The Design、Synthesis And Biological Activity Study Of Pyrimidine-benzoyl RXRα Modulators

Malignant tumors are currently a serious threat to human life,which are the second most fatal disease in the world.Their morbidity and mortality rate have increased year by year.Therefore,the development of highly effective and low-toxicity anti-tumor drugs is one of the important research topics in the pharmaceutical industry today.Retinol X receptor alpha(RXR a)is one of the members of the nuclear receptor superfamily and plays an important role in the physiological processes of cell growth,differentiation,apoptosis,proliferation,and tumor formation.RXR alpha is a potential target for cancer treatment and prevention by interacting with its ligand to form homo/heterodimers and several tumor-associated signaling pathways.Therefore,based on the previous work of the research group,this paper designs and synthesizes a series of pyrimidine-benzoyl Schiff base derivatives,in order to find anti-tumor candidate compounds that act on RXR a.The main research contents of this paper are as follows:(1)Pyrimidine-benzoyl RXR a modulators and the design of their synthetic routes:The synthesis routes with mild reaction conditions and high yields have been designed.The conditions for pyrimidine-benzoyl Schiff base derivatives are optimized as follows:The system is CF3COOH/EtOH;n(substituted benzoylhydrazine):n(substituted benzaldehyde):n(acidic catalyst)= 1:1.05:0.05;the final reactant charge is a substituted benzaldehyde added to the substituted benzoylhydrazide and The reaction system of the catalyst reacts under reflux conditions for 4 hours;(2)Synthesis of the target compounds:116 novel compounds were designed and synthesized based on the optimized reaction conditions studied(unpublished by Scifinder and unreported),and were performed using 1H-NMR,13C-NMR,MS for Structure Characterization;(3)Antitumor cytotoxicity of the target compound and its structure-activity relationship study:The cytotoxic activity of the compound is basically lower than 50 jNM,some of the compounds can reach the nanomolar level;the change of the position 1 substituent has little effect,and the overall appearance of cytotoxicity shows pyridine substitution.The trend of the basal 2>4>3 positions;the 3rd and 4th changes in the 2 positions did not cause significant changes in cytotoxic activity;the electron-withdrawing groups at the 3 position were usually better than the electron-donating groups,while the electron-withdrawing and electron-donating activities were also observed between the two;Finally,we study on the regulation of RXRa:A12,B12,C27,C28,D15,and E14 have been screened by biological activity to have a better ability to kill tumor cells.Further analysis of candidate compounds C28 is performed using Western blot analysis.Anti-tumor effects in cell lines;Reporter gene experiments show that C28 inhibits RXRa effect significantly;Finally,through immunofluorescence experiments to study the mechanism of C28 pro-apoptosis.