Design, synthesis and biological evaluation of novel antitumor spirotetrahydrothiopyran-oxindole derivatives as potent p53-MDM2 inhibitors.

p53-MDM2 protein-protein interaction is a promising target for novel antitumor drug development. Previously, we identified a new class of spirotetrahydrothiopyran-oxindole p53-MDM2 inhibitors by novel organocatalytic enantioselective cascade reactions. Herein, a series of new derivatives were designed, synthesized and assayed to investigate the structure-activity relationships. Among them, compound B14 bearing a novel spiroindole-thiopyranopyridone scaffold exhibited potent MDM2 inhibitory activity as well as antitumor activity, which could effectively induce the apoptosis of A549 cancer cells. It represents a promising lead compound for the development of novel antitumor agents.