Parallel synthesis of indolylquinones and their cell-based insulin mimicry

A synthetic route to bis-indolyldihydroxybenzoquinones was adapted for parallel organic synthesis. The route involves selective conjugate addition of an indole to dichlorobenzoquinone promoted by Bronsted acid, followed by a Lewis acid-promoted conjugate addition of a second indole and a final hydrolysis. Methods for high-throughput purification of the products of this synthesis were also developed. Using these methods, we prepared a library whose structures are based on asterriquinone natural products, which have a wide range of biological activities. In this report, the activities of the library members in activation of the insulin receptor on mammalian cells were examined. Novel compounds were discovered that fall outside earlier developed structure-activity relationships for insulin mimics, supporting the value of systematic investigation (inspired by Nature) for the discovery of novel biologically active molecules.