Structure-Based Design and Synthesis of 2-Benzylidene-benzofuran-3-ones as Flavopiridol Mimics

Structure-Based Design and Synthesis of 2-Benzylidene-benzofuran-3-ones as Flavopiridol Mimics

Novel 2-benzylidene-benzofuran-3-ones were designed and synthesized to mimic flavopiridol, a well-established inhibitor of cyclin-dependent kinases (CDKs) which is currently undergoing clinical evaluation. The underlying design concepts as well as the synthesis and structure−activity relationships (...

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Veröffentlicht in:Journal of medicinal chemistry 2002-04, Vol.45 (9), p.1741-1747
Hauptverfasser: Schoepfer, Joseph, Fretz, Heinz, Chaudhuri, Bhabatosh, Muller, Lionel, Seeber, Egge, Meijer, Laurent, Lozach, Olivier, Vangrevelinghe, Eric, Furet, Pascal
Format: Artikel
Sprache:eng
Schlagworte:
Antineoplastic agents
Benzylidene Compounds - chemical synthesis
Benzylidene Compounds - chemistry
Biological and medical sciences
CDC2 Protein Kinase - antagonists & inhibitors
CDC2 Protein Kinase - chemistry
CDC2-CDC28 Kinases
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinases - antagonists & inhibitors
Cyclin-Dependent Kinases - chemistry
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Flavonoids - chemistry
Furans - chemical synthesis
Furans - chemistry
General aspects
Medical sciences
Models, Molecular
Molecular Mimicry
Pharmacology. Drug treatments
Piperidines - chemistry
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - chemistry
Proto-Oncogene Proteins
Structure-Activity Relationship
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Beschreibung
Zusammenfassung:Novel 2-benzylidene-benzofuran-3-ones were designed and synthesized to mimic flavopiridol, a well-established inhibitor of cyclin-dependent kinases (CDKs) which is currently undergoing clinical evaluation. The underlying design concepts as well as the synthesis and structure−activity relationships (CDKs 1, 2, and 4 enzyme assays) of these mimics are described. Inhibitors of CDKs 1 and 2 that are more potent and selective than flavopiridol were obtained.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm0108348