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Relationship of stereochemical and skeletal diversity of small molecules to cellular measurement space.
|Publication Type||Journal Article|
|Authors||Kim, YK, Arai MA, Arai T., Lamenzo JO, Dean EF 3rd, Patterson N., Clemons PA, and Schreiber SL|
|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.|
|Year of Publication||2004|
|Journal||Journal of the American Chemical Society|
|Date Published (YYYY/MM/DD)||2004/11/17|