Synthesis and biological activities of new di- and trimeric quinoline derivatives

The synthesis of non-peptidic helix mimetics based on a trimeric quinoline scaffold is described. The ability of these new compounds, as well as their synthetic dimeric intermediates, to bind to various members of the Bcl-2 protein anti-apoptotic group is also evaluated. The most interesting derivat...

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Veröffentlicht in:	Bioorganic & medicinal chemistry 2010-10, Vol.18 (19), p.7132-7143
Hauptverfasser:	Broch, Sidonie, Hénon, Hélène, Debaud, Anne-Laure, Fogeron, Marie-Laure, Bonnefoy-Bérard, Nathalie, Anizon, Fabrice, Moreau, Pascale
Format:	Artikel
Sprache:	eng
Schlagworte:	Antineoplastic agents Apoptosis BAK protein Bcl-2 protein bcl-X Protein - antagonists & inhibitors bcl-X Protein - chemistry Binding Sites Biological and medical sciences Dimerization Dose-Response Relationship, Drug Drug Discovery General aspects Helix mimetic Medical sciences Models, Molecular Molecular Structure Pharmacology. Drug treatments Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors Proto-Oncogene Proteins c-bcl-2 - chemistry Quinoline Quinolines - chemical synthesis Quinolines - chemistry Quinolines - pharmacology Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - chemistry Stereoisomerism Structure-Activity Relationship
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Zusammenfassung:	The synthesis of non-peptidic helix mimetics based on a trimeric quinoline scaffold is described. The ability of these new compounds, as well as their synthetic dimeric intermediates, to bind to various members of the Bcl-2 protein anti-apoptotic group is also evaluated. The most interesting derivative of this new series (compound A) inhibited Bcl-x L/Bak, Bcl-x L/Bax and Bcl-x L/Bid interactions with IC 50 values around 25 μM.
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2010.07.029