Bisindolyl Maleimides and Indolylmaleimide Derivatives-A Review of Their Synthesis and Bioactivity.

The evolution of bisindolyl maleimides and indolyl maleimide derivatives and their unique biological activities have stimulated great interest in medicinal chemistry programs. Bisindolylmaleimide (BIM)-type compounds arise from natural sources such as arcyriarubin and are biosynthetically related to indolocarbazoles. BIMs are commonly the immediate synthetic precursors of indolocarbazoles, lacking a central bond between the two aromatic units and making them more flexible and drug-like. Synthetic endeavours within this class of compounds are broad and have led to the development of both remarkably potent and selective protein kinase inhibitors. Clinical BIM examples include ruboxistaurin and enzastaurin, which are highly active inhibitors of protein kinase C-β. While BIMs are widely recognised as protein kinase inhibitors, other modes of activity have been reported, including the inhibition of calcium signalling and antimicrobial activity. Critically, structural differences can be used to exploit new bioactivity and therefore it is imperative to discover new chemical entities to address new targets. BIMs can be highly functionalised or chemically manipulated, which provides the opportunity to generate new derivatives with unique biological profiles. This review will collate new synthetic approaches to BIM-type compounds and their associated bioactivities with a focus on clinical applications.