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This paper describes the automation of standard laboratory equipment, such as HPLC, mass spectrometry and NMR spectroscopy, to generate and analyze large natural product libraries for high-throughput screening. As a proof of principle, the authors generated a library of semi-pure fractions from extracts of the pacific yew tree and submitted them for screening in the National Cancer Society three-cell-line anti-cancer screen. They identified several known taxol derivatives as being bioactive and used microcoil flow-probe NMR spectroscopy to identify the structures from less than 0.05 mg material.
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Eldridge G.R., Vervoort H.C., Lee C.M., Cremin P.A., Williams C.T., Hart S.M., Goering M.G., O'Neil-Johnson M., Zeng L. High-throughput method for the production and analysis of large natural product libraries for drug discovery. Anal. Chem. 74:2002;3963-3971 This paper describes the automation of standard laboratory equipment, such as HPLC, mass spectrometry and NMR spectroscopy, to generate and analyze large natural product libraries for high-throughput screening. As a proof of principle, the authors generated a library of semi-pure fractions from extracts of the pacific yew tree and submitted them for screening in the National Cancer Society three-cell-line anti-cancer screen. They identified several known taxol derivatives as being bioactive and used microcoil flow-probe NMR spectroscopy to identify the structures from less than 0.05 mg material.
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The authors describe a method to culture hitherto uncultivatable microorganisms from marine sediment. They designed an apparatus to co-culture interdependent microbes using diffusion chambers to allow cross-feeding between strains.
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Kaeberlein T., Lewis K., Epstein S.S. Isolating 'uncultivable' microorganisms in pure culture in a simulated natural environment. Science. 296:2002;1127-1129 The authors describe a method to culture hitherto uncultivatable microorganisms from marine sediment. They designed an apparatus to co-culture interdependent microbes using diffusion chambers to allow cross-feeding between strains.
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Schreiber S.L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science. 287:2000;1964-1969.
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This report explores the use of tandem reaction sequences in the context of diversity-oriented synthesis. The authors use reaction pairs so that the product of one reaction becomes the substrate of the next; in this case, they coupled the Ugi 4-component condensation with an intramolecular Diels-Alder reaction, followed by ring-opening metathesis, to generate a complex polycyclic structure in a short reaction sequence.
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Lee D., Sello J.K., Schreiber S.L. Pairwise use of complexity-generating reactions in diversity-oriented organic synthesis. Org. Lett. 2:2000;709-712 This report explores the use of tandem reaction sequences in the context of diversity-oriented synthesis. The authors use reaction pairs so that the product of one reaction becomes the substrate of the next; in this case, they coupled the Ugi 4-component condensation with an intramolecular Diels-Alder reaction, followed by ring-opening metathesis, to generate a complex polycyclic structure in a short reaction sequence.
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Lee, D.1
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A strategy for macrocyclic ring closure and functionalization aimed toward split-pool syntheses
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Lee D., Sello J.K., Schreiber S.L. A strategy for macrocyclic ring closure and functionalization aimed toward split-pool syntheses. J. Am. Chem. Soc. 121:1999;10648-10649.
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Lee, D.1
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Lindsley C.W., Chan L.K., Goess B.C., Joseph R., Shair M.D. Solid-phase biomimetic synthesis of carpanone-like molecules. J. Am. Chem. Soc. 122:2000;422-423.
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Use of biomimetic diversity-oriented synthesis to discover galanthamine-like molecules with biological properties beyond those of the natural product
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These authors provide one of the first successful examples of the use of DOS in the context of a chemical genetics screen. They built a library of natural-product-like compounds using a biomimetic route and discovered a compound that has a unique effect on protein trafficking in mammalian cells.
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Pelish H.E., Westwood N.J., Feng Y., Kirchhausen T., Shair M.D. Use of biomimetic diversity-oriented synthesis to discover galanthamine-like molecules with biological properties beyond those of the natural product. J. Am. Chem. Soc. 123:2001;6740-6741 These authors provide one of the first successful examples of the use of DOS in the context of a chemical genetics screen. They built a library of natural-product-like compounds using a biomimetic route and discovered a compound that has a unique effect on protein trafficking in mammalian cells.
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Blackwell H.E., Perez L., Stavenger R.A., Tallarico J.A., Eatough E.C., Foley M.A., Schreiber S.L. A one-bead, one-stock solution approach to chemical genetics: part 1. Chem. Biol. 8:2001;1167-1182.
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23
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0033615357
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Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen
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Mayer T.U., Kapoor T.M., Haggarty S.J., King R.W., Schreiber S.L., Mitchison T.J. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science. 286:1999;971-974.
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Mayer, T.U.1
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Use of isogenic human cancer cells for high-throughput screening and drug discovery
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Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening
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Grozinger C.M., Chao E.D., Blackwell H.E., Moazed D., Schreiber S.L. Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J. Biol. Chem. 276:2001;38837-38843.
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26
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Peterson R.T., Link B.A., Dowling J.E., Schreiber S.L. Small molecule developmental screens reveal the logic and timing of vertebrate development. Proc. Natl. Acad. Sci. USA. 97:2000;12965-12969.
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0033579188
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Chemical genetic and genomic approaches reveal a role for copper in specific gene activation
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Stockwell B.R., Hardwick J.S., Tong J.K., Schreiber S.L. Chemical genetic and genomic approaches reveal a role for copper in specific gene activation. J. Am. Chem. Soc. 121:1999;10662-10663.
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Stockwell, B.R.1
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28
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0033080348
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High-throughput screening of small molecules in miniaturized mammalian cell-based assays involving post-translational modifications
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Stockwell B.R., Haggarty S.J., Schreiber S.L. High-throughput screening of small molecules in miniaturized mammalian cell-based assays involving post-translational modifications. Chem. Biol. 6:1999;71-83.
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0032582515
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Characterization and quantitation of NF-kappaB nuclear translocation induced by interleukin-1 and tumor necrosis factor-alpha. Development and use of a high capacity fluorescence cytometric system
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Ding G.J., Fischer P.A., Boltz R.C., Schmidt J.A., Colaianne J.J., Gough A., Rubin R.A., Miller D.K. Characterization and quantitation of NF-kappaB nuclear translocation induced by interleukin-1 and tumor necrosis factor-alpha. Development and use of a high capacity fluorescence cytometric system. J. Biol. Chem. 273:1998;28897-28905.
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0036669959
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This is an excellent and comprehensive review of the field of forward chemical genetics with particular emphasis on its application to problems in microbiology.
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Ward G.E., Carey K.L., Westwood N.J. Using small molecules to study big questions in cellular microbiology. Cell Microbiol. 4:2002;471-482 This is an excellent and comprehensive review of the field of forward chemical genetics with particular emphasis on its application to problems in microbiology.
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Identification of hNopp140 as a binding partner for doxorubicin with a phage display cloning method
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Byrd C.A., Bornmann W., Erdjument-Bromage H., Tempst P., Pavletich N., Rosen N., Nathan C.F., Ding A. Heat shock protein 90 mediates macrophage activation by Taxol and bacterial lipopolysaccharide. Proc. Natl. Acad. Sci. USA. 96:1999;5645-5650.
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Dhawan V., Swaffar D.S. A unique paclitaxel-mediated modulation of the catalytic activity of topoisomerase llalpha. Anticancer Drugs. 10:1999;397-404.
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Cyclosporine A is an uncompetitive inhibitor of proteasome activity and prevents NF-kappaB activation
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Dissecting glucose signalling with diversity-oriented synthesis and small-molecule microarrays
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Kuruvilla F.G., Shamji A.F., Sternson S.M., Hergenrother P.J., Schreiber S.L. Dissecting glucose signalling with diversity-oriented synthesis and small-molecule microarrays. Nature. 416:2002;653-657.
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Nature
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Kuruvilla, F.G.1
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GAL4-based yeast three-hybrid system for the identification of small molecule-target protein interactions
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Henthorn D.C., Jaxa-Chamiec A.A., Meldrum E.A. GAL4-based yeast three-hybrid system for the identification of small molecule-target protein interactions. Biochem. Pharmacol. 63:2002;1619-1628.
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40
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0034674919
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Small-molecule microarrays: Covalent attachment and screening of alcohol-containing small molecules on glass slides
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Hergenrother P.J., Depew K.M., Schreiber S.L. Small-molecule microarrays: covalent attachment and screening of alcohol-containing small molecules on glass slides. J. Am. Chem. Soc. 122:2000;7849-7850.
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Hergenrother, P.J.1
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0032879750
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Synthesis and preliminary evaluation of a library of polycyclic small molecules for use in chemical genetic assays
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Tan D.S., Foley M.A., Stockwell B.R., Shair M.D., Schreiber S.L. Synthesis and preliminary evaluation of a library of polycyclic small molecules for use in chemical genetic assays. J. Am. Chem. Soc. 121:1999;9073-9087.
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42
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0032569205
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Stereoselective synthesis of over two million compounds having structural features both reminiscent of natural products and compatible with miniaturized cell-based assays
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Tan D.S., Foley M.A., Shair M.D., Schreiber S.L. Stereoselective synthesis of over two million compounds having structural features both reminiscent of natural products and compatible with miniaturized cell-based assays. J. Am. Chem. Soc. 120:1998;8565-8566.
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Tan, D.S.1
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