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David R Liu - One of the best experts on this subject based on the ideXlab platform.
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Translation of DNA into a Library of 13 000 Synthetic Small-Molecule Macrocycles Suitable for in Vitro Selection
2015Co-Authors: Brian N Tse, Thomas M Snyder, Yinghua Shen, David R LiuAbstract:DNA-templated organic synthesis enables the translation, selection, and amplification of DNA sequences encoding synthetic small-molecule libraries. Previously we described the DNA-templated multistep synthesis and model in vitro selection of a pilot library of 65 Macrocycles. In this work, we report several key developments that enable the DNA-templated synthesis of much larger (>10 000-membered) small-molecule libraries. We developed and validated a capping-based approach to DNA-templated library synthesis that increases final product yields, simplifies the structure and preparation of reagents, and reduces the number of required manipulations. To expand the size and structural diversity of the Macrocycle library, we augmented the number of building blocks in each DNA-templated step from 4 to 12, selected 8 different starting scaffolds which result in 4 Macrocycle ring sizes and 2 building-block orientations, and confirmed the ability of the 36 building blocks and 8 scaffolds to generate DNA-templated Macrocycle products. We computationally generated and experimentally validated an expanded set of codons sufficient to support 1728 combinations of step 1, step 2, and step 3 building blocks. Finally, we developed new high-resolution LC/MS analysis methods to assess the quality of large DNA-templated small-molecule libraries. Integrating these four developments, we executed the translation of 13 824 DNA templates into their corresponding small-molecule Macrocycles. Analysis of the resulting libraries is consistent with excellent (>90%) representation of desired Macrocycle products and a stringent test of sequence specificity suggests a high degree of sequence fidelity during translation. The quality and structural diversity of this expanded DNA-templated library provides a rich starting point for the discovery of functional synthetic small-molecule Macrocycles
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in vitro selection of a dna templated small molecule library reveals a class of macrocyclic kinase inhibitors
Journal of the American Chemical Society, 2010Co-Authors: Ralph E Kleiner, Kaori Sakurai, Christoph E Dumelin, Gerald C Tiu, David R LiuAbstract:DNA-templated organic synthesis enables the translation of DNA sequences into synthetic small-molecule libraries suitable for in vitro selection. Previously, we described the DNA-templated multistep synthesis of a 13 824-membered small-molecule Macrocycle library. Here, we report the discovery of small molecules that modulate the activity of kinase enzymes through the in vitro selection of this DNA-templated small-molecule Macrocycle library against 36 biomedically relevant protein targets. DNA encoding selection survivors was amplified by PCR and identified by ultra-high-throughput DNA sequencing. Macrocycles corresponding to DNA sequences enriched upon selection against several protein kinases were synthesized on a multimilligram scale. In vitro assays revealed that these Macrocycles inhibit (or activate) the kinases against which they were selected with IC50 values as low as 680 nM. We characterized in depth a family of Macrocycles enriched upon selection against Src kinase, and showed that inhibition ...
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translation of dna into a library of 13 000 synthetic small molecule Macrocycles suitable for in vitro selection
Journal of the American Chemical Society, 2008Co-Authors: Brian N Tse, Thomas M Snyder, Yinghua Shen, David R LiuAbstract:DNA-templated organic synthesis enables the translation, selection, and amplification of DNA sequences encoding synthetic small-molecule libraries. Previously we described the DNA-templated multistep synthesis and model in vitro selection of a pilot library of 65 Macrocycles. In this work, we report several key developments that enable the DNA-templated synthesis of much larger (>10,000-membered) small-molecule libraries. We developed and validated a capping-based approach to DNA-templated library synthesis that increases final product yields, simplifies the structure and preparation of reagents, and reduces the number of required manipulations. To expand the size and structural diversity of the Macrocycle library, we augmented the number of building blocks in each DNA-templated step from 4 to 12, selected 8 different starting scaffolds which result in 4 Macrocycle ring sizes and 2 building-block orientations, and confirmed the ability of the 36 building blocks and 8 scaffolds to generate DNA-templated Macrocycle products. We computationally generated and experimentally validated an expanded set of codons sufficient to support 1728 combinations of step 1, step 2, and step 3 building blocks. Finally, we developed new high-resolution LC/MS analysis methods to assess the quality of large DNA-templated small-molecule libraries. Integrating these four developments, we executed the translation of 13,824 DNA templates into their corresponding small-molecule Macrocycles. Analysis of the resulting libraries is consistent with excellent (>90%) representation of desired Macrocycle products and a stringent test of sequence specificity suggests a high degree of sequence fidelity during translation. The quality and structural diversity of this expanded DNA-templated library provides a rich starting point for the discovery of functional synthetic small-molecule Macrocycles.
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dna templated organic synthesis and selection of a library of Macrocycles
Science, 2004Co-Authors: Zev J Gartner, Thomas M Snyder, Brian N Tse, Rozalina Grubina, Jeffrey B Doyon, David R LiuAbstract:The translation of nucleic acid libraries into corresponding synthetic compounds would enable selection and amplification principles to be applied to man-made molecules. We used multistep DNA-templated organic synthesis to translate libraries of DNA sequences, each containing three “codons,” into libraries of sequence-programmed synthetic small-molecule Macrocycles. The resulting DNA-Macrocycle conjugates were subjected to in vitro selections for protein affinity. The identity of a single Macrocycle possessing known target protein affinity was inferred through the sequence of the amplified DNA template surviving the selection. This work represents the translation, selection, and amplification of libraries of nucleic acids encoding synthetic small molecules rather than biological macromolecules.
Jeffrey S. Moore - One of the best experts on this subject based on the ideXlab platform.
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reaction pathways leading to arylene ethynylene Macrocycles via alkyne metathesis
Journal of the American Chemical Society, 2005Co-Authors: Wei Zhang, Jeffrey S. MooreAbstract:Mechanistic studies on the direct formation of arylene ethynylene Macrocycles via alkyne metathesis catalyzed by a molybdenum complex are reported. Gel permeation chromatography (GPC) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry on the products from metathesis of monomer 1 show the initial formation of linear oligomers and large Macrocycles (n > 6), followed by their transformation into the thermodynamically most stable product distribution-mainly the cyclic hexamer. Variable temperature and scrambling experiments reveal the reversibility of Macrocycle formation. Nearly identical product distributions are observed from the cross metathesis of hexacycle 2 with diphenylacetylene and from the metathesis of bis(phenylethynyl) substituted monomer 4, demonstrating that Macrocycle formation is thermodynamically rather than kinetically controlled. The metathesis byproduct, 3-hexyne, is shown to inhibit the catalyst. It is suggested that the relative metathesis rates of dialkylalkynes versus diarylalkynes trap the catalyst in a nonproductive manifold, rendering it unavailable for the productive metathesis of aryl alkylalkyne substrates. This finding indicates that dialkyl-substituted alkyne byproducts should be avoided (or efficiently removed) if the metatheses of aryl substrates, especially those with electron-withdrawing groups, are to proceed to high conversion.
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reaction pathways leading to arylene ethynylene Macrocycles via alkyne metathesis
Journal of the American Chemical Society, 2005Co-Authors: Wei Zhang, Jeffrey S. MooreAbstract:Mechanistic studies on the direct formation of arylene ethynylene Macrocycles via alkyne metathesis catalyzed by a molybdenum complex are reported. Gel permeation chromatography (GPC) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry on the products from metathesis of monomer 1 show the initial formation of linear oligomers and large Macrocycles (n > 6), followed by their transformation into the thermodynamically most stable product distributionmainly the cyclic hexamer. Variable temperature and scrambling experiments reveal the reversibility of Macrocycle formation. Nearly identical product distributions are observed from the cross metathesis of hexacycle 2 with diphenylacetylene and from the metathesis of bis(phenylethynyl) substituted monomer 4, demonstrating that Macrocycle formation is thermodynamically rather than kinetically controlled. The metathesis byproduct, 3-hexyne, is shown to inhibit the catalyst. It is suggested that the relative metathesis rates of dialkylalkynes v...
Floyd E. Romesberg - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Characterization of the Arylomycin Lipoglycopeptide Antibiotics and the Crystallographic Analysis of Their Complex with Signal Peptidase
2016Co-Authors: Jian Liu, Chuanyun Luo, Peter A. Smith, Jodie K. Chin, Malcolm G. P. Page, Mark Paetzel, Floyd E. RomesbergAbstract:Glycosylation of natural products, including antibiotics, often plays an important role in determining their physical properties and their biological activity, and thus their potential as drug candidates. The arylomycin class of antibiotics inhibits bacterial type I signal peptidase and is comprised of three related series of natural products with a lipopeptide tail attached to a core Macrocycle. Previously, we reported the total synthesis of several A series derivatives, which have unmodified core Macrocycles, as well as B series derivatives, which have a nitrated Macrocycle. We now report the synthesis and biological evaluation of lipoglycopeptide arylomycin variants whose Macrocycles are glycosylated with a deoxy-α-mannose substituent, and also in some cases hydroxylated. The synthesis of the derivatives bearing each possible deoxy-α-mannose enantiomer allowed us to assign the absolute stereochemistry of the sugar in the natural product and also to show that while glycosylation does not alter antibacterial activity, it does appear to improve solubility. Crystallographic structural studies of a lipoglycopeptide arylomycin bound to its signal peptidase target reveal the molecular interactions that underlie inhibition and also that the mannose is directed away from the binding site into solvent which suggests that other modifications may be made at the same position to further increase solubility and thus reduce protein binding and possibly optimize the pharmacokinetics of the scaffold
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Synthesis and characterization of the arylomycin lipoglycopeptide antibiotics and the crystallographic analysis of their complex with signal peptidase.
Journal of the American Chemical Society, 2011Co-Authors: Jian Liu, Chuanyun Luo, Peter A. Smith, Jodie K. Chin, Malcolm G. P. Page, Mark Paetzel, Floyd E. RomesbergAbstract:Glycosylation of natural products, including antibiotics, often plays an important role in determining their physical properties and their biological activity, and thus their potential as drug candidates. The arylomycin class of antibiotics inhibits bacterial type I signal peptidase and is comprised of three related series of natural products with a lipopeptide tail attached to a core Macrocycle. Previously, we reported the total synthesis of several A series derivatives, which have unmodified core Macrocycles, as well as B series derivatives, which have a nitrated Macrocycle. We now report the synthesis and biological evaluation of lipoglycopeptide arylomycin variants whose Macrocycles are glycosylated with a deoxy-α-mannose substituent, and also in some cases hydroxylated. The synthesis of the derivatives bearing each possible deoxy-α-mannose enantiomer allowed us to assign the absolute stereochemistry of the sugar in the natural product and also to show that while glycosylation does not alter antibacte...
Wei Zhang - One of the best experts on this subject based on the ideXlab platform.
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reaction pathways leading to arylene ethynylene Macrocycles via alkyne metathesis
Journal of the American Chemical Society, 2005Co-Authors: Wei Zhang, Jeffrey S. MooreAbstract:Mechanistic studies on the direct formation of arylene ethynylene Macrocycles via alkyne metathesis catalyzed by a molybdenum complex are reported. Gel permeation chromatography (GPC) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry on the products from metathesis of monomer 1 show the initial formation of linear oligomers and large Macrocycles (n > 6), followed by their transformation into the thermodynamically most stable product distribution-mainly the cyclic hexamer. Variable temperature and scrambling experiments reveal the reversibility of Macrocycle formation. Nearly identical product distributions are observed from the cross metathesis of hexacycle 2 with diphenylacetylene and from the metathesis of bis(phenylethynyl) substituted monomer 4, demonstrating that Macrocycle formation is thermodynamically rather than kinetically controlled. The metathesis byproduct, 3-hexyne, is shown to inhibit the catalyst. It is suggested that the relative metathesis rates of dialkylalkynes versus diarylalkynes trap the catalyst in a nonproductive manifold, rendering it unavailable for the productive metathesis of aryl alkylalkyne substrates. This finding indicates that dialkyl-substituted alkyne byproducts should be avoided (or efficiently removed) if the metatheses of aryl substrates, especially those with electron-withdrawing groups, are to proceed to high conversion.
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reaction pathways leading to arylene ethynylene Macrocycles via alkyne metathesis
Journal of the American Chemical Society, 2005Co-Authors: Wei Zhang, Jeffrey S. MooreAbstract:Mechanistic studies on the direct formation of arylene ethynylene Macrocycles via alkyne metathesis catalyzed by a molybdenum complex are reported. Gel permeation chromatography (GPC) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry on the products from metathesis of monomer 1 show the initial formation of linear oligomers and large Macrocycles (n > 6), followed by their transformation into the thermodynamically most stable product distributionmainly the cyclic hexamer. Variable temperature and scrambling experiments reveal the reversibility of Macrocycle formation. Nearly identical product distributions are observed from the cross metathesis of hexacycle 2 with diphenylacetylene and from the metathesis of bis(phenylethynyl) substituted monomer 4, demonstrating that Macrocycle formation is thermodynamically rather than kinetically controlled. The metathesis byproduct, 3-hexyne, is shown to inhibit the catalyst. It is suggested that the relative metathesis rates of dialkylalkynes v...
Brian N Tse - One of the best experts on this subject based on the ideXlab platform.
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Translation of DNA into a Library of 13 000 Synthetic Small-Molecule Macrocycles Suitable for in Vitro Selection
2015Co-Authors: Brian N Tse, Thomas M Snyder, Yinghua Shen, David R LiuAbstract:DNA-templated organic synthesis enables the translation, selection, and amplification of DNA sequences encoding synthetic small-molecule libraries. Previously we described the DNA-templated multistep synthesis and model in vitro selection of a pilot library of 65 Macrocycles. In this work, we report several key developments that enable the DNA-templated synthesis of much larger (>10 000-membered) small-molecule libraries. We developed and validated a capping-based approach to DNA-templated library synthesis that increases final product yields, simplifies the structure and preparation of reagents, and reduces the number of required manipulations. To expand the size and structural diversity of the Macrocycle library, we augmented the number of building blocks in each DNA-templated step from 4 to 12, selected 8 different starting scaffolds which result in 4 Macrocycle ring sizes and 2 building-block orientations, and confirmed the ability of the 36 building blocks and 8 scaffolds to generate DNA-templated Macrocycle products. We computationally generated and experimentally validated an expanded set of codons sufficient to support 1728 combinations of step 1, step 2, and step 3 building blocks. Finally, we developed new high-resolution LC/MS analysis methods to assess the quality of large DNA-templated small-molecule libraries. Integrating these four developments, we executed the translation of 13 824 DNA templates into their corresponding small-molecule Macrocycles. Analysis of the resulting libraries is consistent with excellent (>90%) representation of desired Macrocycle products and a stringent test of sequence specificity suggests a high degree of sequence fidelity during translation. The quality and structural diversity of this expanded DNA-templated library provides a rich starting point for the discovery of functional synthetic small-molecule Macrocycles
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translation of dna into a library of 13 000 synthetic small molecule Macrocycles suitable for in vitro selection
Journal of the American Chemical Society, 2008Co-Authors: Brian N Tse, Thomas M Snyder, Yinghua Shen, David R LiuAbstract:DNA-templated organic synthesis enables the translation, selection, and amplification of DNA sequences encoding synthetic small-molecule libraries. Previously we described the DNA-templated multistep synthesis and model in vitro selection of a pilot library of 65 Macrocycles. In this work, we report several key developments that enable the DNA-templated synthesis of much larger (>10,000-membered) small-molecule libraries. We developed and validated a capping-based approach to DNA-templated library synthesis that increases final product yields, simplifies the structure and preparation of reagents, and reduces the number of required manipulations. To expand the size and structural diversity of the Macrocycle library, we augmented the number of building blocks in each DNA-templated step from 4 to 12, selected 8 different starting scaffolds which result in 4 Macrocycle ring sizes and 2 building-block orientations, and confirmed the ability of the 36 building blocks and 8 scaffolds to generate DNA-templated Macrocycle products. We computationally generated and experimentally validated an expanded set of codons sufficient to support 1728 combinations of step 1, step 2, and step 3 building blocks. Finally, we developed new high-resolution LC/MS analysis methods to assess the quality of large DNA-templated small-molecule libraries. Integrating these four developments, we executed the translation of 13,824 DNA templates into their corresponding small-molecule Macrocycles. Analysis of the resulting libraries is consistent with excellent (>90%) representation of desired Macrocycle products and a stringent test of sequence specificity suggests a high degree of sequence fidelity during translation. The quality and structural diversity of this expanded DNA-templated library provides a rich starting point for the discovery of functional synthetic small-molecule Macrocycles.
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dna templated organic synthesis and selection of a library of Macrocycles
Science, 2004Co-Authors: Zev J Gartner, Thomas M Snyder, Brian N Tse, Rozalina Grubina, Jeffrey B Doyon, David R LiuAbstract:The translation of nucleic acid libraries into corresponding synthetic compounds would enable selection and amplification principles to be applied to man-made molecules. We used multistep DNA-templated organic synthesis to translate libraries of DNA sequences, each containing three “codons,” into libraries of sequence-programmed synthetic small-molecule Macrocycles. The resulting DNA-Macrocycle conjugates were subjected to in vitro selections for protein affinity. The identity of a single Macrocycle possessing known target protein affinity was inferred through the sequence of the amplified DNA template surviving the selection. This work represents the translation, selection, and amplification of libraries of nucleic acids encoding synthetic small molecules rather than biological macromolecules.
