Nitrogen-containing flavonoid analogues as CDK1/cyclin B inhibitors: synthesis, SAR analysis, and biological activity.
A series of nitrogen-containing flavonoid analogues were designed and synthesized by Mannich reaction, and screened for the inhibitory activities of cyclin-dependent kinases using a FRET-based biochemical assay method. The results showed that C-8 nitrogen-containing baicalein analogues 3a-3f exhibited potent CDK1/Cyclin B inhibitory activities. 5,6,7-Trihydroxy-8-(dimethylaminomethyl)-2-phenyl-4H-chromen-4-one 3a, 5,6,7-trihydroxy-8-(pyrrolid inylmethyl)-2-phenyl-4H-chromen-4-one 3b, and 5,6,7-trihydroxy-8-(piperidinylmethyl)-2-phenyl-4H-chromen-4-one 3c (IC(50) 1.05-1.28 microM) were about sixfold more potent than baicalein 2 (IC(50) 6.53 microM). 5,6,7-Trihydroxy-8-(morpholinomethyl)-2-phenyl-4H-chromen-4-one 3d, 5,6,7-trihydroxy-8-(thiomorpholinomethy)-2-phenyl-4H-chrom en-4-one 3e, and 5,6,7-trihydroxy-8-(4-methylpiperazinylmethyl)-2-phenyl-4H-chromen-4-one 3f (IC(50) 0.27-0.38 microM) were about 20-fold more potent than baicalein, and were at the same level as flavopiridol (IC(50) 0.33 microM).
Zhang
Shixuan
S
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Zhongshan Road 158-90, Dalian 116012, PR China. zhangsx56@yahoo.com.cn
Ma
Jigang
J
Bao
Yongming
Y
Yang
Puwen
P
Zou
Liang
L
Li
Kangjian
K
Sun
Xiaodan
X
D000818:Animals; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D019926:Cyclin B / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D009584:Nitrogen / Q000737:chemistry*; D013329:Structure-Activity Relationship
D019926:Cyclin B; D005419:Flavonoids; D016203:CDC2 Protein Kinase; D009584:Nitrogen