Design And Synthesis Of ?-lactone Proteasome Inhibitors

Objective: The ubiquitin-proteasome system(UPS)can mediate the degradation of 80% ?85% proteins in eukaryotic organisms,and ubiquitin is responsible for labeling proteins that need to be degraded.However,the proteasome is the degrading core in the UPS.It is consistent of a 20 S proteasome and two 19 S proteasomes at both ends.The ubiquitin-labeled protein is recognized by 19 S proteasomes,and then sent to the 20 S proteasome for degradation.The degraded short peptide is sent out by the 19 S proteasome.Some studies have found that inhibition of UPS can have a inhibition effect on tumor cells.Proteasome inhibitors have gradually become the hot spot of anti-tumor researches.In 2003,the first proteasome inhibitor bortezomib was approved for marketing by the FDA of American.It can get the survival of patients with multiple myeloma to increase by twice to three times.However,it is also easy for bortezomib to develop drug resistance.Therefore,the research of new generation proteasome inhibitor has become the research focus.Homobelactosin C is obtained by structural modification of a second-generation proteasome inhibitor belactoin C.It is a proteasome inhibitor with good proteasome inhibitory activity.In this project,by the the structural modification Homobelactosin C,to explore structure-effect relationship.Methods: The reported peptide proteasome inhibitor Homobelactosin C was considered as a lead compound.Homobelactosin C was divided into a pharmacophore part,a link arm part,and an N-terminal part.Structural modifications were made to the linker arm portion and the N-terminal amino acid.Results: Three Homobelactosin C derivatives were synthesized,and the target compounds and their intermediates were characterized by NMR and MS,and their properties were determined and analyzed.