title: Design, synthesis, and antiproliferative and CDK2-cyclin a inhibitory activity of novel flavopiridol analogues.
abstract: The design and synthesis of a small library of 8-amidoflavone, 8-sulfonamidoflavone, 8-amido-7-hydroxyflavone, and heterocyclic analogues of flavopiridol is reported. The potential activity of these compounds as kinase inhibitors was evaluated by cytotoxicity studies in MCF-7 and ID-8 cancer cell lines and inhibition of CDK2-Cyclin A enzyme activity in vitro. The antiproliferative and CDK2-Cyclin A inhibitory activity of these analogues was significantly lower than the activity of flavopiridol. Molecular docking simulations were carried out and these studies suggested a different binding orientation inside the CDK2 binding pocket for these analogues compared to flavopiridol.
authors.affiliation: Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, University of Kansas, Lawrence, KS 66045-7582, USA.
authors.forename: Yu Mi
authors.initials: YM
authors.lastname: Ahn
authors.forename: Lakshminarayana
authors.initials: L
authors.lastname: Vogeti
authors.forename: Chun-Jing
authors.initials: CJ
authors.lastname: Liu
authors.forename: Hari K R
authors.initials: HK
authors.lastname: Santhapuram
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: White
authors.forename: Veena
authors.initials: V
authors.lastname: Vasandani
authors.forename: Lester A
authors.initials: LA
authors.lastname: Mitscher
authors.forename: Gerald H
authors.initials: GH
authors.lastname: Lushington
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hanson
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Powell
authors.forename: Richard H
authors.initials: RH
authors.lastname: Himes
authors.forename: Katherine F
authors.initials: KF
authors.lastname: Roby
authors.forename: Qizhuang
authors.initials: Q
authors.lastname: Ye
authors.forename: Gunda I
authors.initials: GI
authors.lastname: Georg
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D002855:Chromatography, Thin Layer; D019925:Cyclin A / Q000037:antagonists & inhibitors*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D005419:Flavonoids / Q000138:chemical synthesis* / Q000494:pharmacology*; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D019925:Cyclin A; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007202:Indicators and Reagents; D010880:Piperidines; C077990:alvocidib; D000255:Adenosine Triphosphate; D051357:Cyclin-Dependent Kinase 2