Towards the Synthesis Dual-Inhibitors of Fatty Acid Synthase and the Human 20S Proteasome as Anticancer Agents

Abstract

Human fatty acid synthase (FAS) and the human 20S proteasome are useful targets for anticancer chemotherapy, and the latter target has been validated as a target for treatment of various forms of cancer. Belactosin C, cinnabaramide A, and orlistat are three β-lactone containing compounds that have been shown to inhibit either FAS or the human 20S proteasome, leading to tumor cell death via apoptosis. This project describes the design and synthesis of novel dual inhibitors of these two enzyme targets premised on these three β-lactone containing compounds with the goal of finding a more potent and “druggable” inhibitor. The key step in this synthesis of the described synthetic strategy toward these dual inhibitors is a nucleophile catalyzed aldol lactonization (NCAL) process to form the γ-lactam fused β-lactone core.