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 the overall yields of 2.3–6.4% from the commercially available santonin without using any protecting groups and transition-metal catalysts, which mimicked their biosynthetic proposal chemically. In addition, this work also revised hedyosumins B (7) and C (8) 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 contained tumor growth in vivo.