title: Relationship of stereochemical and skeletal diversity of small molecules to cellular measurement space.
abstract: 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.
authors.affiliation: 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.
authors.forename: Young-kwon
authors.initials: YK
authors.lastname: Kim
authors.forename: Midori A
authors.initials: MA
authors.lastname: Arai
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Arai
authors.forename: Julia O
authors.initials: JO
authors.lastname: Lamenzo
authors.forename: Elton F
authors.initials: EF
authors.lastname: Dean
authors.forename: Nick
authors.initials: N
authors.lastname: Patterson
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D016000:Cluster Analysis; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004950:Esterases / Q000378:metabolism; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D004247:DNA; D004950:Esterases