title: Soluble 3',6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period.
abstract: Glycogen synthase kinase -3 (GSK-3) is a key enzyme involved in numerous physiological events and in major diseases, such as Alzheimer's disease, diabetes, and cardiac hypertrophy. Indirubins are bis-indoles that can be generated from various natural sources or chemically synthesized. While rather potent and selective as GSK-3 inhibitors, most indirubins exhibit low water solubility. To address the issue of solubility, we have designed novel analogues of 6-bromo-indirubin-3'-oxime with increased hydrophilicity based on the GSK-3/indirubins cocrystal structures. The new derivatives with an extended amino side chain attached at position 3' showed potent GSK-3 inhibitory activity, enhanced selectivity, and dramatically increased water solubility. Furthermore, some of them displayed little or no cytotoxicity. The new indirubins inhibit GSK-3 in a cellular reporter model. They alter the circadian period measured in rhythmically expressing cell cultures, suggesting that they might constitute tools to investigate circadian rhythm regulation.
authors.affiliation: Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, University of Athens, Panepistimiopolis Zografou, GR-15771 Athens, Greece.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Vougogiannopoulou
authors.forename: Yoan
authors.initials: Y
authors.lastname: Ferandin
authors.forename: Karima
authors.initials: K
authors.lastname: Bettayeb
authors.forename: Vassilios
authors.initials: V
authors.lastname: Myrianthopoulos
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.forename: Yunzhen
authors.initials: Y
authors.lastname: Fan
authors.forename: Carl Hirschie
authors.initials: CH
authors.lastname: Johnson
authors.forename: Prokopios
authors.initials: P
authors.lastname: Magiatis
authors.forename: Alexios-Leandros
authors.initials: AL
authors.lastname: Skaltsounis
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mikros
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
mesh_terms: D000818:Animals; D001665:Binding Sites; D017605:Bromine Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002940:Circadian Rhythm / Q000187:drug effects*; D018360:Crystallography, X-Ray; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D051176:beta Catenin / Q000378:metabolism
chemical_list: D017605:Bromine Compounds; D007211:Indoles; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3; C027185:indirubin