Design, Synthesis And Anticancer Activity Study Of Chalcone Derivates As Cyclin-dependent Kinase Inhibitors

Cancer has constituted major harm to the healthy of human. During the past decades, a vast body of literature from molecular oncology research has illustrated the relevance of cell cycle deregulation in human cancer and the gene products that regulate the key cell cycle machinery have been investigated as anticancer drug targets. The three basic tumors cell cycle defects-unscheduled proliferation which results from constitutive mitogenic signalling and defective responses to anti-mitogenic signals, genomic instability(GIN) and chromosomal instability(CIN)-are mediated, directly or indirectly, by misregulation of cyclin-dependent kinases (CDKs). Therefore, selective inhibition of CDKs may limit the progression of a tumor cell cycle and facilitate the induction of apoptotic pathways. Furthermore, exploitation of CDKs inhibitors will make it a new highlight in anticancer field.Base on the former research on flavonoids as CDKs inhibitors in our lab, and the structure analysis of CDKs inhibitors which complexated with CDK2 and SAR of Flavopiridol analogues, Compound L41 was chosen as a lead compound. Given enough consideration of several regions of ATP-binding pocket, keeping the hydrogen bond in hinge region and ribose/phosphate region, a series of Chalcones (including twenty compounds) which targeting CDKs were designed, synthesized and evaluated for CyclinB/CDK1 inhibitory activity as well as their antitumor activity against seven human tumor cell lines such as HCT116, A549, MCF-7 and so on in vitro.The results of CDK1 inhibitory assay indicated that compounds A4,A7,A8,A10,A19,B2 showed the same activity levels at 50μM concentration.The result of cytotoxicity activity against HCT116 showed that Chalcones with N-Boc group exhibited much lower cytotoxicity than their corresponding BOC-deprotected chalcones. Moreover, compounds A5,A7,A8,A9,B2,4A13 showed higher inhibitory than the leading compoud L41 against HCT116. Therefore, these six compouds were chosen to determine cytotoxicity against other human tumor cell lines, such as A549,MCF-7,Hela and so on. The consequence showed that compounds A5,A8 exhibited higher activity than L41 against all these seven tumor cell lines. Moreover, the IC50 of compound A8 against MDA-MB231 is 0.83μM.In view of the fact that Flavopiridol as a pan-CDK inhibitor can limit tumor proliferation through several different mechanism, compound A8 was choosen for further research because of its notable activity in vitro assay. The results indicated that compound A8 arrest MCF-7 cells in S phase of the cell cycle at 1μM concentration.Moreover, the animal antitumor test models in vivo for these potential therapeutic compounds have been established.Besides all above the works, the improved synthesis of L41 hydrochlorate, the modified method not only provided possibilities of further developing of these compounds with mild reaction condition and simple operation but also improved the water solubility of these chalcones. Moreover, it was accidentally found that coupling of the key intermediate (3-1) and several substituted benzaldehyde allowed for synthesis of flavonone derivates 4B1-3, not chalcones. And the suitable conditions for the synthesis of chalcones were obtained.