Issue 46, 2023

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

Abstract

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.

Graphical abstract: Unprecedented sesterterpenoids, orientanoids A–C: discovery, bioinspired total synthesis and antitumor immunity

Supplementary files

Article information

Article type
Edge Article
Submitted
12 Aug. 2023
Accepted
05 Nov. 2023
First published
06 Nov. 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2023,14, 13410-13418

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

C. Zheng, J. Zhao, C. Yuan, X. Peng, M. Geng, J. Ai, Y. Fan and J. Yue, Chem. Sci., 2023, 14, 13410 DOI: 10.1039/D3SC04238C

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