| Relationship of stereochemical and skeletal diversity of small molecules to cellular measurement space. | |
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MedLine Citation:
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PMID: 15535697 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Systematic and quantitative measurements of the roles of stereochemistry and skeleton-dependent conformational restriction were made using multidimensional screening. We first used diversity-oriented synthesis to synthesize the same number (122) of [10.4.0] bicyclic products (B) and their corresponding monocyclic precursors (M). We measured the ability of these compounds to modulate a broad swath of biology using 40 parallel cell-based assays. We analyzed the results using statistical methods that revealed illuminating relationships between stereochemistry, ring number, and assay outcomes. Conformational restriction by ring-closing metathesis increased the specificity of responses among active compounds and was the dominant factor in global activity patterns. Hierarchical clustering also revealed that stereochemistry was a second dominant factor; whereas the stereochemistry of macrocyclic appendages was a determinant for bicyclic compounds, the stereochemistry of the carbohydrates was a determinant for the monocyclic compounds of global activity patterns. These studies illustrate a quantitative method for measuring stereochemical and skeletal diversity of small molecules and their cellular consequences. |
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Authors:
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Young-kwon Kim; Midori A Arai; Takayoshi Arai; Julia O Lamenzo; Elton F Dean; Nick Patterson; Paul A Clemons; Stuart L Schreiber |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of the American Chemical Society Volume: 126 ISSN: 0002-7863 ISO Abbreviation: J. Am. Chem. Soc. Publication Date: 2004 Nov |
Date Detail:
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Created Date: 2004-11-10 Completed Date: 2004-12-28 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 7503056 Medline TA: J Am Chem Soc Country: United States |
Other Details:
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Languages: eng Pagination: 14740-5 Citation Subset: IM |
Affiliation:
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Howard Hughes Medical Institute, Department of Chemistry and Chemical Biology, and The Eli and Edythe Broad Institute, Program in Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Bicyclo Compounds, Heterocyclic / chemical synthesis, chemistry*, pharmacology* Cluster Analysis Combinatorial Chemistry Techniques / methods DNA / biosynthesis, drug effects Drug Evaluation, Preclinical / methods* Esterases / metabolism Intracellular Membranes / drug effects, physiology Membrane Potentials / drug effects Mitochondria / drug effects, physiology Stereoisomerism Structure-Activity Relationship |
| Chemical | |
Reg. No./Substance:
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0/Bicyclo Compounds, Heterocyclic; 9007-49-2/DNA; EC 3.1.-/Esterases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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