Novel bis(indolyl)maleimide pyridinophanes that are potent, selective inhibitors of glycogen synthase kinase-3

Novel bis(indolyl)maleimide pyridinophanes 3, 9a, 9b, 10a, 10b, and 11 were prepared by cobalt-mediated [2+2+2] cycloaddition of an appropriate α,ω-diyne with an N,N-dialkylcyanamide. These macrocyclic heterophanes were found to be potent, selective inhibitors of glycogen synthase kinase-3β. An X-ray structure of a co-crystal of GSK-3β and 3 (IC50 = 3 nM) depicts the hydrogen bonding and hydrophobic interactions in the ATP-binding pocket of this serine/threonine protein kinase.

Graphical abstractBis(indolyl)maleimide pyridinophanes (‘multiheterophane’), from cobalt-mediated[2+2+2] cycloaddition, were found to be potent, selective inhibitors of GSK-3β. An X-ray structure of a co-crystal with GSK-3β is reported.Figure optionsDownload full-size imageDownload as PowerPoint slide