Organocatalytic Asymmetric Synthesis of Spiro-oxindole Piperidine Derivatives That Reduce Cancer Cell Proliferation by Inhibiting MDM2-p53 Interaction

摘要

Asymmetric synthesis of pharmacologically interesting piperidine-fused spiro-oxindole derivatives has been achieved via an organocatalytic Michael/aza-Henry/hemiaminalization cascade reaction. Chiral compounds synthesized by this strategy potently inhibited the proliferation of several breast cancer cell lines. MeChanistic studies suggest that the most potent compound 9e can directly interfere with MDM2-p53 interactions and elevate protein levels of p53 and p21, thereby inducing cell cycle arrest and mitochondrial apoptosis.