Design, synthesis, and antiproliferative and CDK2-cyclin a inhibitory activity of novel flavopiridol analogues.
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.
Ahn
Yu Mi
YM
Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, University of Kansas, Lawrence, KS 66045-7582, USA.
Vogeti
Lakshminarayana
L
Liu
Chun-Jing
CJ
Santhapuram
Hari K R
HK
White
Jonathan M
JM
Vasandani
Veena
V
Mitscher
Lester A
LA
Lushington
Gerald H
GH
Hanson
Paul R
PR
Powell
Douglas R
DR
Himes
Richard H
RH
Roby
Katherine F
KF
Ye
Qizhuang
Q
Georg
Gunda I
GI
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
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