title: Discovery of a new family of bis-8-hydroxyquinoline substituted benzylamines with pro-apoptotic activity in cancer cells: synthesis, structure-activity relationship, and action mechanism studies.
abstract: Bis-8-hydroxyquinoline substituted benzylamines have been synthesized and screened for their antitumor activity on KB3 cell line model. Synthesis of this series of new analogues was accomplished using a one pot specific methodology which allows the synthesis of both bis- and mono-8-hydroxyquinoline substituted benzylamines. Among the synthesized compounds two compounds (4a and 5a), respectively, named JLK 1472 and JLK 1486, were particularly potent on KB3 cell line. Their CC(50) values being, respectively, 2.6 and 1.3 nM. Screened on a panel of cell lines showing various phenotype alterations, both compounds were found inactive on some cell lines such as PC3 (prostate cell line) and SF268 (neuroblastoma cell line) while highly active on other different cell lines. Mechanistic studies reveal that these two analogues did not affect tubulin and microtubules neither they exert a proteasomal inhibition effect. In contrast 4a and 5a activate specifically caspase 3/7 and not caspase 8 and 9, suggesting that their biological target should be located upstream from caspase 3/7. Moreover their cytotoxic effect is potentiated by the pro-apoptotic effects of TRAIL.
authors.affiliation: Laboratoire de Chimie Biomoléculaire, IBDML-UMR-6216-CNRS, Faculté des Sciences Luminy, Université de la Méditerranée, Parc Scientifique de Luminy, Case 901, 13288 Marseille Cedex 9, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Moret
authors.forename: Younes
authors.initials: Y
authors.lastname: Laras
authors.forename: Thierry
authors.initials: T
authors.lastname: Cresteil
authors.forename: Geneviève
authors.initials: G
authors.lastname: Aubert
authors.forename: Dou Q
authors.initials: DQ
authors.lastname: Ping
authors.forename: Chen
authors.initials: C
authors.lastname: Di
authors.forename: Magali
authors.initials: M
authors.lastname: Barthélémy-Requin
authors.forename: Christophe
authors.initials: C
authors.lastname: Béclin
authors.forename: Vincent
authors.initials: V
authors.lastname: Peyrot
authors.forename: Diane
authors.initials: D
authors.lastname: Allegro
authors.forename: Amandine
authors.initials: A
authors.lastname: Rolland
authors.forename: Francesca
authors.initials: F
authors.lastname: De Angelis
authors.forename: Evelina
authors.initials: E
authors.lastname: Gatti
authors.forename: Philippe
authors.initials: P
authors.lastname: Pierre
authors.forename: Luca
authors.initials: L
authors.lastname: Pasquini
authors.forename: Eleonora
authors.initials: E
authors.lastname: Petrucci
authors.forename: Ugo
authors.initials: U
authors.lastname: Testa
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Kraus
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001596:Benzylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D020169:Caspases / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D006912:Hydroxyquinolines; D008297:Male; D013329:Structure-Activity Relationship; D053221:TNF-Related Apoptosis-Inducing Ligand
chemical_list: D000970:Antineoplastic Agents; D001596:Benzylamines; D006912:Hydroxyquinolines; D053221:TNF-Related Apoptosis-Inducing Ligand; D020169:Caspases