C1 and N5 derivatives of cerpegin: Synthesis of a new series based on structure-activity relationships to optimize their inhibitory effect on 20S proteasome

摘要

Thirty-two new derivatives of cerpegin (1,1,5-trimethylfuro[3,4-c]pyridine- 3,4-dione) were designed and synthesized in high yield by a new method, combining several C1 and N5 substituents. All compounds were tested for their inhibitory effect on the CT-L, T-L and PA proteolytic activities of a purified mammalian 20S proteasome. Only one molecule inhibited both CT-L and PA activities. Sixteen molecules specifically inhibited PA at the micromolar range, out of which fourteen had IC50 values around 5 μM and two had IC50 values closer to 2 μM. Except in one case, neither calpain I nor cathepsin B was inhibited. In silico docking suggests a unique mode of binding of the most efficient compounds to the β1 catalytic site (PA activity) in relation to the chemical nature of C1 substituents.