Synthesis and preliminary evaluation of a library of polycyclic small molecules for use in chemical genetic assays

(-)-Shikimic acid, 3, was converted into both enantiomers of epoxycyclohexe nol carboxylic acid, 7, which were attached to a solid support via a photoc leavable linker; Tandem acylation-1,3-dipolar cycloaddition with nitrones 1 1a-g yielded tetracyclic templates 12a-g. After development of several effi cient coupling reactions of iodobenzyl tetracycles 12b-d and completion of extensive validation protocols, a split-pool synthesis yielded a binary enc oded library calculated to contain 2.18 million polycyclic compounds. These compounds are compatible with miniaturized cell-based "forward" chemical g enetic assays designed to explore biological pathways and "reverse" chemica l genetic assays designed to explore protein function. As a simple illustra tion of the potential of these compounds, several were shown to activate a TGF-beta-responsive reporter gene in mammalian cells.