Nitrogen-containing flavonoid analogues as CDK1/cyclin B inhibitors: synthesis, SAR analysis, and biological activity.

Abstract 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-4 H -chromen-4-one 3a , 5,6,7-trihydroxy-8-(pyrrolid inylmethyl)-2-phenyl-4 H -chromen-4-one 3b , and 5,6,7-trihydroxy-8-(piperidinylmethyl)-2-phenyl-4 H -chromen-4-one 3c (IC 50 1.05–1.28 μM) were about sixfold more potent than baicalein 2 (IC 50 6.53 μM). 5,6,7-Trihydroxy-8-(morpholinomethyl)-2-phenyl-4 H -chromen-4-one 3d , 5,6,7-trihydroxy-8-(thiomorpholinomethy)-2-phenyl-4 H -chrom en-4-one 3e , and 5,6,7-trihydroxy-8-(4-methylpiperazinylmethyl)-2-phenyl-4 H -chromen-4-one 3f (IC 50 0.27–0.38 μM) were about 20-fold more potent than baicalein, and were at the same level as flavopiridol (IC 50 0.33 μM).