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Relationship of stereochemical and skeletal diversity of small molecules to cellular measurement space.

Publication TypeJournal Article
AuthorsKim, YK, Arai MA, Arai T., Lamenzo JO, Dean EF 3rd, Patterson N., Clemons PA, and Schreiber SL
AbstractSystematic 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 Publication2004
JournalJournal of the American Chemical Society
Volume126
Issue45
Pages14740-5
Date Published (YYYY/MM/DD)2004/11/17
ISSN Number0002-7863
DOI10.1021/ja048170p
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/15535697?dopt=Abstract