Cystargolide-based amide and ester Pz analogs as proteasome inhibitors and anticancer agents

A series of cystargolide-based beta-lactone analogs containing nitrogen atoms at the Pz portion of the scaffold were prepared and evaluated as proteasome inhibitors and for their cytotoxicity profile towards several cancer cell lines. Inclusion of one, two or even three nitrogen atoms at the Pz portion of the cystargolide scaffold is well-tolerated, producing analogs with low nanomolar proteasome inhibition activity, in many cases superior to carfilzomib. Additionally, analog 8g, containing an ester and pyrazine group at Pz, was shown to possess significant activity towards RPMI 8226 cells (IC50 = 21 nM) and to be less cytotoxic towards the normal tissue model MCF10A cells than carfilzomib.