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.
Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Cell Death / drug effects
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Cell Survival / drug effects
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Dimerization
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Gene Expression / drug effects*
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Humans
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Inhibitory Concentration 50
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Leukocytes, Mononuclear / cytology
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Leukocytes, Mononuclear / drug effects*
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Leukocytes, Mononuclear / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Minor Histocompatibility Antigens
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Myeloid Cell Leukemia Sequence 1 Protein
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Protein Binding
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Quinolines / chemical synthesis*
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Quinolines / pharmacology
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism*
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bcl-X Protein / genetics
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bcl-X Protein / metabolism*
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BCL2-related protein A1
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BCL2L1 protein, human
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Mcl1 protein, mouse
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Membrane Proteins
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Minor Histocompatibility Antigens
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Myeloid Cell Leukemia Sequence 1 Protein
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Quinolines
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bcl-2-Associated X Protein
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bcl-X Protein