Synthesis and biological evaluation of novel macrocyclic bis-7-azaindolylmaleimides as potent and highly selective glycogen synthase kinase-3β (GSK-3β) inhibitors☆

Abstract Palladium catalyzed cross-coupling reactions were used to synthesize two key intermediates 3 and 5 that resulted in the synthesis of novel series of macrocyclic bis-7-azaindolylmaleimides. Among the three series of macrocycles, the oxygen atom and thiophene containing linkers yielded molecules with higher inhibitory potency at GSK-3β ( K i =0.011–0.079 μM) while the nitrogen atom containing linkers yielded molecules with lower potency ( K i =0.150–>1 μM). Compound 33 and 36 displayed 1–2 orders of magnitude selectivity at GSK-3β against CDK2, PKCβII, Rsk3 and little or no inhibitions to the other 62 protein kinases. Compound 46 was at least 100-fold more selective towards GSK-3β than PKCβII, and it had little or no activity against a panel of 65 protein kinases, almost behaved as a GSK-3β ‘specific inhibitor’. All three compounds showed good potency in GS assay. Molecular docking studies were conducted in an attempt to rationalize the GSK-3β selectivity of azaindolylmaleimides. The high selectivity, inhibitory potency and cellular activities of these non-crown-ether typed molecules may provide them as a valuable pharmacological tools in elucidating the complex roles of GSK-3β in cell signaling pathways and the potential usage for the treatment of elevated level of GSK-3β involved diseases.