title: 9-cyano-1-azapaullone (cazpaullone), a glycogen synthase kinase-3 (GSK-3) inhibitor activating pancreatic beta 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.
authors.affiliation: Institut für Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstrasse 55, Braunschweig, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Stukenbrock
authors.forename: Rainer
authors.initials: R
authors.lastname: Mussmann
authors.forename: Marcus
authors.initials: M
authors.lastname: Geese
authors.forename: Yoan
authors.initials: Y
authors.lastname: Ferandin
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.forename: Thomas
authors.initials: T
authors.lastname: Lemcke
authors.forename: Simone
authors.initials: S
authors.lastname: Kegel
authors.forename: Alexander
authors.initials: A
authors.lastname: Lomow
authors.forename: Ulrike
authors.initials: U
authors.lastname: Burk
authors.forename: Cord
authors.initials: C
authors.lastname: Dohrmann
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Matthias
authors.initials: M
authors.lastname: Austen
authors.forename: Conrad
authors.initials: C
authors.lastname: Kunick
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D004791:Enzyme Inhibitors; D007211:Indoles; C529449:cazpaullone; D038362:Glycogen Synthase Kinase 3