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    624 results match your criteria ACS Combinatorial Science [Journal]

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    How Many Bulk Metallic Glasses Are There?
    ACS Comb Sci 2017 Sep 13. Epub 2017 Sep 13.
    Quantitative prediction of glass forming ability using a priori known parameters is highly desired in metallic glass development; however proven to be challenging due to the complexity of glass formation. Here we estimate the number of potential metallic glasses (MGs) and bulk metallic glasses (BMGs) forming systems and alloys, from empirically determined alloy design rules based on a priori known parameters. Specifically, we take into account atomic size ratio, heat of mixing, and liquidus temperature, which we quantify on binary glasses and centimeter-sized BMGs. Read More

    Library design-facilitated high-throughput sequencing of synthetic peptide libraries.
    ACS Comb Sci 2017 Sep 11. Epub 2017 Sep 11.
    A methodology to achieve high-throughput de novo sequencing of synthetic peptide mixtures is reported. The approach leverages shotgun nano-liquid chromatography coupled with tandem mass spectrometry-based de novo sequencing of library mixtures (up to 2000 peptides), as well as automated data analysis protocols to filter away incorrect assignments, noise and synthetic side-products. To increase the confidence in sequencing results, mass spectrometry-friendly library designs were developed, which enabled unambiguous decoding of up to 600 peptide sequences per hour while maintaining greater than 85% sequence identification rate in most cases. Read More

    Gold-Catalyzed Solid-Phase Synthesis of 3,4-Dihydropyrazin-2(1H)-ones: Relevant Pharmacophores and Peptide Backbone Constraints.
    ACS Comb Sci 2017 Sep 12. Epub 2017 Sep 12.
    Department of Organic Chemistry, Faculty of Science, Palacký University , 17. Listopadu 12, 771 46 Olomouc, Czech Republic.
    Here, we report the efficient solid-phase synthesis of N-propargyl peptides using Fmoc-amino acids and propargyl alcohol as key building blocks. Gold-catalyzed nucleophilic addition to the triple bond induced C-N bond formation, which triggered intramolecular cyclization, yielding 1,3,4-trisubstituted-5-methyl-3,4-dihydropyrazin-2(1H)-ones. Conformations of acyclic and constrained peptides were compared using a two-step conformer distribution analysis at the molecular mechanics level and density functional theory. Read More

    Array-Based Rational Design of Short Peptide Probe-Derived from an Anti-TNT Monoclonal Antibody.
    ACS Comb Sci 2017 Sep 8. Epub 2017 Sep 8.
    JST, ImPACT, Sanban-cho 5, Chiyoda-ku, Tokyo 102-0075, Japan.
    Complementarity-determining regions (CDRs) are sites on the variable chains of antibodies responsible for binding to specific antigens. In this study, a short peptide probe for recognition of 2,4,6-trinitrotoluene (TNT), was identified by testing sequences derived from the CDRs of an anti-TNT monoclonal antibody. The major TNT-binding site in this antibody was identified in the heavy chain CDR3 by antigen docking simulation and confirmed by an immunoassay using a spot-synthesis based peptide array comprising amino acid sequences of six CDRs in the variable region. Read More

    Polymer-Supported Stereoselective Synthesis of Benzoxazino[4,3-b][1,2,5]thiadiazepinone 6,6-dioxides.
    ACS Comb Sci 2017 Aug 31. Epub 2017 Aug 31.
    Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University , Hněvotínská 5, 779 00 Olomouc, Czech Republic.
    Herein, we report the stereoselective synthesis of trisubstituted benzoxazino[4,3-b][1,2,5]thiadiazepinone 6,6-dioxides from polymer-supported Fmoc-Ser(tBu)-OH and Fmoc-Thr(tBu)-OH. After the solid-phase synthesis of N-alkylated-N-sulfonylated intermediates using various 2-nitrobenzenesulfonyl chlorides and bromoketones, the target compounds were obtained via trifluoroacetic acid (TFA)-mediated cleavage from the resin, followed by cyclization of the diazepinone scaffold. Except for the threonine-based intermediates, the inclusion of triethylsilane (TES) in the cleavage cocktail yielded a specific configuration of the newly formed C(3) chiral center. Read More

    Oligonucleotide Hybridization Combined with Competitive Antibody Binding for the Truncation of a High-Affinity Aptamer.
    ACS Comb Sci 2017 Sep 5. Epub 2017 Sep 5.
    Division of Chemistry, Faculty of Science and Technology, Thammasat University , Pathumthani 12120, Thailand.
    Truncation can enhance the affinity of aptamers for their targets by limiting nonessential segments and therefore limiting the molecular degrees of freedom that must be overcome in the binding process. This study demonstrated a truncation protocol relying on competitive antibody binding and the hybridization of complementary oligonucleotides, using platelet derived growth factor BB (PDGF-BB) as the model target. On the basis of the immunoassay results, an initial long aptamer was truncated to a number of sequences with lengths of 36-40 nucleotides (nt). Read More

    Parallel Chemistry Approach to Identify Novel Nuclear Receptor Ligands Based on the GW0742 Scaffold.
    ACS Comb Sci 2017 Sep 5. Epub 2017 Sep 5.
    Department of Chemistry and Biochemistry, Milwaukee Institute for Drug Discovery, University of Wisconsin , Milwaukee, Wisconsin 53211, United States.
    We describe the parallel synthesis of novel analogs of GW0742, a peroxisome proliferator-activated receptor δ (PPARδ) agonist. For that purpose, modified reaction conditions were applied, such as a solid-phase palladium-catalyzed Suzuki coupling. In addition, tetrazole-based compounds were generated as a bioisostere for carboxylic acid-containing ligand GW0742. Read More

    1,3-Dipolar Cycloaddition Reactions for the Synthesis of Novel Oxindole Derivatives and Their Cytotoxic Properties.
    ACS Comb Sci 2017 Sep 7. Epub 2017 Sep 7.
    Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology Hyderabad 500 007, India.
    The multicomponent reaction between isatin, amino acid, but-2-ynedioates, and phenacyl bromide has been developed using microwave irradiation under catalyst and base-free conditions in aqueous medium. This synthetic protocol is useful for the synthesis of various functionalized spirooxindole derivatives. This MCR exhibits a broad substrate scope with excellent yields and shorter reaction time. Read More

    Machine Learning Using Combined Structural and Chemical Descriptors for Prediction of Methane Adsorption Performance of Metal Organic Frameworks (MOFs).
    ACS Comb Sci 2017 Sep 5. Epub 2017 Sep 5.
    Department of Chemical and Biomolecular Engineering, University of Connecticut , Storrs, Connecticut 06269, United States.
    Using molecular simulation for adsorbent screening is computationally expensive and thus prohibitive to materials discovery. Machine learning (ML) algorithms trained on fundamental material properties can potentially provide quick and accurate methods for screening purposes. Prior efforts have focused on structural descriptors for use with ML. Read More

    Shape Memory Micro- and Nanowire Libraries for the High-Throughput Investigation of Scaling Effects.
    ACS Comb Sci 2017 Sep 14;19(9):574-584. Epub 2017 Aug 14.
    Institute for Materials, Faculty of Mechanical Engineering, Ruhr-Universität Bochum , 44801 Bochum, Germany.
    The scaling behavior of Ti-Ni-Cu shape memory thin-film micro- and nanowires of different geometry is investigated with respect to its influence on the martensitic transformation properties. Two processes for the high-throughput fabrication of Ti-Ni-Cu micro- to nanoscale thin film wire libraries and the subsequent investigation of the transformation properties are reported. The libraries are fabricated with compositional and geometrical (wire width) variations to investigate the influence of these parameters on the transformation properties. Read More

    A Linker for the Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC6 Inhibitors.
    ACS Comb Sci 2017 Sep 6. Epub 2017 Sep 6.
    Department of Chemistry, Technical University of Denmark , DK-2800 Kongens Lyngby, Denmark.
    We herein present broadly useful, readily available and nonintegral hydroxylamine linkers for the routine solid-phase synthesis of hydroxamic acids. The developed protocols enable the efficient synthesis and release of a wide range of hydroxamic acids from various resins, relying on high control and flexibility with respect to reagents and synthetic processes. A trityl-based hydroxylamine linker was used to synthesize a library of peptide hydroxamic acids. Read More

    Fabrication of TiO2-Reduced Graphene Oxide Nanorod Composition Spreads Using Combinatorial Hydrothermal Synthesis and Their Photocatalytic and Photoelectrochemical Applications.
    ACS Comb Sci 2017 Sep 8;19(9):585-593. Epub 2017 Aug 8.
    Institute of Nanotechnology and Microsystems Engineering, National Cheng Kung University , No.1, University Road, Tainan City 70101, Taiwan.
    This study is the first to employ combinatorial hydrothermal synthesis and facile spin-coating technology to fabricate TiO2-reduced graphene oxide (rGO) nanorod composition spreads. The features of this study are (1) the development of a self-designed spin-coating wedge, (2) the systemic investigation of the structure-property relationship of the system, (3) the high-throughput screening of the optimal ratio from a wide range of compositions for photocatalytic and photoelectrochemical (PEC) applications, and (4) the effective coupling between the density gradient TiO2 nanorod array and the thickness gradient rGO. The formation of rGO in the fabricated TiO2-rGO sample was monitored through Fourier transform infrared spectrometry. Read More

    Fabrication of a New Lineage of Artificial Luciferases from Natural Luciferase Pools.
    ACS Comb Sci 2017 Sep 9;19(9):594-599. Epub 2017 Aug 9.
    Department of Applied Chemistry, Faculty of Science and Technology, Keio University , 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.
    The fabrication of artificial luciferases (ALucs) with unique optical properties has a fundamental impact on bioassays and molecular imaging. In this study, we developed a new lineage of ALucs with unique substrate preferences by extracting consensus amino acids from the alignment of 25 copepod luciferase sequences available in natural luciferase pools. The primary sequence was first created with a sequence logo generator resulting in a total of 11 sibling sequences. Read More

    Selection of Effective HTRA3 Activators Using Combinatorial Chemistry.
    ACS Comb Sci 2017 Sep 24;19(9):565-573. Epub 2017 Aug 24.
    Faculty of Chemistry, University of Gdansk , PL80952 Gdansk, Poland.
    Herein, we report selection, synthesis, and enzymatic evaluation of a peptidomimetic library able to increase proteolytic activity of HtrA3 (high temperature requirement A) protease. Iterative deconvolution in solution of synthesized modified pentapeptides yielded two potent HtrA3 activators acting in the micromolar range (HCOO-CH2O-C6H4-OCH2-CO-Tyr-Asn-Phe-His-Asn-OH and HCOO-CH2O-C6H4-OCH2-CO-Tyr-Asn-Phe-His-Glu-OH). Both compounds increased proteolysis of an artificial HtrA3 substrate over 40-fold in a selective manner. Read More

    An Efficient One-Pot Synthesis of Densely Functionalized Fused-Quinolines via Sequential Ugi4CC and Acid-Mediated Povarov-Type Reaction.
    ACS Comb Sci 2017 Sep 8;19(9):600-608. Epub 2017 Aug 8.
    Medicinal Chemistry & Biotechnology Division, CSIR-Indian Institute of Chemical Technology , Hyderabad-500 007, India.
    A divergent synthesis of fused-quinolines has been explored by performing Ugi four-component condensation and sulfuric acid promoted deprotection/Povarov-type reaction in one-pot. The process involves Ugi condensation of propiolic acids, aldehydes/ketones, aminoaldehyde acetals and isocyanides followed by sulfuric acid promoted deprotection and Povarov-type reaction with anilines in ethanol. This method enables straightforward access to the structurally diverse 2,3-dihydro-1H-pyrrolo[3,4-b]quinolin-1-ones (DHPQ), 3,4-dihydrobenzo[b][1,6]naphthyridin-1(2H)-ones (DHBN), and 2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinolin-1-ones (THAQ), starting from readily available starting materials. Read More

    High-Throughput Structural and Functional Characterization of the Thin Film Materials System Ni-Co-Al.
    ACS Comb Sci 2017 Aug 11. Epub 2017 Aug 11.
    Institute for Materials, Ruhr-Universität Bochum , 44780 Bochum, Germany.
    High-throughput methods were used to investigate a Ni-Co-Al thin film materials library, which is of interest for structural and functional applications (superalloys, shape memory alloys). X-ray diffraction (XRD) measurements were performed to identify the phase regions of the Ni-Co-Al system in its state after annealing at 600 °C. Optical, electrical, and magneto-optical measurements were performed to map functional properties and confirm XRD results. Read More

    Microwave-Assisted Synthesis of Diversely Substituted Quinoline-Based Dihydropyridopyrimidine and Dihydropyrazolopyridine Hybrids.
    ACS Comb Sci 2017 Aug 26;19(8):555-563. Epub 2017 Jul 26.
    Department of Inorganic and Organic Chemistry, Universidad de Jaén , 23071 Jaén, Spain.
    An efficient, catalyst-free, and one-pot three-component procedure for the synthesis of novel and nitrogen rich dihydropyrido[2,3-d]pyrimidines and dihydro-1H-pyrazolo[3,4-b]pyridines bearing a quinoline pharmacophore fragment is provided. Reactions proceeded in DMF under microwave irradiation of three-component mixtures of formyl-quinoline derivatives, primary heterocyclic amines and cyclic 1,3-diketones. Interestingly, when conventional heating at reflux was used for the starting 5-amino-1-phenylpyrazole, the corresponding aromatized pyrazolopyridines were obtained as the main products. Read More

    Bias-Free Chemically Diverse Test Sets from Machine Learning.
    ACS Comb Sci 2017 Aug 27;19(8):544-554. Epub 2017 Jul 27.
    Data61 CSIRO , Molecular & Materials Modelling, Door 34, Goods Shed, Village Street, Docklands, Victoria 3008, Australia.
    Current benchmarking methods in quantum chemistry rely on databases that are built using a chemist's intuition. It is not fully understood how diverse or representative these databases truly are. Multivariate statistical techniques like archetypal analysis and K-means clustering have previously been used to summarize large sets of nanoparticles however molecules are more diverse and not as easily characterized by descriptors. Read More

    Systematic First-Principles Study of Binary Metal Hydrides.
    ACS Comb Sci 2017 Aug 25;19(8):513-523. Epub 2017 Jul 25.
    Université Paris Est , ICMPE (UMR 7182), CNRS, UPEC, F-94320 Thiais, France.
    First-principles calculations were systematically performed for 31 binary metal-hydrogen (M-H) systems on a set of 30 potential crystal structures selected on the basis of experimental data and possible interstitial sites. For each M-H system, the calculated enthalpies of formation were represented as functions of H composition. The zero-point energy correction was considered for the most stable hydrides via additional harmonic phonon calculations. Read More

    Poisson Statistics of Combinatorial Library Sampling Predict False Discovery Rates of Screening.
    ACS Comb Sci 2017 Aug 26;19(8):524-532. Epub 2017 Jul 26.
    Department of Chemistry and †Doctoral Program in Chemical and Biological Sciences, The Scripps Research Institute , 130 Scripps Way, Jupiter, Florida 33458, United States.
    Microfluidic droplet-based screening of DNA-encoded one-bead-one-compound combinatorial libraries is a miniaturized, potentially widely distributable approach to small molecule discovery. In these screens, a microfluidic circuit distributes library beads into droplets of activity assay reagent, photochemically cleaves the compound from the bead, then incubates and sorts the droplets based on assay result for subsequent DNA sequencing-based hit compound structure elucidation. Pilot experimental studies revealed that Poisson statistics describe nearly all aspects of such screens, prompting the development of simulations to understand system behavior. Read More

    Identification of Biologically Active Pyrimido[5,4-b]indoles That Prolong NF-κB Activation without Intrinsic Activity.
    ACS Comb Sci 2017 Aug 13;19(8):533-543. Epub 2017 Jul 13.
    Moores UCSD Cancer Center, University of California San Diego , La Jolla, California 92093, United States.
    Most vaccine adjuvants directly stimulate and activate antigen presenting cells but do not sustain immunostimulation of these cells. A high throughput screening (HTS) strategy was designed to identify compounds that would sustain NF-κB activation by a stimulus from the Toll-like receptor (TLR)4 ligand, lipopolysaccharide (LPS). Several pilot studies optimized the parameters and conditions for a cell based NF-κB reporter assay in human monocytic THP-1 cells. Read More

    Modeling and Optimization of NLDH/PVDF Ultrafiltration Nanocomposite Membrane Using Artificial Neural Network-Genetic Algorithm Hybrid.
    ACS Comb Sci 2017 Jul 23;19(7):464-477. Epub 2017 Jun 23.
    Faculty of Chemistry, Kharazmi University , 15719-14911 Tehran, Iran.
    In this research, MgAl-CO3(2-) nanolayered double hydroxide (NLDH) was synthesized through a facile coprecipitation method, followed by a hydrothermal treatment. The prepared NLDHs were used as a hydrophilic nanofiller for improving the performance of the PVDF-based ultrafiltration membranes. The main objective of this research was to obtain the optimized formula of NLDH/PVDF nanocomposite membrane presenting the best performance using computational techniques as a cost-effective method. Read More

    "On-Water" Facile Synthesis of Novel Pyrazolo[3,4-b]pyridinones Possessing Anti-influenza Virus Activity.
    ACS Comb Sci 2017 Jul 23;19(7):437-446. Epub 2017 Jun 23.
    Guangdong Provincial Key Laboratory of New Drug Screening, Guangzhou Key Laboratory of Drug Research for Emerging Virus Prevention and Treatment, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou 510515, China.
    A facile and versatile "on-water" protocol for the synthesis of pyrazolo[3,4-b]pyridinones was developed by the unprecedented construction of two rings and five new bonds in one-pot. It was proved that water was an important promoter of the reaction and PEG2000 was found to improve the reaction in terms of yield. 32 Derivatives were newly synthesized and most of them were prepared in an hour. Read More

    High-Throughput Platform for Synthesis of Melamine-Formaldehyde Microcapsules.
    ACS Comb Sci 2017 Jul 15;19(7):447-454. Epub 2017 Jun 15.
    Polymer Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University , Krijgslaan 281 S4-bis, 9000 Ghent, Belgium.
    The synthesis of microcapsules via in situ polymerization is a labor-intensive and time-consuming process, where many composition and process factors affect the microcapsule formation and its morphology. Herein, we report a novel combinatorial technique for the preparation of melamine-formaldehyde microcapsules, using a custom-made and automated high-throughput platform (HTP). After performing validation experiments for ensuring the accuracy and reproducibility of the novel platform, a design of experiment study was performed. Read More

    Interplay Of Stereochemistry, Conformational Rigidity, And Ease Of Synthesis For 13-Membered Cyclic Peptidomimetics Containing APC Residues.
    ACS Comb Sci 2017 Jun 31;19(6):414-421. Epub 2017 May 31.
    Department of Chemistry, Texas A & M University , Box 30012, College Station, Texas 77842, United States.
    As part of a program to design small molecules that bind proteins, we require cyclic peptides (or peptidomimetics) that are severely constrained such that they adopt one predominant conformation in solution. This paper describes syntheses of the 13-membered cyclic tetrapeptides 1 containing aminopyrrolidine carboxyl (APC) residues. A linear precursor was prepared and used to determine optimal conditions for cyclization of that substrate. Read More

    "In Water": Organocatalyzed Diastereoselective Multicomponent Reactions toward 2-Azapyrrolizidine Alkaloid Scaffolds.
    ACS Comb Sci 2017 Jul 20;19(7):455-463. Epub 2017 Jun 20.
    Department of Chemistry, Pondicherry University , Puducherry 605 014, India.
    Synthesis of the 2-aza analogues of pyrrolizidine and spirooxindole-2-azapyrrolizidine hybrid, a spiro-tetracyclic scaffold possessing multiple contiguous stereocenters, by an exclusive regio-, chemo-, and diastereoselective multicomponent reaction in water is reported. This logical and didactical tactic has integrated the principles of an ideal organic synthesis, privileged substructure-based diversity-oriented synthesis, and biology-oriented synthesis to access hybrid heterocyclic scaffolds. Read More

    Synthesis and Screening of Phase Change Chalcogenide Thin Film Materials for Data Storage.
    ACS Comb Sci 2017 Jul 12;19(7):478-491. Epub 2017 Jun 12.
    Ilika Technologies, Kenneth Dibben House, University of Southampton Science Park , Chilworth, Southampton, SO16 7NS, United Kingdom.
    A combinatorial synthetic methodology based on evaporation sources under an ultrahigh vacuum has been used to directly synthesize compositional gradient thin film libraries of the amorphous phases of GeSbTe alloys at room temperature over a wide compositional range. An optical screen is described that allows rapid parallel mapping of the amorphous-to-crystalline phase transition temperature and optical contrast associated with the phase change on such libraries. The results are shown to be consistent with the literature for compositions where published data are available along the Sb2Te3-GeTe tie line. Read More

    Development of a High-Throughput Ion-Exchange Resin Characterization Workflow.
    ACS Comb Sci 2017 Jun 18;19(6):422-436. Epub 2017 May 18.
    Dow Water & Process Solutions , 1801 Larkin Center Drive, Midland, Michigan 48674, United States.
    A novel high-throughout (HTR) ion-exchange (IEX) resin workflow has been developed for characterizing ion exchange equilibrium of commercial and experimental IEX resins against a range of different applications where water environment differs from site to site. Because of its much higher throughput, design of experiment (DOE) methodology can be easily applied for studying the effects of multiple factors on resin performance. Two case studies will be presented to illustrate the efficacy of the combined HTR workflow and DOE method. Read More

    Diastereoselective Synthesis of Symmetrical and Unsymmetrical Tetrahydropyridines Catalyzed by Bi(III) Immobilized on Triazine Dendrimer Stabilized Magnetic Nanoparticles.
    ACS Comb Sci 2017 Jun 22;19(6):356-364. Epub 2017 May 22.
    Catalysis Division, Department of Chemistry, University of Isfahan , Isfahan 81746-73441, Iran.
    Unsymmetrical 1,2,5,6-tetrahydropyridine-3-carboxylates were obtained for the first time from a five-component Fe3O4@TDSN-Bi(III)-catalyzed reaction of aryl aldehydes, aryl amines, and ethyl acetoacetate. This magnetically separable catalyst enabled the selective incorporation of two different aryl amines or two different aryl aldehydes into the product, and provided excellent yields, short reaction times, mild reaction conditions, satisfactory catalyst recyclability, and low catalyst loading. Read More

    High-Throughput Investigation of a Lead-Free AlN-Based Piezoelectric Material, (Mg,Hf)xAl1-xN.
    ACS Comb Sci 2017 Jun 16;19(6):365-369. Epub 2017 May 16.
    Department of Robotics, Tohoku University , 980-8577 Sendai, Japan.
    We conducted a high-throughput investigation of the fundamental properties of (Mg,Hf)xAl1-xN thin films (0 < x < 0.24) aiming for developing high-performance AlN-based piezoelectric materials. For the high-throughput investigation, we prepared composition-gradient (Mg,Hf)xAl1-xN films grown on a Si(100) substrate at 600 °C by cosputtering AlN and MgHf targets. Read More

    On-the-Fly Data Assessment for High-Throughput X-ray Diffraction Measurements.
    ACS Comb Sci 2017 Jun 24;19(6):377-385. Epub 2017 May 24.
    Stanford Synchrotron Radiation Lightsource , SLAC National Accelerator Laboratory, Menlo Park, California 94025, United States.
    Investment in brighter sources and larger and faster detectors has accelerated the speed of data acquisition at national user facilities. The accelerated data acquisition offers many opportunities for the discovery of new materials, but it also presents a daunting challenge. The rate of data acquisition far exceeds the current speed of data quality assessment, resulting in less than optimal data and data coverage, which in extreme cases forces recollection of data. Read More

    Synthesis of Aminofuran-Linked Benzimidazoles and Cyanopyrrole-Fused Benzimidazoles by Condition-Based Skeletal Divergence.
    ACS Comb Sci 2017 Jul 3;19(7):492-499. Epub 2017 May 3.
    Department of Applied Chemistry, 1001 Ta-Hseuh Road, National Chiao-Tung University , Hsinchu 300-10, Taiwan.
    A condition-based skeletal divergent synthesis was explored to achieve skeletal diversity in two component condensation reaction. Cyanomethyl benzimidazole was reacted with α-bromoketone under thermal conditions to furnish 2-aminofuranyl-benzimidazoles, while the same reaction afforded 3-cyano-benzopyrrolo-imidazoles under microwave irradiation. Two nonequivalent nucleophilic centers on benzimidazole moiety were manipulated elegantly by different reaction conditions to achieve the skeletal diversity. Read More

    Assembly of Macrocycle Dye Derivatives into Particles for Fluorescence and Photoacoustic Applications.
    ACS Comb Sci 2017 Jun 15;19(6):397-406. Epub 2017 May 15.
    Department of Chemical and Biological Engineering, Princeton University , Princeton, New Jersey 08544, United States.
    Optical imaging is a rapidly progressing medical technique that can benefit from the development of new and improved optical imaging agents suitable for use in vivo. However, the molecular rules detailing what optical agents can be processed and encapsulated into in vivo presentable forms are not known. We here present the screening of series of highly hydrophobic porphyrin, phthalocyanine, and naphthalocyanine dye macrocycles through a self-assembling Flash NanoPrecipitation process to form a series of water dispersible dye nanoparticles (NPs). Read More

    Combinatorial Library Based on Restriction Enzyme-mediated Modular Assembly.
    ACS Comb Sci 2017 Jun 28;19(6):351-355. Epub 2017 Apr 28.
    College of Life Sciences, Qingdao University , Qingdao, 266071, P.R. China.
    Combinatorial approaches in directed evolution were proven to be more efficient for exploring sequence space and innovating function of protein. Here, we presented the modular assembly of secondary structures (MASS) for constructing a combinatorial library. In this approach, secondary structure elements were extracted from natural existing protein. Read More

    Speeding up Early Drug Discovery in Antiviral Research: A Fragment-Based in Silico Approach for the Design of Virtual Anti-Hepatitis C Leads.
    ACS Comb Sci 2017 Aug 1;19(8):501-512. Epub 2017 May 1.
    LAQV@REQUIMTE/Department of Chemistry and Biochemistry, University of Porto , 4169-007 Porto, Portugal.
    Hepatitis C constitutes an unresolved global health problem. This infectious disease is caused by the hepatotropic hepatitis C virus (HCV), and it can lead to the occurrence of life-threatening medical conditions, such as cirrhosis and liver cancer. Nowadays, major clinical concerns have arisen because of the appearance of multidrug resistance (MDR) and the side effects especially associated with long-term treatments. Read More

    One-Pot Synthesis of Densely Substituted Pyrazolo[3,4-b]-4,7-dihydropyridines.
    ACS Comb Sci 2017 May 18;19(5):279-285. Epub 2017 Apr 18.
    Center for Bioinformatics, Pondicherry University , Puducherry-605 014, India.
    We have achieved a facile synthesis of a combinatorial library of densely substituted pyrazolo[3,4-b]-4,7-dihydropyridines- the mimics of antigenital wart drug podophyllotoxin-from 5-aminopyrazoles and 4-(methylthio) 4H-chromenes. The C(4) pyrazolyl 4H-chromenes, which also possess structural features of podophyllotoxin, were isolable intermediates in the two-step, one-pot condensation. The condensation took place in a one-pot, multicomponent manner when 3-oxo-3-phenylpropanenitriles, hydrazine (precursors for 5-aminopyrazoles) and 4-(methylthio)-4H-chromenes were heated in refluxing ethanol. Read More

    Prescreening of Nicotine Hapten Linkers in Vitro To Select Hapten-Conjugate Vaccine Candidates for Pharmacokinetic Evaluation in Vivo.
    ACS Comb Sci 2017 May 17;19(5):286-298. Epub 2017 Apr 17.
    Minneapolis Medical Research Foundation , Minneapolis, Minnesota 55404, United States.
    Since the demonstration of nicotine vaccines as a possible therapeutic intervention for the effects of tobacco smoke, extensive effort has been made to enhance nicotine specific immunity. Linker modifications of nicotine haptens have been a focal point for improving the immunogenicity of nicotine, in which the evaluation of these modifications usually relies on in vivo animal models, such as mice, rats or nonhuman primates. Here, we present two in vitro screening strategies to estimate and predict the immunogenic potential of our newly designed nicotine haptens. Read More

    Combinatorial Library Screening with Liposomes for Discovery of Membrane Active Peptides.
    ACS Comb Sci 2017 May 13;19(5):299-307. Epub 2017 Apr 13.
    Department of Biochemistry and Molecular Medicine, University of California Davis , 2700 Stockton Boulevard, Sacramento, California 95817, United States.
    Membrane active peptides (MAPs) represent a class of short biomolecules that have shown great promise in facilitating intracellular delivery without disrupting cellular plasma membranes. Yet their clinical application has been stalled by numerous factors: off-target delivery, a requirement for high local concentration near cells of interest, degradation en route to the target site, and in the case of cell-penetrating peptides, eventual entrapment in endolysosomal compartments. The current method of deriving MAPs from naturally occurring proteins has restricted the discovery of new peptides that may overcome these limitations. Read More

    Combinatorial Synthesis of Acacen-Type Ligands and Their Coordination Compounds.
    ACS Comb Sci 2017 Jun 13;19(6):386-396. Epub 2017 Apr 13.
    Faculty of Chemistry and Chemical Technology, University of Ljubljana , Večna pot 113, SI-1000 Ljubljana, Slovenia.
    A highly modular synthetic method for the preparation of acacen-type ligands and their coordination compounds was developed. A series of 46 acacen-type ligands were synthesized by a combinatorial acid-catalyzed transamination between six primary diamines and eight enaminones. The bis-enaminone products were used as tetradentate ligands for coordination of copper(II), nickel(II), cobalt(II), and palladium(II). Read More

    A One-Pot Multicomponent 1,3-Dipolar Cycloaddition Strategy: Combinatorial Synthesis of Dihydrothiophenone-Engrafted Dispiro Hybrid Heterocycles.
    ACS Comb Sci 2017 May 11;19(5):308-314. Epub 2017 Apr 11.
    Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University , Madurai-625021, Tamil Nadu, India.
    The combinatorial syntheses of a library of novel dihydrothiophenone-engrafted dispiro oxindole/indenoquinoxaline-pyrrolidine/pyrrolothiazole/indolizine hybrid heterocycles have been realized through a chemo-, regio-, and stereoselective multicomponent 1,3-dipolar cycloaddition strategy. Read More

    High-Throughput Synthesis of Support Materials for Olefin Polymerization Catalyst.
    ACS Comb Sci 2017 May 13;19(5):331-342. Epub 2017 Apr 13.
    Graduate School of Advanced Science and Technology, Japan Advanced Institute of Science and Technology , 1-1 Asahidai, Nomi, Ishikawa 923-1292, Japan.
    Rational catalyst design necessitates fundamental knowledge on the structure-performance relationship, while the synthetic throughput for heterogeneous Ziegler-Natta olefin polymerization catalysts has long prevented the acquisition of a statistical database. In this contribution, an in-house reactor system was developed to realize the parallel synthesis of support materials for Ziegler-Natta catalysts for the first time. The developed system enabled parallel synthesis of 24 magnesium ethoxide samples with excellent reproducibility and morphological control comparable to a conventional experiment. Read More

    Titratable Avidity Reduction Enhances Affinity Discrimination in Mammalian Cellular Selections of Yeast-Displayed Ligands.
    ACS Comb Sci 2017 May 31;19(5):315-323. Epub 2017 Mar 31.
    Department of Chemical Engineering and Materials Science and ‡Department of Medicinal Chemistry, University of Minnesota-Twin Cities , Minneapolis, Minnesota 55455, United States.
    Yeast surface display selections against mammalian cell monolayers have proven effective in isolating proteins with novel binding activity. Recent advances in this technique allow for the recovery of clones with even micromolar binding affinities. However, no efficient method has been shown for affinity-based selection in this context. Read More

    Diversity-Oriented Synthesis of Libraries Based on Benzofuran and 2,3-Dihydrobenzofuran Scaffolds.
    ACS Comb Sci 2017 Jun 27;19(6):370-376. Epub 2017 Mar 27.
    Department of Chemistry, Umeå University , SE90187 Umeå, Sweden.
    Benzofuran and 2,3-dihydrobenzofuran scaffolds are core components in a large number of biologically active natural and synthetic compounds including approved drugs. Herein, we report efficient synthetic protocols for preparation of libraries based on 3-carboxy 2-aryl benzofuran and 3-carboxy 2-aryl trans-2,3-dihydrobenzofuran scaffolds using commercially available salicylaldehydes, aryl boronic acids or halides and primary or secondary amines. The building blocks were selected to achieve variation in physicochemical properties and statistical molecular design and subsequent synthesis resulted in 54 lead-like compounds with molecular weights of 299-421 and calculated octanol/water partition coefficients of 1. Read More

    Synthesis of 3,5-Disubstituted Isoxazoles Containing Privileged Substructures with a Diverse Display of Polar Surface Area.
    ACS Comb Sci 2017 Jun 23;19(6):407-413. Epub 2017 Mar 23.
    Department of Chemistry, CRI Center for Chemical Proteomics, Seoul National University , Seoul 08826, Korea.
    We designed and synthesized the molecular framework of 3,5-disubstituted isoxazoles containing privileged substructures with various substituents which uniquely display polar surface area in a diverse manner. A library of 3,5-disubstituted isoxazoles were systematically prepared via 1,3-dipolar cycloaddition of alkynes with nitrile oxides prepared by two complementary synthetic routes; method A utilized a halogenating agent with a base and method B utilized a hypervalent iodine reagent. Through the biological evaluation of corresponding isoxazoles via three independent phenotypic assays, the different pattern of biological activities was shown according to the type of privileged substructure and substituent. Read More

    Evaluating the Effect of Peptoid Lipophilicity on Antimicrobial Potency, Cytotoxicity, and Combinatorial Library Design.
    ACS Comb Sci 2017 Apr 16;19(4):229-233. Epub 2017 Mar 16.
    Middle Tennessee State University , Department of Chemistry, 1301 East Main Street, Murfreesboro, Tennessee 37132, United States.
    Growing prevalence of antibiotic resistant bacterial infections necessitates novel antimicrobials, which could be rapidly identified from combinatorial libraries. We report the use of the peptoid library agar diffusion (PLAD) assay to screen peptoid libraries against the ESKAPE pathogens, including the optimization of assay conditions for each pathogen. Work presented here focuses on the tailoring of combinatorial peptoid library design through a detailed study of how peptoid lipophilicity relates to antibacterial potency and mammalian cell toxicity. Read More

    Analysis of Current DNA Encoded Library Screening Data Indicates Higher False Negative Rates for Numerically Larger Libraries.
    ACS Comb Sci 2017 Apr 17;19(4):234-238. Epub 2017 Mar 17.
    Roche Pharmaceutical Research and Early Development (pRED) Roche Innovation Center Basel, F. Hoffmann-La Roche, Ltd. , Grenzacherstrasse 124 CH-4070 Basel, Switzerland.
    To optimize future DNA-encoded library design, we have attempted to quantify the library size at which the signal becomes undetectable. To accomplish this we (i) have calculated that percent yields of individual library members following a screen range from 0.002 to 1%, (ii) extrapolated that ∼1 million copies per library member are required at the outset of a screen, and (iii) from this extrapolation predict that false negative rates will begin to outweigh the benefit of increased diversity at library sizes >10(8). Read More

    Application of Pictet-Spengler Reaction to Indole-Based Alkaloids Containing Tetrahydro-β-carboline Scaffold in Combinatorial Chemistry.
    ACS Comb Sci 2017 Apr 17;19(4):199-228. Epub 2017 Mar 17.
    Department of Chemistry, School of Advanced Sciences, VIT University , Vellore-632014, India.
    Indole-based alkaloids are well-known in the literature for their diverse biological properties. Polysubstituted optically active tetrahydro-β-carboline derivatives functionalized on C-1 position are the common structural motif in most of the indole-based alkaloids, as well as highly marketed drugs. The stereoselective Pictet-Spengler reaction is one of the currently most important synthetic techniques used for the preparation of these privileged tetrahydro-β-carboline scaffolds. Read More

    Cellular Uptake Mechanism of Cationic Branched Polypeptides with Poly[l-Lys] Backbone.
    ACS Comb Sci 2017 Apr 9;19(4):246-254. Epub 2017 Mar 9.
    MTA-ELTE Research Group of Peptide Chemistry , Pázmány Péter st. 1/A, 1117 Budapest, Hungary.
    Cationic macromolecular carriers can be effective carriers for small molecular compounds, drugs, epitopes, or nucleic acids. Polylysine-based polymeric branched polypeptides have been systematically studied on the level of cells and organisms as well. In the present study, we report our findings on the cellular uptake characteristics of nine structurally related polylysine-based polypeptides with cationic side chains composed of (i) single amino acid (poly[Lys(Xi)], XiK) or (ii) oligo[dl-alanine] (poly[Lys(dl-Alam)], AK) or (iii) oligo[dl-alanine] with an additional amino acid (X) at the terminal position (poly[Lys(Xi-dl-Alam)] (XAK)) or (iv) at the position next to the polylysine backbone (poly[Lys(dl-Alam-Xi)] (AXK)). Read More

    Efficient Synthesis of Fused Oxazepino-isoquinoline Scaffolds via an Ugi, Followed by an Intramolecular Cyclization.
    ACS Comb Sci 2017 May 16;19(5):324-330. Epub 2017 Mar 16.
    Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences , 319 Honghe Avenue, Yongchuan, Chongqing 402160, China.
    A mild and efficient protocol was developed for the synthesis of oxazepino-isoquinolines via a one-pot Ugi four-component reaction, followed by the intramolecular addition of the resulting alcohol to an alkyne moiety under microwave irradiation conditions. Notably, this process only required one purification step, providing facile access to two series of complex and potentially interesting biologically active scaffolds. Read More

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