Unprecedented sesterterpenoids, orientanoids A-C: discovery, bioinspired total synthesis and antitumor immunity

Sesterterpenoids are a very rare class of important natural products. Three new skeletal spiro sesterterpenoids, named orientanoids A-C (1-3), were isolated from Hedyosmum orientale. Their structures were determined by a combination of spectroscopic data, X-ray crystallography, and total synthesis. To obtain adequate materials for biological research, the bioinspired total syntheses of 1-3 were effectively achieved in 7-8 steps in overall yields of 2.3-6.4% from the commercially available santonin without using any protecting groups. In addition, this work also revised the stereochemistry of hedyosumins B (6) and C (10) as 11R-configuration. Tumor-associated macrophages (TAMs) have emerged as important therapeutic targets in cancer therapy. The in-depth biological evaluation revealed that these sesterterpenoids antagonized the protumoral and immunosuppressive functional phenotype of macrophages in vitro. Among them, the most potent and major compound 1 inhibited protumoral M2-like macrophages and activated cytotoxic CD8+ T cells, and consequently inhibited tumor growth in vivo. We report a holistic study of the isolation, structure elucidation, total syntheses, and biological evaluation of three unprecedented sesterterpenoids, orientanoids A-C (1-3).