title: Synthesis and biological activities of polyquinoline derivatives: new Bcl-2 family protein modulators.
abstract: The synthesis of quinoline derivatives, designed to interact with Bcl-x(L), and to inhibit its interaction with pro-apoptotic partners, is described and their biological effects investigated. We showed that 5 out of 28 synthetized compounds restored cell death of 3T3 cells overexpressing Bcl-x(L) following serum starvation. Active compounds were further characterized for their binding capacity to the anti-apoptotic member of the Bcl-2 family, Bcl-x(L) as well as Bcl-2, Bfl-1 and Mcl-1, and for their pro-apoptotic activities toward lymphoid tumor cells and peripheral blood mononuclear cells. Altogether our results indicate that dimeric, rather than trimeric quinoline derivatives, represent a new attractive class of BH3 mimetics for cancer therapy.
authors.affiliation: Clermont Université, Université Blaise Pascal, Institut de Chimie de Clermont-Ferrand, BP 10448, 63000 Clermont-Ferrand, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Saugues
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Debaud
authors.forename: Fabrice
authors.initials: F
authors.lastname: Anizon
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonnefoy
authors.forename: Pascale
authors.initials: P
authors.lastname: Moreau
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019281:Dimerization; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C096816:BCL2-related protein A1; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011804:Quinolines; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein