| Natural proteasome inhibitors such as omuralide and salinosporamide A exhibit potent cancer cell cytotoxicity, through selective inhibition of the 20S proteasome. Recently, the mechanism of resistance to salinosporamide A was proposed by Moore (UCSD, SIO) based on gene analysis of sediment bacteria Salinospora which produces the compound. In this research, initial design and the synthesis of salinosporamide A-resistant proteasome inhibitor is demonstrated. It features a stereoselective Ugi 4-center 3-component condensation reaction of gamma-ketoacid with novel convertible isocyanides. This forms a functionalized pyroglutamic acid, and further manipulations afford the fused gamma-lactam-beta-lactone core bicyclic ring of the natural product, which is essential to the action of the inhibition. |
