Τίτλος:
Soluble 3′,6-substituted indirubins with enhanced selectivity toward glycogen synthase kinase -3 alter circadian period
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Vougogiannopoulou, K.
Ferandin, Y.
Bettayeb, K.
Myrianthopoulos, V.
Lozach, O.
Fan, Y.
Johnson, C.H.
Magiatis, P.
Skaltsounis, A.-L.
Mikros, E.
Meijer, L.
Περιοδικό:
Journal of Medicinal Chemistry
Λέξεις-κλειδιά:
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
