TY - JOUR
TI - 3′-substituted 7-halogenoindirubins, a new class of cell death inducing agents
AU - Ferandin, Y.
AU - Bettayeb, K.
AU - Kritsanida, M.
AU - Lozach, O.
AU - Polychronopoulos, P.
AU - Magiatis, P.
AU - Skaltsounis, A.-L.
AU - Meijer, L.
JO - Journal of Medicinal Chemistry
PY - 2006
VL - 49
TODO - 15
SP - 4638-4649
PB - 
SN - 0022-2623, 1520-4804
TODO - 10.1021/jm060314i
TODO - 1 methyl 7 bromoindirubin 3' [o (2 dimethylaminoethyl)oxime];  7 bromoindirubin 3' [o (2 dimethylaminoethyl)oxime];  7 bromoindirubin 3' [o (2 piperazin 1 ylethyl)oxime];  7 bromoindirubin 3' [o (2 pyrrolidin 1 ylethyl)oxime];  7 bromoindirubin 3' oxime;  antineoplastic agent;  caspase;  cyclin dependent kinase;  halogen;  indirubin;  indole derivative;  phosphotransferase;  phosphotransferase inhibitor;  unclassified drug;  antineoplastic agent;  bromine;  chlorine;  fluorine;  indirubin;  indole derivative;  iodine, antineoplastic activity;  apoptosis;  article;  bacterium;  controlled study;  drug mechanism;  drug protein binding;  drug screening;  drug synthesis;  drug targeting;  human;  human cell;  mammal;  molecular model;  mollusc;  plant;  solubility;  stereospecificity;  structure activity relation;  tumor cell line;  cell death;  chemical structure;  chemistry;  drug effect;  stereoisomerism;  synthesis, Antineoplastic Agents;  Bromine;  Cell Death;  Cell Line, Tumor;  Chlorine;  Drug Screening Assays, Antitumor;  Fluorine;  Humans;  Indoles;  Iodine;  Models, Molecular;  Stereoisomerism;  Structure-Activity Relationship
TODO - Indirubins are kinase inhibitory bis-indoles that can be generated from various plant, mollusk, mammalian, and bacterial sources or chemically synthesized. We here report on the synthesis and biological evaluation of 3′-substituted 7-halogenoindirubins. Molecular modeling and kinase assays suggest that steric hindrance prevents 3′-substituted 7-halogenoindirubins from interacting with classical kinase targets of other indirubins such as cyclin-dependent kinases and glycogen synthase kinase-3. Surprisingly 3′-substituted 7-halogeno-indirubins induce cell death in a diversity of human tumor cell lines. Although some 3′-substituted 7-halogenoindirubins appear to induce effector caspase-independent, nonapoptotic cell death, others trigger the landmarks of classical apoptosis. A structure-activity relationship study was performed to optimize 3′-substituted 7-halogenoindirubins with respect to solubility and cell death induction. Despite their unidentified targets, 3′-substituted 7-halogenoindirubins constitute a new promising family of antitumor agents. © 2006 American Chemical Society.
ER -