Synthesis and Preliminary Evaluation of a Library of Polycyclic Small Molecules for Use in Chemical Genetic Assays

Citations Over TimeTop 1% of 1999 papers

Abstract

(−)-Shikimic acid, 3, was converted into both enantiomers of epoxycyclohexenol carboxylic acid, 7, which were attached to a solid support via a photocleavable linker. Tandem acylation−1,3-dipolar cycloaddition with nitrones 11a−g yielded tetracyclic templates 12a−g. After development of several efficient coupling reactions of iodobenzyl tetracycles 12b−d and completion of extensive validation protocols, a split-pool synthesis yielded a binary encoded library calculated to contain 2.18 million polycyclic compounds. These compounds are compatible with miniaturized cell-based “forward” chemical genetic assays designed to explore biological pathways and “reverse” chemical genetic assays designed to explore protein function. As a simple illustration of the potential of these compounds, several were shown to activate a TGF-β-responsive reporter gene in mammalian cells.

Related Papers

• → PubChem Substance and Compound databases(2015)5,337 cited
• → Public Domain HTS Fingerprints: Design and Evaluation of Compound Bioactivity Profiles from PubChem’s Bioassay Repository(2016)67 cited
• → Investigating the correlations among the chemical structures, bioactivity profiles and molecular targets of small molecules(2010)29 cited
• → Similar compounds versus similar conformers: complementarity between PubChem 2-D and 3-D neighboring sets(2016)19 cited
• → Validity of PubChem compounds supplied by Patentscope or SureChEMBL(2022)6 cited