Design, Synthesis And Activity Screening Of α-substituted 1,3-diketone P53-MDM2/MDMX Dual-Target Inhibitors

p53 protein is one of the important tumor suppressors in the cell,MDM2 and MDMX are its important regulators,and the interaction between the two is also an important anti-tumor target.At present,MDM2 inhibitors have entered clinical research,but there are serious side effects and resistance.Both MDMX and MDM2 are homologous proteins with structural similarities,which suggests the possibility of developing MDM2/MDMX dual target inhibitors.However,the research progress on dual-target small-molecule inhibitors is currently slow.This project is expected to obtain a dual-target inhibitor of p53-MDM2/MDMX with better activity.The research team completed the design and synthesis of the p53-MDM2/MDMX protein inhibitor based on the natural product chalcone skeleton in the early stage,and obtained the MDM2/MDMX inhibitor with better activity,especially the compound D16 has the best activity but the activity There is room for further improvement.This subject is based on the previous research foundation and hopes to improve the physical and chemical properties of the compound and increase its activity.Through molecular docking and literature research,on the basis of retaining the substituents of the A ring and C ring of the original compound,a 1,3-diketone skeleton was initially constructed,and a benzyl group(ring B)was introduced in its α-position,which was computer-aided Designed molecular docking studies and found that the newly designed compounds can well occupy three key active cavities(Phe19,Trp23 and Leu26)for MDM2/MDMX protein binding.Compared with chalcone skeleton has a further improvement.Since 1,3-diketone has a certain degree of keto and enol tautomerism,it can increase the polarity compared to chalcone;in addition,the enol form of 1,3-diketone can form a six-membered The intramolecular hydrogen bonds of the ring can increase the stability of its skeleton structure.In this paper,a total of 38 target compounds were designed and synthesized,and activity screening was conducted.Among them,22 single-substituted compounds were synthesized in the initial screening,and the biological activity screening was carried out by using the CCK-8 method in vitro anti-tumor activity test and fluorescence polarization experiment,and the compound S6 with better activity was selected for secondary optimization:secondary optimization synthesized 12 compounds After active screening,the compound S24 with better activity was finally obtained.The anti-tumor cell proliferation activity and MDM2 protein binding inhibitory activity in vitro were significantly improved.It showed good inhibitory activity against p53 wild-type tumor cells and p53 knockout type.Tumor cells have poor anti-proliferative activity,and also have good anti-proliferative activity against tumor cells with high expression of MDM2 U87MG and tumor cells with high expression of MDMX SH-SY5Y;Based on compound S24,4 more compounds were synthesized and the A ring fluorine was discussed The effect of the substituents on the activity showed that the change of the position of the A-ring fluoro substituent changed its cell activity and protein activity to varying degrees.Based on the results of the activity study,the structure-activity relationship of α-substituted 1,3-diketone compounds was studied,which will be of guiding significance for further research based on p53-MDM2/MDMX dual-target inhibitors.