@article{3062288,
    title = "Soluble 3′,6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period",
    author = "Vougogiannopoulou, K. and Ferandin, Y. and Bettayeb, K. and Myrianthopoulos, V. and Lozach, O. and Fan, Y. and Johnson, C.H. and Magiatis, P. and Skaltsounis, A.-L. and Mikros, E. and Meijer, L.",
    journal = "Journal of Medicinal Chemistry",
    year = "2008",
    volume = "51",
    number = "20",
    pages = "6421-6431",
    issn = "0022-2623, 1520-4804",
    doi = "10.1021/jm800648y",
    keywords = "6 bromoindirubin 3' [o (2 bromoethyl)oxime];  6 bromoindirubin 3' [o (2 diethylaminoethyl)oxime];  6 bromoindirubin 3' [o (2 dimethylaminoethyl)oxime];  6 bromoindirubin 3' [o (2 hydroxyethyl)oxime];  6 bromoindirubin 3' [o (2 morpholin 1 ylethyl)oxime];  6 bromoindirubin 3' [o (2 piperazin 1 ylethyl)oxime];  6 bromoindirubin 3' [o (2 pyrrolidin 1 ylethyl)oxime];  6 bromoindirubin 3' [o (2,3 dihydroxypropyl)oxime];  6 bromoindirubin 3' [o (n,n diethylcarbamyl)oxime];  6 bromoindirubin 3' [o [2 (4 methylpiperazin 1 yl)ethyl]oxime];  6 bromoindirubin 3' [o [2 [4 (2 hydroxyethyl)piperazin 1 yl]ethyl]oxime];  6 bromoindirubin 3' [o [2 [4 (2 methoxyethyl)piperazin 1 yl]ethyl]oxime];  6 bromoindirubin 3' [o [2 [4 [2 (2 hydroxyethoxy)ethyl]piperazin 1 yl]ethyl]oxime];  6 bromoindirubin 3' [o [2 [n methyl n (2,3 dihydroxypropyl)amino]ethyl]oxime];  6 bromoindirubin 3' [o [2 [n,n (2 hydroxyethyl)amino]ethyl]oxime];  6 bromoindirubin 3' oxime derivative;  glycogen synthase kinase 3;  glycogen synthase kinase 3 inhibitor;  indirubin derivative;  unclassified drug;  unindexed drug;  beta catenin;  bromine derivative;  indirubin;  indole derivative;  protein kinase inhibitor, animal cell;  article;  binding affinity;  cell assay;  circadian rhythm;  controlled study;  crystal structure;  cytopathogenic effect;  drug design;  drug mechanism;  drug potency;  drug selectivity;  drug solubility;  drug structure;  drug synthesis;  enzyme assay;  enzyme inhibition;  human;  human cell;  hydrophilicity;  IC 50;  molecular model;  nonhuman;  pharmacophore;  rat;  regulatory mechanism;  animal;  binding site;  cell line;  chemical structure;  chemistry;  drug antagonism;  drug effect;  hydrophobicity;  metabolism;  phosphorylation;  solubility;  structure activity relation;  synthesis;  X ray crystallography, Animals;  beta Catenin;  Binding Sites;  Bromine Compounds;  Cell Line;  Circadian Rhythm;  Crystallography, X-Ray;  Glycogen Synthase Kinase 3;  Humans;  Hydrophobicity;  Indoles;  Models, Molecular;  Molecular Structure;  Phosphorylation;  Protein Kinase Inhibitors;  Rats;  Solubility;  Structure-Activity Relationship",
    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. © 2008 American Chemical Society."
}