The Design And Synthesis Of CDKs Inhibitors With Flavonoids Strcture

The full name of CDKs is cyclin-dependent-kinases, which with cyclins and other small molecules become an impotant part of cell cycle regulation. A large of scientific studies has shown, the abnormal of activity and levels of CDKs has direct an indirect relationship with the formation of cancer. Therefore, the research of CDKs innibitors has became a hot issue in the area of new anti-cancer drug research.Flavopiridol as the first drug which entered the clinical study has shown an excellent inhibitory activity in vitro activity tests, whereby inhibition of CDKs for flavonoids attracted wide attention.In this paper, the research work is divided into two parts:First, the design of the target molecules, the second is the synthesis target molecules.In the part of molecular design, we-used the computer simulation assited the design of target molecukes. We have mainly completed the following work:1. We used the computer simulation to predict the bingding pose of molecular and protein, and found two important amino-acid residues:Asp.86 and Asp.145.2. We have done the SAR analysis of 9 natural flavonoids and lead compounds 3a and 3f, then concluded three methods to increase the inhibitory activity of molecules: Firstly, increase the number of hydrophobic groups such as hydroxyl group and amino group on the A ring, and replace or change their position. Secondly, add the hydrophobic groups such as hydroxyl group and amino group on the C ring, replace or change the position of these hydrophobic goups in order to deremine the best strcture. Thirdly, introduce the methuylene amino groups in the position of C-8 in order to promote the inhibitory activity.3. We determined the three series of compounds named with 2A serie,3 A serie and 4A serie as our target compounds.In the second part the synthesis of target compounds, we mainly solved the following problems:1. We have designed two routes to synthesis the target compounds:route one used natural flavonoid——bacailein as material, route two is denove synthetic route.2. By comparing and testing, we finalized a denovo synthetic route of target molecules, and successfully synthesized all target compounds.3. Successfully synthesized 17 kinds of all new compounds of three series.