title: Structure-activity relationships and mechanism of action of antitumor bis 8-hydroxyquinoline substituted benzylamines.
abstract: A series of twenty six 8-hydroxyquinoline substituted amines, structurally related to compounds 2 and 3, were synthesized to evaluate the effects of structural changes on antitumor activity and understand their mechanism of action. The studies were performed on a wide variety of cancer cell lines within glioma and carcinoma models. The results obtained from chemical models and biological techniques such as microarrays suggest the following hypothesis that a quinone methide intermediate which does not react with DNA but which gives covalent protein thiol adducts. Micro-array analysis showed that the drugs induce the expression of a variety of stress related genes responsible for the cytotoxic and cytostatic effects in carcinoma and glioblastoma cells respectively. The described analogues could represent new promising anti-cancer candidates with specific action mechanisms, targeting accessible thiols from specific proteins and inducing potent anti-cancer effects.
authors.affiliation: Laboratoire de Chimie Biomoléculaire, CNRS, IBDML-UMR-6216, Campus de Luminy, Case 907, 13288 Marseille cedex 09, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Madonna
authors.forename: Christophe
authors.initials: C
authors.lastname: Béclin
authors.forename: Younes
authors.initials: Y
authors.lastname: Laras
authors.forename: Vincent
authors.initials: V
authors.lastname: Moret
authors.forename: Aline
authors.initials: A
authors.lastname: Marcowycz
authors.forename: Delphine
authors.initials: D
authors.lastname: Lamoral-Theys
authors.forename: Jacques
authors.initials: J
authors.lastname: Dubois
authors.forename: Magali
authors.initials: M
authors.lastname: Barthelemy-Requin
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Lenglet
authors.forename: Sabine
authors.initials: S
authors.lastname: Depauw
authors.forename: Thierry
authors.initials: T
authors.lastname: Cresteil
authors.forename: Geneviève
authors.initials: G
authors.lastname: Aubert
authors.forename: Valérie
authors.initials: V
authors.lastname: Monnier
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: David-Cordonnier
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Kraus
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D016227:Benzoquinones / Q000737:chemistry; D001596:Benzylamines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D009711:Nucleotides / Q000378:metabolism; D015125:Oxyquinoline / Q000737:chemistry*; D013312:Stress, Physiological / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D001596:Benzylamines; D009711:Nucleotides; C004532:quinone; D015125:Oxyquinoline; D004247:DNA; C030796:benzylamine; D005978:Glutathione