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

Young Kwon Kim, Midori A. Arai, Takayoshi Arai, Julia O. Lamenzo, Elton F. Dean, Nick Patterson, Paul A. Clemons, Stuart L. Schreiber

Research output: Contribution to journalArticlepeer-review

127 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)14740-14745
Number of pages6
JournalJournal of the American Chemical Society
Issue number45
Publication statusPublished - 2004 Nov 17
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry


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