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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 and 22 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-azaindolylmaleimides 28 and 29 exhibited little or no inhibitions to a panel of 50 protein kinases. Compound 29 almost behaved as a GSK-3β specific inhibitor. Both 28 and 29 displayed good potency in GS cell-based assay. Molecular docking studies were conducted in an attempt to rationalize the GSK-3β selectivity of azaindolylmaleimides.

No evidence was found for the presence of bis-chloromethyl ether (bis-CME) in the resin at the detection limit ∼10 ppb with use of the hollow fiber probe-mass spec-trometric technique. The kinetic data indicate that bis-CME hydrolyzes rapidly and, therefore, cannot exist in any extended period of time in the resin solution.