Synthesis And SAR Evaluation Of Flavonoid Derivatives As CDKs Inhibitors

Protein kinases regulate many critical biological mechanisms,including metabolism and cell growth,proliferation,and differentiation.Aberrations in the activity of the kinases involved in signal transduction have been linked to many humandiseases.The discovery of more than 600 kinases encoded by the human genome has spurred development of rapid screening techniques for potential drugs against these enzymes.Flavonoids are found in many plants,they have various biological potencies.However, naturally occurring flavonoids have mild biological activity.In this paper,a series of flavonoid derivatives were designed and synthesized,the inhibitory activity and structure-activity relationship(SAR)towards CDK1/Cyclin B were explored.A series of flavonoid derivatives were designed and synthesized through Mannich reaction,and screened for the inhibitory activities of cyclin-dependent kinases by a FRET-based biochemical assay method.The results showed that 8 nitrogen-containing baicalein derivatives exhibited potent CDK1/Cyclin B inhibitory activities.8-dimethylaminol methyl-baicalein,8-pyrrolidinylmethyl-baicalein and 8-piperidinylmethyl-baicalein(IC₅₀ 1.05-1.28μM)were about 14-fold more potent than baicalin(IC₅₀14.36μM).8-morpholino methyl-baicalein,8-thiomorpholinomethyl-baicalein and 8-(4-methylpiperazinylmethyl)-baicalein(IC₅₀0.27-0.38μM)were about 50-fold more potent than baicalin,and were at the same level as Flavopiridol(IC₅₀0.33μM).SAR suggested that the presence of the nitrogen on position 8 is very important and introduction of second heteroatom on position 8 would increase inhibitory potency;5,6,7 hydroxyl and 4 carbonyl are vital for inhibitory activity; The lipophilic substitutes on position 2 is critical,hydrophilic substitutes would be detrimental to inhibitory potency.In this paper,seventeen nitrogen-containing flavonoid analogues were designed and prepared by Mannich reaction.Totally twenty two flavonoid analogues were assayed for their CDK1/Cyclin B inhibitory activity,selected three compounds which have protent CDK1/Cyclin B inhibitory activity.8-(4-methylpiperazinylmethyl)-baicalein was firstly designed and prepared,which was expected to be a novel kind of CDK1/Cyclin B inhibitor.