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

ABSTRACT: The peptidic ?-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 ?-lactone (P1), peptidic core, (Px and Py), and end-cap (Pz) of our scaffold. The cystargolide derivative 5k, structurally unique at both Py and P1, exhibited the most promising inhibitory activity for the ?5 subunit of human proteasomes (IC50?=?3.1?nM) and significant cytotoxicity towards MCF-7 (IC50?=?416?nM), MDA-MB-231 (IC50?=?74?nM) and RPMI 8226 (IC50?=?41?nM) cancer cell lines. Cellular infiltration assays revealed that minor structural modifications have significant effects on the ability of our PIs to inhibit intracellular proteasomes, and we identified 5k as a promising candidate for continued therapeutic studies. Our novel drug lead 5k is a more potent proteasome inhibitor than carfilzomib with mid-to-low nanomolar IC50 measurements and it is cytotoxic against multiple cancer cell lines at levels approaching those of carfilzomib.

SUBMITTER: Niroula D 

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

REPOSITORIES: biostudies-literature