metadata view is used to visualize the search results and help users to retrieve specific visualizations from past analysis. Finally, three case studies are presented and the support offered by the framework for developing exploration awareness is discussed. These case studies show that the key-aspects of overview and search mechanisms play a critical role in supporting exploration awareness during asynchronous collaboration. The key aspects overview most helps the analysts understand their collaborators’ analysis strategies (IEEE Comput. Graph. Appl.
The Micro Guide to Process Modeling in BPMN
To check the relevance of modern methods of business process modeling for applications in projects of life science automation, this book gives numerous real world scenarios to introduce BPM notation. Over 50 implementations in 2008 demonstrate how Business Process Modeling Notation (BPMN) is an important and successful standard of the Object Management Group (OMG). The book starts with BPMN background information, master definitions, BPMN concepts, and process archetypes. All BPMN shapes of the actual standardization process are discussed in examples of practice, which are easy to understand and to translate into other fields of application. The compact book is helpful in parsing informal business conversation into a formal BPMN of activities, events, and flow control structure elements. In separate chapters workflow descriptions cover short time frames (typically in SMEs) as well as relatively longer time frames and examples of many workflow patterns (TIPS Technical Publishing, Inc. Tom Debevoise,
Opportunities and Constraints: The Current Struggle with BPMN
The latest representative from process modeling languages is the Business Process Modeling Notation (BPMN), which was developed by an industrial consortium (www.bpmi.org). A lot of BPM software tools are available from a lot of IT solution vendors. The Workflow Management Group (www.wfmc.org) has revised its developments into the direction of BPMN in 2008, so the importance of the BPMN standard for multi branches application increased in the last year. The article considers three aspects of research, the capabilities and deficiencies of BPMN for process modeling practice, the factors of user acceptance of BPMN, and the question of how BPMN is used in practice. The article summarizes statistical information from more as 500 usable responses of BPMN modelers from all over the world. Based on the statistical material the top ten most popular software tools for business modeling in BPMN are listed as well as the most popular tool functionality. The article gives information about user problems with BMPM and actual challenges of improvements. This provides important support for preparing decisions and investigation of modern methods of business process management independent of branches of the applicants (Business Process Management Journal,