Tetrahydroisoquinoline (THIQ) is a privileged scaffold with wide range of pharmacological activities, which are also existed in many natural alkaloids. For instance, the families of naphthyridinomycin, saframycin, quinocarcin and compound (+)-crispine A, noscapine possess remarkable antitumor activities. The fact that Trabectedin has even been licensed by the European Medicines Agency for the treatment of soft tissue sarcoma. For these reasons, the development of reliable synthetic approaches to synthesize THIQ derivatives become an extremely attractive area. Another attractive synthetic target is the C3-spirooxindole framework, which shows intriguing bioactivities, including antitumor effects. Previous studies have established a series of effective methods for the enantioselective synthesis of N-containing heterocycles fused spirooxindole. However, the combination of C3-spirooxindoles and the antitumor THIQ skeleton has rarely been reported. Herein, we developed an organocatalytic Mannich/hemiaminalization cascade reaction for the construction of chiral THIQ-fused spirooxindoles, which hybridize two privileged scaffolds in antitumor natural products. Some of them can inhibit the proliferation and invasion of colon adenocarcinoma cells. Mechanistic studies demonstrated the most efficient compound, 3m, inhibits the activation of Ras-GTP, ultimately initiating mitochondrial apoptosis.

Organocatalytic mannich-hemiaminalization cascade strategy for the asymmetric synthesis of spirooxindole tetrahydroisoquinoline derivatives as novel Ras-GTP inhibitors

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.