The Design,Synthesis And Bioactivity Evaluation Of ?-Lactone Inhibitors Against 20S Proteasome

Objective:The ubiquitin proteasome system?UPS?is an important protein degradation pathway in eukaryotic cells which regulate and control many important biological processes,such as signal transduction,cell cycle control,transcriptional regulation,inflammation and apoptosis.Interfere with the system can effectively control the occurrence and development of the tumor.20S proteasome have already become the screening target of the research of antitumor drugs.Methods:By means of computer-aided drug design,this project designed and synthesized two kinds of compounds who containing?-lactone structure.However the process is based on the previous research of monocycle Homobelactosin C and bicyclo-Omuralide respectively.Meanwhile evaluate the inhibitory activity of the target compounds through enzyme cell experiment,structure-activity relationship model was established through the analysis of the active data.Result:We successfully synthesized a kind of monocycle?-lactone proteasome inhibitor and a pyrrolo-lactone one which all of the target compounds were characterized by ¹H-NMR,¹³C-NMR and MS,active data is got under the enzyme activity in vitro test.AM-P-HP,however,whose IC₅₀ is 54nmol,functioning in the same way with Homobelactone C towards?5-subunit with Gold docking software.