title: 3'-Substituted 7-halogenoindirubins, a new class of cell death inducing agents.
abstract: 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-halogenoindirubins 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.
authors.affiliation: Cell Cycle Group & UPS2682, C.N.R.S., Station Biologique, B.P. 74, 29682 Roscoff Cedex, Bretagne, France.
authors.forename: Yoan
authors.initials: Y
authors.lastname: Ferandin
authors.forename: Karima
authors.initials: K
authors.lastname: Bettayeb
authors.forename: Marina
authors.initials: M
authors.lastname: Kritsanida
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Polychronopoulos
authors.forename: Prokopios
authors.initials: P
authors.lastname: Magiatis
authors.forename: Alexios-Leandros
authors.initials: AL
authors.lastname: Skaltsounis
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001966:Bromine; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002713:Chlorine; D004354:Drug Screening Assays, Antitumor; D005461:Fluorine; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007455:Iodine; D008958:Models, Molecular; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D005461:Fluorine; D002713:Chlorine; D007455:Iodine; D001966:Bromine; C027185:indirubin