Development of novel epoxyketone macrocyclic peptidyl proteasome inhibitors through OPA-mediated one-step cyclization...

Cyclization is a pivotal strategy for enhancing the drug-like characteristics of polypeptides. To develop potent and metabolically stable proteasome inhibitors, we generated a macrocyclic peptide skeleton using a straightforward and efficient cyclization strategy. Subsequent stability assessments confirmed the practicality of this approach. Leveraging this skeleton, we designed and synthesized a series of epoxyketone macrocyclic peptidyl proteasome inhibitors. Approximately half of these compounds showcased robust inhibitory potency, with IC₅₀ values below 200 nM against chymotrypsin-like (ChT-L, β5) activity. Notably, compounds 6f, 6g, and 6m demonstrated pronounced anti-proliferative activities at low nanomolar concentrations against three hematoma cell lines (RPMI-8226, RS4;11, and MV-4-11) as well as the NCI-H1299 cell line. These findings highlight the potential of these cyclic peptides to bolster the stability of proteasome inhibitors, thereby providing valuable insights for the advancement of innovative proteasome inhibitor therapies.