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Polyoxygenated cembrane-type diterpenes from the Hainan soft coral Lobophytum crassum as a promising source of anticancer agents with ErbB3 and ROR1 inhibitory potential

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

A detailed chemical investigation of the Hainan soft coral Lobophytum crassum led to the identification of a class of polyoxygenated cembrane-type macrocyclic diterpenes (1–28), including three new flexible cembranoids, lobophycrasins E–G (2–4), and twenty-five known analogues. Their structures were elucidated by combining extensive spectroscopic data analysis, quantum mechanical–nuclear magnetic resonance (QM-NMR) methods, the modified Mosher’s method, X-ray diffraction analysis, and comparison with data reported in the literature. Bioassays revealed that sixteen cembranoids inhibited the proliferation of H1975, MDA-MB231, A549, and H1299 cells. Among them, Compounds 10, 17, and 20 exhibited significant antiproliferative activities with IC50 values of 1.92–8.82 μM, which are very similar to that of the positive control doxorubicin. Molecular mechanistic studies showed that the antitumour activity of Compound 10 was closely related to regulation of the ROR1 and ErbB3 signalling pathways. This study may provide insight into the discovery and utilization of marine macrocyclic cembranoids as lead compounds for anticancer drugs.

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Fig. 1
Fig. 2
Fig. 3
Fig. 4: The structural elucidation of compounds 2–4.
Fig. 5: Effects of Compound 10 on the proliferation and cell cycle progression of NSCLC cells.
Fig. 6: The inhibitory effects of Compound 10 on the migration and invasion of NSCLC cells.
Fig. 7: Effects of Compound 10 on ROS production and apoptosis in NSCLC cells.
Fig. 8: Compound 10 regulated the ROR1 and ErbB3 signalling pathways.
Fig. 9

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Acknowledgements

This research was financially supported by the National Natural Science Foundation of China (Nos. 22167010 and 81991521), the National Key Research and Development Program of China (No. 2022YFC2804100), the Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (No. 23KJB350011), the Shandong Laboratory Program (SYS202205), and the Basic Research Project of Guizhou University (No. 2023-51).

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  1. These authors contributed equally: Shou-mao Shen, Dan-dan Yu

Authors and Affiliations

  1. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China

    Shou-mao Shen, Dan-dan Yu, Lin-mao Ke, Li-gong Yao, Ming-zhi Su & Yue-wei Guo

  2. School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China

    Shou-mao Shen

  3. School of Pharmacy, Yancheng Teachers University, Yancheng, 224002, China

    Shou-mao Shen

  4. School of Medicine, Shanghai University, Shanghai, 200444, China

    Yue-wei Guo

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Contributions

SMS, DDY, and LMK: Investigation, data curation, software, and writing—original draft preparation. LGY: collection of marine material. MZS: Writing-review and editing, visualization. YWG: Writing-review and editing, supervision, visualization, and funding acquisition.

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Correspondence to Ming-zhi Su or Yue-wei Guo.

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Shen, Sm., Yu, Dd., Ke, Lm. et al. Polyoxygenated cembrane-type diterpenes from the Hainan soft coral Lobophytum crassum as a promising source of anticancer agents with ErbB3 and ROR1 inhibitory potential. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01347-z

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