Synthesis and Cellular Profiling of Diverse Organosilicon Small Molecules

Small-molecule synthesis coupled with cellular profiling using multidimensional screening can be used to assess the impact of varying stereochemical and appendage contexts on biological activity. In this communication, we describe the synthesis and cellular profiling of chiral organosilicon small molecules derived from a crotylsilane annulation pathway. We considered that incorporating a main-group element, such as silicon, within the chiral environment of a more complex product could provide new structures where the distinctive chemical properties of silicon may contribute to new biological activity. The annulation of various indole-2,3-dione (isatin) reagents with functionalized crotylsilanes provides efficient access to spiro-oxindole structures for biological evaluation. The modular placement of aryl iodide functional groups in the isatin component can be used in appending processes for further substitution, such as conversion of the aryl iodide to various amido functionalities using the Buchwald amidation. The high-feature biological signatures revealed from multidimensional screening provide a first quantitative glimpse of the rich activities of silicon-containing small molecules within varying stereochemical and appendage contexts. Furthermore, these signatures demonstrate the validity of implementing functional group and stereochemical diversity (cf. differential performance of enantiomeric pairs of products).