1. Synthesis and Discovery of Macrocyclic Polyoxygenated Bis-7-azaindolylmaleimides as a Novel Series of Potent and Highly Selective Glycogen Synthase Kinase-3β Inhibitors
- Author
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Kuo, G.-H., Prouty, C., DeAngelis, A., Shen, L., O'Neill, D. J., Shah, C., Connolly, P. J., Murray, W. V., Conway, B. R., Cheung, P., Westover, L., Xu, J. Z., Look, R. A., Demarest, K. T., Emanuel, S., Middleton, S. A., Jolliffe, L., Beavers, M. P., and Chen, X.
- Abstract
Attempts to design the macrocyclic maleimides as selective protein kinase C γ inhibitors led to the unexpected discovery of a novel series of potent and highly selective glycogen synthase kinase-3β (GSK-3β) inhibitors. Palladium-catalyzed cross-coupling reactions were used to synthesize the key intermediates
17 and22 that resulted in the synthesis of novel macrocycles. All three macrocyclic series (bisindolyl-, mixed 7-azaindoleindolyl-, and bis-7-azaindolylmaleimides) were found to have submicromolar inhibitory potency at GSK-3β with various degrees of selectivity toward other protein kinases. To gain the inhibitory potency at GSK-3β, the ring sizes of these macrocycles may play a major role. To achieve the selectivity at GSK-3β, the additional nitrogen atoms in the indole rings may contribute to a significant degree. Overall, the bis-7-azaindolylmaleimides28 and29 exhibited little or no inhibitions to a panel of 50 protein kinases. Compound29 almost behaved as a GSK-3β specific inhibitor. Both28 and29 displayed good potency in GS cell-based assay. Molecular docking studies were conducted in an attempt to rationalize the GSK-3β selectivity of azaindolylmaleimides.- Published
- 2003