Design,Synthesis And Activity Of The ?-lactone 20S Proteasome Inhibitors

The ubiquitin-proteasome system?ubiquitin-proteasome system,UPS?is an important pathway for the hydrolysis of cell cycle regulatory proteins in vivo.Its abnormality can cause a variety of diseases,such as tumors,Alzheimer's disease,etc.Therefore,UPS has become an important anti-tumor pathway.Proteasome is an important drug design target in this system.At present,there are many types of inhibitors against proteasomes,which can be divided into two major categories:peptides and non-peptides.Among the peptide inhibitors,the boric acid drug bortezomib and the epoxy ketone drug carfilzomib are the first-line drugs for the treatment of osteoblastoma;the non-peptide inhibitors in the?-lactone drug,Marizomib,have also entered clinical III.In this study,peptide fragments of peptide drugs and pharmacophores of?-lactone drugs were selected to synthesize monocyclic?-lactone inhibitors.The synthetic route was determined by reverse synthesis analysis,and 7 target compounds were synthesized.The intermediate and target compounds were characterized by ¹H-NMR,¹³C-NMR and HRMS.The target compound was tested for in vitro enzymatic activity,where in compound NZ-1 showed better inhibitor activity(IC₅₀=52.90±0.24nM).The Gold docking software was used to analyze the binding mode of lactones,which provided a theoretical basis for the development of 20S proteasome inhibitors.