ACS Combinatorial Science最新文献

{"title":"High-Throughput Experimentation and Continuous Flow Evaluation of Nucleophilic Aromatic Substitution Reactions","authors":"Zinia Jaman, David L. Logsdon, Botond Szilágyi, Tiago J. P. Sobreira, Deborah Aremu, Larisa Avramova, R. Graham Cooks*, David H. Thompson*","doi":"10.1021/acscombsci.9b00212","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00212","url":null,"abstract":"Nucleophilic aromatic substitution (SNAr) reactions were optimized using high-throughput experimentation techniques for execution under flow conditions. A total of 3072 unique reactions were evaluated with an analysis time of ∼3.5 s per reaction using a system that combines a liquid handling robot for reaction mixture preparation with desorption electrospray ionization (DESI) mass spectrometry (MS) for analysis. The reactions were performed in bulk microtiter arrays with and without incubation. In-house developed software was used to process the data and generate heat maps of the results. This information was then used to select the most promising conditions for continuous synthesis under microfluidic reactor conditions. Our results show that this HTE approach provides robust guidance for narrowing the range of conditions needed for optimization of SNAr reactions.","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00212","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"902546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Static Combinatorial Chemistry: A High-Pressure Approach to the Synthesis of Macrocyclic Benzoamide Libraries","authors":"Grzegorz Pikus,&nbsp;Agata Tyszka-Gumkowska,&nbsp;Janusz Jurczak*","doi":"10.1021/acscombsci.0c00024","DOIUrl":"https://doi.org/10.1021/acscombsci.0c00024","url":null,"abstract":"<p >We investigated the yield and distribution of macrocyclic products formed in combinatorial libraries (CLs) obtained via double-amidation reactions of methyl diesters with α,ω-diamines. The application of the static combinatorial chemistry (SCC) approach allowed us to generate a large number of macrocyclic diamides and tetraamides in single experiments. We show that high-pressure conditions accelerate the macrocyclization process but also have a great impact on the distribution of macrocyclic products in the presented libraries, promoting the formation of macrocyclic compounds and eliminating the linear ones. The distribution of macrocyclic products was also found to be strongly dependent on the structural features of the substrates employed. Furthermore, in three- and four-substrate CLs we observed the formation of a new type of hybrid tetraamides consisting of three different components.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.0c00024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"862491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-Throughput Synthesis and Screening of Rapidly Degrading Polyanhydride Nanoparticles","authors":"Adam S. Mullis,&nbsp;Sarah J. Jacobson,&nbsp;Balaji Narasimhan*","doi":"10.1021/acscombsci.9b00162","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00162","url":null,"abstract":"<p >Combinatorial techniques can accelerate the discovery and development of polymeric nanodelivery devices by pairing high-throughput synthesis with rapid materials characterization. Biodegradable polyanhydrides demonstrate tunable release, high cellular internalization, and dose sparing properties when used as nanodelivery devices. This nanoparticle platform shows promising potential for small molecule drug delivery, but the pace of understanding and rational design of these nanomedicines is limited by the low throughput of conventional characterization. This study reports the use of a high-throughput method to synthesize libraries of a newly synthesized, rapidly eroding polyanhydride copolymer based on 1,8-bis(<i>p</i>-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) and sebacic acid (SA) monomers. The high-throughput method enabled efficient screening of copolymer microstructure, revealing weak block-type and alternating architectures. The high-throughput method was adapted to synthesize nanoparticle libraries encapsulating hydrophobic model drugs. Drug release from these nanoparticles was rapid, with a majority of the payload released within 3 days. Drug release was dramatically slowed at acidic pH, which could be useful for oral drug delivery. Rhodamine B (RhoB) release kinetics generally followed patterns of polymer erosion kinetics, while Coomassie brilliant blue (CBB) released the fastest from the slowest degrading polymer chemistry and vice versa. These differences in trends between copolymer chemistry and release kinetics were hypothesized to arise from differences in mixing thermodynamics. A high-throughput method was developed to synthesize polymer–drug film libraries and characterize mixing thermodynamics by melting point depression. Rhodamine B had a negative χ for all copolymers with &lt;30 mol % CPTEG tested, indicating a tendency toward miscibility. By contrast, CBB χ increased, eventually becoming positive near 15:85 CPTEG:SA, with increasing CPTEG content. This indicates an increasing tendency toward phase separation in CPTEG-rich copolymers. These <i>in vitro</i> results screening polymer–drug interactions showed good agreement with <i>in silico</i> predictions from Hansen solubility parameter estimation and were able to explain the observed differences in model drug release trends.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00162","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"970857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined Spatially Resolved Characterization of Antireflection and Antisoiling Coatings for PV Module Glass","authors":"Stephanie L. Moffitt,&nbsp;Conor Riley,&nbsp;Benjamin H. Ellis,&nbsp;Robert A. Fleming,&nbsp;Corey S. Thompson,&nbsp;Patrick D. Burton,&nbsp;Margaret E. Gordon,&nbsp;Andriy Zakutayev,&nbsp;Laura T. Schelhas*","doi":"10.1021/acscombsci.9b00213","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00213","url":null,"abstract":"<p >Characterization of photovoltaic (PV) module materials throughout different stages of service life is crucial to understanding and improving the durability of these materials. Currently the large-scale of PV modules (&gt;1 m²) is imbalanced with the small-scale of most materials characterization tools (≤1 cm²). Furthermore, understanding degradation mechanisms often requires a combination of multiple characterization techniques. Here, we present adaptations of three standard materials characterization techniques to enable mapping characterization over moderate sample areas (≥25 cm²). Contact angle, ellipsometry, and UV–vis spectroscopy are each adapted and demonstrated on two representative samples: a commercial multifunctional coating for PV glass and an oxide combinatorial sample library. Best practices are discussed for adapting characterization techniques for large-area mapping and combining mapping information from multiple techniques.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00213","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"938681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Critical Evaluation of Photo-cross-linking Parameters for the Implementation of Efficient DNA-Encoded Chemical Library Selections","authors":"Alessandro Sannino,&nbsp;Adrián Gironda-Martínez,&nbsp;Émile M. D. Gorre,&nbsp;Luca Prati,&nbsp;Jacopo Piazzi,&nbsp;Jörg Scheuermann,&nbsp;Dario Neri*,&nbsp;Etienne J. Donckele*,&nbsp;Florent Samain*","doi":"10.1021/acscombsci.0c00023","DOIUrl":"https://doi.org/10.1021/acscombsci.0c00023","url":null,"abstract":"<p >The growing importance of DNA-encoded chemical libraries (DECLs) as tools for the discovery of protein binders has sparked an interest for the development of efficient screening methodologies, capable of discriminating between high- and medium-affinity ligands. Here, we present a systematic investigation of selection methodologies, featuring a library displayed on single-stranded DNA, which could be hybridized to a complementary oligonucleotide carrying a diazirine photoreactive group. Model experiments, performed using ligands of different affinity to carbonic anhydrase IX, revealed a recovery of preferential binders up to 10%, which was mainly limited by the highly reactive nature of carbene intermediates generated during the photo-cross-linking process. Ligands featuring acetazolamide or p-phenylsulfonamide exhibited a higher recovery compared to their counterparts based on 3-sulfamoyl benzoic acid, which had a lower affinity toward the target. A systematic evaluation of experimental parameters revealed conditions that were ideally suited for library screening, which were used for the screening of a combinatorial DECL library, featuring 669?240 combinations of two sets of building blocks. Compared to conventional affinity capture procedures on protein immobilized on solid supports, photo-cross-linking provided a better discrimination of low-affinity CAIX ligands over the background signal and therefore can be used as a tandem methodology with the affinity capture procedures.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.0c00023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"458446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thin-Film Microtensile-Test Structures for High-Throughput Characterization of Mechanical Properties","authors":"T. Oellers,&nbsp;V. G. Arigela,&nbsp;C. Kirchlechner,&nbsp;G. Dehm*,&nbsp;A. Ludwig*","doi":"10.1021/acscombsci.9b00182","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00182","url":null,"abstract":"A photolithographic process for the rapid fabrication of thin-film tensile-test structures is presented. The process is applicable to various physical vapor deposition techniques and can be used for the combinatorial fabrication of thin film tensile test structure materials libraries for the high throughput characterization of mechanical properties. The functionality of the fabrication process and the feasibility of performing high-quality measurements with these structures is demonstrated with Cu tensile-test structures. In addition, the scalability from unary structures to libraries with compositional variations is demonstrated.","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00182","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"426627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diversity-Oriented Library Synthesis from Steviol and Isosteviol-Derived Scaffolds","authors":"Trinh A. D. Holth,&nbsp;Michael A. Walters,&nbsp;Oliver E. Hutt,&nbsp;Gunda I. Georg*","doi":"10.1021/acscombsci.9b00186","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00186","url":null,"abstract":"<p >The readily available natural product stevioside provides a unique diterpene core structure that can be explored for small molecule library development by diversity-oriented synthesis and functional group transformations. Validation arrays were prepared from steviol, isosteviol, and related analogues, derived from stevioside, to produce over 90 compounds. These compounds were submitted to the NIH Molecular Libraries Small Molecule Repository for screening in the Molecular Libraries Screening Center Network. Micromolar hits were identified in multiple high-throughput assays for several library members. A cheminformatics analysis of the compounds was performed that verified the expected diversity and complexity of this set of compounds. The screening results indicate that scaffolds-derived natural products can provide screening hits against multiple target proteins.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"422801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design of an Automated Reagent-Dispensing System for Reaction Screening and Validation with DNA-Tagged Substrates","authors":"Jens Bobers,&nbsp;Mateja Klika Škopić,&nbsp;Robin Dinter,&nbsp;Piriyanth Sakthithasan,&nbsp;Laura Neukirch,&nbsp;Christian Gramse,&nbsp;Ralf Weberskirch,&nbsp;Andreas Brunschweiger*,&nbsp;Norbert Kockmann*","doi":"10.1021/acscombsci.9b00207","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00207","url":null,"abstract":"<p >Laboratory automation strategies have vast potential for accelerating discovery processes. They enable higher efficiency and throughput for time-consuming screening procedures and reduce error-prone manual steps. Automating repetitive procedures can for instance support chemists in optimizing chemical reactions. Particularly, the technology of DNA-encoded libraries (DELs) may benefit from automation techniques, since translation of chemical reactions to DNA-tagged reactants often requires screening of multiple reaction parameters and evaluation of large numbers of reactants. Here, we describe a portable, automated system for reagent dispensing that was designed from open source materials. The system was validated by performing amide coupling of carboxylic acids to DNA-linked amine and a micelle-mediated Povarov reaction to DNA-tagged hexahydropyrroloquinolines. The latter reaction required accurate pipetting of multiple components including different solvents and a surface-active reagent. Analysis of reactions demonstrated that the robotic system achieved high accuracy comparable to experimentation by an experienced chemist with the potential of higher throughput.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00207","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"411209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Palladium-Catalyzed Cascade Reactions of δ-Ketonitriles with Arylboronic Acids: Synthesis of Pyridines","authors":"Xinrong Yao,&nbsp;Linjun Qi,&nbsp;Renhao Li*,&nbsp;Qianqian Zhen,&nbsp;Jichao Liu,&nbsp;Zhiwei Zhao,&nbsp;Yinlin Shao,&nbsp;Maolin Hu*,&nbsp;Jiuxi Chen*","doi":"10.1021/acscombsci.9b00198","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00198","url":null,"abstract":"<p >This study presents the first example of the Pd-catalyzed cascade reactions of 5-oxohexanenitrile with arylboronic acids, affording important synthon 2-methylpyridines that can be further translated through C(sp³)-H functionalization to construct pyridine derivatives. Furthermore, this chemistry allows 5-oxo-5-arylpentanenitrile to react with arylboronic acids to provide unsymmetrical 2,6-diarylpyridines. This protocol paves the way for the practical and atom economical syntheses of valuable pyridines with broad functional groups in moderate to excellent yields under mild conditions.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00198","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"409626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Amphiphilic Polymer-Supported Strategy Enables Chemical Transformations under Anhydrous Conditions for DNA-Encoded Library Synthesis","authors":"Yves Ruff,&nbsp;Roberto Martinez,&nbsp;Xavier Pellé,&nbsp;Pierre Nimsgern,&nbsp;Pascale Fille,&nbsp;Maxim Ratnikov,&nbsp;Frédéric Berst*","doi":"10.1021/acscombsci.9b00164","DOIUrl":"https://doi.org/10.1021/acscombsci.9b00164","url":null,"abstract":"<p >The use of DNA-encoded libraries has emerged as a powerful hit generation technology. Combining the power of combinatorial chemistry to enumerate large compound collections with the efficiency of affinity selection in pools, the methodology makes it possible to interrogate vast chemical space against biological targets of pharmaceutical relevance. Thus, the chemical transformations employed for the synthesis of encoded libraries play a crucial role in the identification of diverse and drug-like starting points. Currently established transformations have mostly been limited to water-compatible reactions to accommodate the growing oligonucleotide tag. Herein, we describe the development of a practical catch-and-release methodology utilizing a cationic, amphiphilic PEG-based polymer to perform chemical transformations on immobilized DNA conjugates under anhydrous conditions. We demonstrate the usefulness of our APTAC (amphiphilic polymer-facilitated transformations under anhydrous conditions) approach by performing several challenging transformations on DNA-conjugated small molecules in pure organic solvents: the addition of a carbanion equivalent to a DNA-conjugated ketone in tetrahydrofuran, the synthesis of saturated heterocycles using the tin (Sn) amine protocol (SnAP) in dichloromethane, and the dual-catalytic (Ir/Ni) metallaphotoredox decarboxylative cross-coupling of carboxylic acids to DNA-conjugated aryl halides in DMSO. In addition, we demonstrate the feasibility of the latter in multititer-plate format.</p>","PeriodicalId":14,"journal":{"name":"ACS Combinatorial Science","volume":null,"pages":null},"PeriodicalIF":3.784,"publicationDate":"2020-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1021/acscombsci.9b00164","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"403074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}