Synthesis and Discovery of Macrocyclic Polyoxygenated Bis-7-azaindolylmaleimides as a Novel Series of Potent and Highly Selective Glycogen Synthase Kinase-3β Inhibitors

Abstract

Attempts to design the macrocyclic maleimides as selective protein kinase C gamma inhibitors led to the unexpected discovery of a novel series of potent and highly selective glycogen synthase kinase-3beta (GSK-3beta) 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-3beta with various degrees of selectivity toward other protein kinases. To gain the inhibitory potency at GSK-3beta, the ring sizes of these macrocycles may play a major role. To achieve the selectivity at GSK-3beta, 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-3beta 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-3beta selectivity of azaindolylmaleimides.

Regulation of Nanog Expression by Phosphoinositide 3-Kinase-dependent Signaling in Murine Embryonic Stem Cells

“…ES cells were cultured with LIF in the presence of either LY294002 alone or together with the MEK inhibitor U0126 or with either of two structurally distinct GSK-3 inhibitors BIO (17) or TD114-2 (compound 12 in Ref. 39). Inhibition of MEK/ERK signaling was unable to reverse the decrease in Nanog expression observed when PI3Ks were inhibited; see Fig.…”

Highly Potent and Specific GSK‐3β Inhibitors That Block Tau Phosphorylation and Decrease α‐Synuclein Protein Expression in a Cellular Model of Parkinson's Disease

“…Over the years, a variety of staurosporine analogues have been synthesized and optimized for the inhibition of several different kinase targets, including GSK-3b. [5][6][7][8][9] However, the SAR pat-…”

Generating pancreatic β-cells from embryonic stem cells by manipulating signaling pathways

“…A large number of GSK3 inhibitors have been reported. Examples include maleimides such as SB-216763 (Coghlan et al 2000) and bis-7-azaindolylmaleimide (Kuo et al 2003), indirubins such as indirubin-3 0 -monoxime (Leclerc et al 2001) and 6-bromoindirubin-3 0 -oxime (Meijer et al 2003), pyrazolopyrimidine and benzimidazole-pyrazolopyrimidine derivatives (Peat et al 2004a,b) as well as lithium ions (Stambolic et al 1996), AR-A014418 (Bhat et al 2003) and CHIR 98014 (Ring et al 2003). However, these are not specific to GSK3b and can also inhibit GSK3a and other kinases, so more specific Wnt inhibition may be achievable by targeting other pathway components.…”