Structure-activity relationships and mechanism of action of antitumor bis 8-hydroxyquinoline substituted benzylamines.
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.
Madonna
Sébastien
S
Laboratoire de Chimie Biomoléculaire, CNRS, IBDML-UMR-6216, Campus de Luminy, Case 907, 13288 Marseille cedex 09, France.
Béclin
Christophe
C
Laras
Younes
Y
Moret
Vincent
V
Marcowycz
Aline
A
Lamoral-Theys
Delphine
D
Dubois
Jacques
J
Barthelemy-Requin
Magali
M
Lenglet
Gaëlle
G
Depauw
Sabine
S
Cresteil
Thierry
T
Aubert
Geneviève
G
Monnier
Valérie
V
Kiss
Robert
R
David-Cordonnier
Marie-Hélène
MH
Kraus
Jean-Louis
JL
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
D000970:Antineoplastic Agents; D016227:Benzoquinones; D001596:Benzylamines; D009711:Nucleotides; C004532:quinone; D015125:Oxyquinoline; D004247:DNA; C030796:benzylamine; D005978:Glutathione