Soluble 3',6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period.
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.
Vougogiannopoulou
Konstantina
K
Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, University of Athens, Panepistimiopolis Zografou, GR-15771 Athens, Greece.
Ferandin
Yoan
Y
Bettayeb
Karima
K
Myrianthopoulos
Vassilios
V
Lozach
Olivier
O
Fan
Yunzhen
Y
Johnson
Carl Hirschie
CH
Magiatis
Prokopios
P
Skaltsounis
Alexios-Leandros
AL
Mikros
Emmanuel
E
Meijer
Laurent
L
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
D017605:Bromine Compounds; D007211:Indoles; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3; C027185:indirubin