Τίτλος:
3′-substituted 7-halogenoindirubins, a new class of cell death inducing agents
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Ferandin, Y.
Bettayeb, K.
Kritsanida, M.
Lozach, O.
Polychronopoulos, P.
Magiatis, P.
Skaltsounis, A.-L.
Meijer, L.
Περιοδικό:
Journal of Medicinal Chemistry
Λέξεις-κλειδιά:
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
