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

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.