Atramacronins A−P, eudesmane-type sesquiterpenoid dimers from Atractylodes macrocephala with anti-hepatocellular carcinoma activities

Abstract

Atractylodes macrocephala Koidz. (A. macrocephala) is a medicinal and edible plant species belonging to the Compositae family. Its rhizome serves both therapeutic and nutritional purposes in China. This investigation led to the isolation of thirteen novel rearranged 9(8→7)-abeo-eudesmane-type sesquiterpenoid dimers (SDs), atramacronins A−M (1−13), three eudesmane-type SDs, atramacronins N−P (14−16), and two previously identified meroterpenoids, atrachinenin G (17) and atrachinenin Ι (18), from Atractylodes macrocephala. Structure elucidation was accomplished through comprehensive spectroscopic analysis and single-crystal X-ray diffraction. Compounds 1, 4−7, 9, and 10 exhibited notable cytotoxicity against Hep3B, HepG2, and Huh7 cell lines, with half maximal inhibitory concentration (IC₅₀) values ranging from 3.71 to 13.99 μmol·L⁻¹.

Keywords

Atractylodes macrocephala / Sesquiterpenoid / Cytotoxic activity / Hepatocellular carcinoma

References

[1] Yang L, Yu H, Hou A, et al.A review of the ethnopharmacology, phytochemistry, pharmacology, application, quality control, processing, toxicology, and pharmacokinetics of the dried rhizome of Atractylodes macrocephala. Front Pharmacol. 2021;12:727154. https://doi.org/10.3389/fphar.2021.727154.

[2] Pei T, Dai Y, Tan X, et al. Yupingfeng San exhibits anticancer effect in hepatocellular carcinoma cells via the MAPK pathway revealed by HTS² technology. J Ethnopharmacol. 2023;306:116134. https://doi.org/10.1016/j.jep.2023.116134.

[3] Yang X, Feng Y, Liu Y, et al. Fuzheng Jiedu Xiaoji Formulation inhibits hepatocellular carcinoma progression in patients by targeting the AKT/CyclinD1/p21/p27 pathway. Phytomedicine. 2021;87:153575. https://doi.org/10.1016/j.phymed.2021.153575.

[4] Bailly C. Atractylenolides, essential components of atractylodes-based traditional herbal medicines: antioxidant, anti-inflammatory and anticancer properties. Eur J Pharmacol. 2021;891:173735. https://doi.org/10.1016/j.ejphar.2020.173735.

[5] Jiang Y, Guo K, Wang P, et al. The antitumor properties of atractylenolides: molecular mechanisms and signaling pathways. Biomed Pharmacother. 2022;155:113699. https://doi.org/10.1016/j.biopha.2022.113699.

[6] Ma L, Chen Y, Shan W, et al.Natural disesquiterpenoids: an update. Nat Prod Rep. 2020; 37:999-1030. https://doi.org/10.1039/C9NP00062C.

[7] Ma Y, Dou X, Tian X. Natural disesquiterpenoids: an overview of their chemical structures, pharmacological activities, and biosynthetic pathways. Phytochem Rev. 2020; 19:983-1043. https://doi.org/10.1007/s11101-020-09698-1.

[8] Meng F, Wang Z, Peng S, et al. Recent advances of sesquiterpenoid dimers from Compositae: distribution, chemistry and biological activities. Phytochem Rev. 2024; 23:625-655. https://doi.org/10.1007/s11101-023-09911-x.

[9] Zhan ZJ, Ying YM, Ma LF, et al. Natural disesquiterpenoids. Nat Prod Rep. 2011; 28:594-629. https://doi.org/10.1039/c0np00050g.

[10] Zhao WY, Yan JJ, Liu TT, et al. Natural sesquiterpenoid oligomers: a chemical perspective. Eur J Med Chem. 2020;203:112622. https://doi.org/10.1016/j.ejmech.2020.112622.

[11] Zhang H, Li J, Si J, et al. Atramacronoids A-C, three eudesmanolide sesquiterpene-phenol hybrids with an unprece dente d C-C linkage from the rhizomes of Atractylodes macrocephala. Chin Chem Lett. 2023;34:107743. https://doi.org/10.1016/j.cclet.2022.107743.

[12] Chen F, Liu D, Fu J, et al. (±)-Atrachinenins A-C, three pairs of caged C27 meroterpenoids from the rhizomes of Atractylodes chinensis. Chin J Chem. 2021; 40:460-466. https://doi.org/10.1002/cjoc.202100700.

[13] Chen F, Liu D, Ren W, et al. Atrachinenins D-S, novel meroterpenoids with geranyl hydroquinone moiety from Atractylodes chinensis by the LC/MS-based molecular decoy and targeted isolation. Bioorg Chem. 2024;144:107111. https://doi.org/10.1016/j.bioorg.2024.107111.

[14] Lauro G, Das P, Riccio R, et al. DFT/NMR approach for the configuration assignment of groups of stereoisomers by the combination and comparison of experimental and predicted sets of data. J Org Chem. 2020; 85:3297-3306. https://doi.org/10.1021/acs.joc.9b03129.

[15] Zhou Y, Gao H, Wu X, et al. Chemical constituents of petroleum ether extracted from Atractylodes japonica. Acta Chin Med Pharm. 2020; 48(4):26-29. https://doi.org/10.19664/j.cnki.1002-2392.200209.

[16] Zhao YN, Gao G, Ma JL, et al. Two new sesquiterpenes from the rhizomes of Atractylodes macrocephala and their biological activities. Nat Prod Res. 2022; 36(5):1230-1235. https://doi.org/10.1080/14786419.2020.1869970.

[17] Wang HX, Liu CM, Liu Q, et al. Three types of sesquiterpenes from rhizomes of Atractylodes lancea. Phytochemistry. 2008; 69:2088-2094. https://doi.org/10.1016/j.phytochem.2008.04.008.

[18] Zhang WJ, Li XH, Shi YP. A pair of epimeric spirosesquiterpenes from the roots of Ligularia fischeri. J Nat Prod. 2010; 73:143-146. https://doi.org/10.1021/np900492b.

[19] Meng FC, Ma YX, Zhan HH, et al. Lignans from the seeds of Herpetospermum pedunculosum and their farnesoid X receptor-activating effect. Phytochemistry. 2022;193:113010. https://doi.org/10.1016/j.phytochem.2021.113010.

[20] Lodewyk MW, Soldi C, Jones PB, et al. The correct structure of aquatolide-experimental validation of a theoretically-predicted structural revision. J Am Chem Soc. 2012; 134:18550-18553. https://doi.org/10.1021/ja3089394.