A new series of N5 derivatives of the 1,1,5-trimethyl furo[3,4-c]pyridine-3,4-dione (cerpegin) selectively inhibits the post-acid activity of mammalian 20S proteasomes

A large set of N5-derivatives of cerpegin (1,1,5-trimethyl furo[3,4-c]pyridine-3,4-dione) was designed and synthesized in high yields by a simple and handy method using various primary amines for a pyridine cycle synthesis. The effects of 29 derivatives on the three types of catalytic sites of purified mammalian 20S proteasomes (CT-L, T-L and PA) were measured. Most of the new compounds specifically inhibited the PA activity, in the micromolar range. Docking experiments support these results. Moreover, neither calpain I nor cathepsin B were inhibited.

Graphical abstractA new class of 20S proteasome inhibitors, derived from the 1,1,5-trimethyl furo[3,4-c]pyridine-3,4-dione scaffold of cerpegin, is described. Most of them specifically inhibited the post-acid (PA) activity of mammalian proteasomes. Docking experiments performed on representative members of this new class corroborate the specificities observed in vitro and suggest a model for inhibition.Figure optionsDownload full-size imageDownload as PowerPoint slide