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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....

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Detalles Bibliográficos
Autores principales: Zheng, Cheng-Yu, Zhao, Jin-Xin, Yuan, Chang-Hao, Peng, Xia, Geng, Meiyu, Ai, Jing, Fan, Yao-Yue, Yue, Jian-Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10685275/
https://www.ncbi.nlm.nih.gov/pubmed/38033907
http://dx.doi.org/10.1039/d3sc04238c
Descripción
Sumario: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.