title: Structure-based design and synthesis of 2-benzylidene-benzofuran-3-ones as flavopiridol mimics.
abstract: 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.
authors.affiliation: Oncology Research, NOVARTIS Pharma AG, 4002 Basle, Switzerland. joseph.schoeper@pharma.novertis.com
authors.forename: Joseph
authors.initials: J
authors.lastname: Schoepfer
authors.forename: Heinz
authors.initials: H
authors.lastname: Fretz
authors.forename: Bhabatosh
authors.initials: B
authors.lastname: Chaudhuri
authors.forename: Lionel
authors.initials: L
authors.lastname: Muller
authors.forename: Egge
authors.initials: E
authors.lastname: Seeber
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.forename: Eric
authors.initials: E
authors.lastname: Vangrevelinghe
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
mesh_terms: D001597:Benzylidene Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D005419:Flavonoids / Q000737:chemistry*; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D018716:Molecular Mimicry; D010880:Piperidines / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry; D011518:Proto-Oncogene Proteins; D013329:Structure-Activity Relationship
chemical_list: D001597:Benzylidene Compounds; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005663:Furans; D010880:Piperidines; D011518:Proto-Oncogene Proteins; C077990:alvocidib; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases