Design, Synthesis And Structure-Activity Relationships Study Of Flavonoids As CDKs Inhibitors

Cancer is the second leading cause of death after cardiovascular disease. Most of antitumor drugs used in clinic had the disadvantages of high toxicity and multidrug resistance. In recent years, there has been a growing interest in the search for antitumor drugs with high efficacy, low toxicity and minimum side effects.Take account of SAR of flavopiridol and the structural basis of the CDKs inhibitory activity which had been elucidated by an X-ray crystal structure of CDK2 in complex with flavopiridol, it was chosed as a lead compound, the 4-keto plus 5-hydroxy groups of the compound and the o-chlorophenyl ring in position 2 of the chromenone moiety were kept, which the former can benefit from interacting with the hinge ringe of CDK2 ( bidendate hydrogen bonds with the backbone of CDK2 residues Leu 83 and Glu 81) and the latter can formed interactions with hydrophobic pocket in CDK2. The above two pharmacophore plus different amino units via one carbon atom were connected with the flavonoid backbone. Thus, a series of chalcone, flavone, flavanone and aurone derivatives were designed, synthesized and tested for their CDK1/Cyclin B inhibitory activity as well as their antitumour activity against six tumor cell lines in vitro cellular assay. The result showed that most of chalcone derivatives exhibited high CDKl/Cyclin B inhibitory activity, and the IC₅₀ values of four compounds were more active than flavopiridol. Further antiproliferative activity also showed that most of chalcone derivatives exerted high cytotoxicity against six tumor cell lines;Flavone, flavanone and aurone derivatives only exhibited high inhibitory activity on HL-60 cells and/or MCF-7 cells. Compound 5, which possessed broad antitumor spectrum and CDK1/Cyclin B inhibitory activity, was selected to investigate the cytotoxic mechanism in PC-3 cells. The results indicated that apoptosis pathway did contribution to the antitumor activity.On the basis of CDKl/Cyclin B inhibitory activity and antiproliferative activity of four flavonoid derivatives, some chalcone derivatives were found possessing high CDK1 inhibitory activity and antiproliferative activity. They can be selected as novel antitumor leads by CDK1 inhibition for further research. The result will provideexperimental and theoretical clues for designing of more potent CDK1 inhibitors.Another part work of this dissertation is the methodology research of the cleavage of methyl ethers of methoxyflavone and methoxychalcone derivatives. The cleavage of mono-, di-, trimethoxy-flavones by different O-demethylation reagents were compared. We found [BMIMHAI2CI7] could exhibit the same O-demethylation as the conventional O-demethylation reagents. The desired products were obtained in moderate to good yields. This method adopted here provided a facile and efficient approach for preparation of polyhydroxylflavone derivatives.We also found that O-demethylated flavanone derivatives could be directly obtained by the reaction of polymethoxychalcone derivatives with hydrohalic acid by one-pot strategy. Reaction conditions of cyclization and O-demethylation of polymethoxychalcones were further studied and the optimizing conditions of cyclization and selective C5-O-demethylation or C5, C7-O-demethylation were obtained. It is a practical and efficient routine for synthesis of polyhydroxyflavanone derivatives.