Design, synthesis, and evaluation of cystargolide-based β-lactones as potent proteasome inhibitors.

ABSTRACT: The peptidic β-lactone proteasome inhibitors (PIs) cystargolides A and B were used to conduct structure-activity relationship (SAR) studies in order to assess their anticancer potential. A total of 24 different analogs were designed, synthesized and evaluated for proteasome inhibition, for cytotoxicity towards several cancer cell lines, and for their ability to enter intact cells. X-ray crystallographic analysis and subunit selectivity was used to determine the specific subunit binding associated with the structural modification of the β-lactone (P₁), peptidic core, (P_x and P_y), and end-cap (P_z) of our scaffold. The cystargolide derivative 5k, structurally unique at both P_y and P₁, exhibited the most promising inhibitory act

SUBMITTER: Niroula D 

PROVIDER: S-EPMC6168434 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature