9-Cyano-1-azapaullone (Cazpaullone), a Glycogen Synthase Kinase-3 (GSK-3) Inhibitor Activating Pancreatic β Cell Protection and Replication

Abstract

Recently, the serine/threonine kinase glycogen synthase kinase-3 (GSK-3) emerged as a regulator of pancreatic beta cell growth and survival. On the basis of the previous observation that GSK-3 inhibitors like 1-azakenpaullone promote beta cell protection and replication, paullone derivatives were synthesized including 1-aza-, 2-aza-, and 12-oxapaullone scaffolds. In enzymatic assays distinct 1-azapaullones were found to exhibit selective GSK-3 inhibitory activity. Within the series of 1-azapaullones, three derivatives stimulated INS-1E beta cell replication and protected INS-1E cells against glucolipotoxicity induced cell death. Cazpaullone (9-cyano-1-azapaullone), the most active compound in the protection assays, also stimulated the replication of primary beta cells in isolated rat islets. Furthermore, cazpaullone showed a pronounced transient stimulation of the mRNA expression of the beta cell transcription factor Pax4, an important regulator of beta cell development and growth. These features distinguish cazpaullone as a unique starting point for the development of beta cell regenerative agents which might be useful in the treatment of diabetes.

Reprogramming of murine fibroblasts to induced pluripotent stem cells with chemical complementation of Klf4

“…Previous work with kenpaullone has demonstrated a wide range of biological utility, extending from maintenance of pancreatic ␤ cell survival and proliferation (35) to the induction of apoptosis in cancer cells (36). Kenpaullone's diverse range of activity is a direct result of its kinase inhibition promiscuity (SI Text, Tables S1 and S2).…”

2-tert-Butyl-5,6,7,8,9,10-hexahydrocyclohepta[b]indole

“…1 H-NMR and 13 C-NMR spectra were recorded on a Bruker Avance DRX-400 (NMR laboratories of the Chemical Institutes of the Technische Universitä t Braunschweig) using DMSO-d 6 …”

“…Abstract: 2-tert- 6,7,8,9,indole was synthesized by reaction of cycloheptanone and (4-tert-butylphenyl)hydrazine hydrochloride in the presence of sodium acetate and sulfuric acid in glacial acetic acid via Fischer indole synthesis. .…”

“…As commercially available agents paullones are widely used as biochemical tools. Among other biological properties, paullones have demonstrated antiproliferative activity on cancer cell lines on the one hand [1][2][3][4][5] and protection of insulin producing pancreatic beta cells against apoptosis on the other hand [6]. Recently paullone chalcone hybrid structures 1 were reported to inhibit the growth of Leishmania amastigotes in vitro [7].…”

Concise synthesis and CDK/GSK inhibitory activity of the missing 9-azapaullones

“…Seminal studies on these compounds by Kunick et al repeatedly demonstrated that the fused tetracyclic unit incorporating three aromatic rings and an ε-lactam component (including the methylene group), the indole proton and a strongly electron withdrawing group at C-9 (preferably one with at least one lone pair of electrons capable of accepting a hydrogen bond) are all prerequisites for strong CDK1/cyclin B (and GSK 3α/β)-inhibitory activity. [11][12][13] A diverse array of these compounds have been synthesised (including azapaullone 5a and 12-azapaullone derivative 5b 18 -a potent and selective inhibitor of GSK-3), [11][12][13] however, we were intrigued by the absence of the azapaullone derivative 6 from all screened libraries. 9-Azapaullone (6) would be a compound of considerable interest -the pyridine ring nitrogen renders the aromatic ring electron deficient in a similar manner to the nitro group of alsterpaullone (3), and as such is an interesting target for its potential potency/specificity alone, however it could also be either alkylated or most importantly (given the SAR identified by Kunick) oxidised to afford compounds such as 7a-b respectively.…”