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

2007; Elsevier BV; Volume: 17; Issue: 10 Linguagem: Inglês

10.1016/j.bmcl.2007.02.059

1464-3405

Han‐Cheng Zhang, Llorente V. R. Boñaga, Hong Ye, Claudia K. Derian, Bruce P. Damiano, Bruce E. Maryanoff,

Synthesis of Organic Compounds

Novel bis(indolyl)maleimide pyridinophanes 3, 9a, 9b, 10a, 10b, and 11 were prepared by cobalt-mediated [2+2+2] cycloaddition of an appropriate alpha,omega-diyne with an N,N-dialkylcyanamide. These macrocyclic heterophanes were found to be potent, selective inhibitors of glycogen synthase kinase-3beta. An X-ray structure of a co-crystal of GSK-3beta and 3 (IC(50)=3nM) depicts the hydrogen bonding and hydrophobic interactions in the ATP-binding pocket of this serine/threonine protein kinase.