Proteasome inhibition by the natural products epoxomicin and dihydroeponemycin: Insights into specificity and potency

While two structurally related epoxyketone-containing antitumor natural products, epoxomicin and eponemycin, share the proteasome as a common intracellular target, they differ in their antiproliferative activity, proteasome subunit binding specificity, and rates of proteasome inhibition. As a first step towards understanding such differences and developing novel proteasome subunit-specific inhibitors, we report here the synthesis and characterization of epoxomicin/dihydroeponemycin chimerae. Two structurally related epoxyketone-containing natural products, epoxomicin (1) and dihydroeponemycin (2), display differential antiproliferative activity, proteasome subunit binding specificity, and rates of proteasome inhibition. To understand these differences, we report here the synthesis and characterization of epoxomicin/dihydroeponemycin chimerae.