Benzo-fused ten-membered ring meroterpenoids: sources, chemical diversity, biological activities, and biosynthesis

Abstract

Meroterpenoids, a class of hybrid natural products derived from both terpenoid and non-terpenoid biosynthetic pathways, serve as a prolific source of drug leads, because of their structural complexity and extensive bioactivities. Meroterpenoids have provided many clinical drugs or promising leads, such as mycophenolic acid (an immunosuppressant), territrem B (an acetylcholinesterase inhibitor), and pyripyropene A (a cholesterol acyltransferase-2 inhibitor). Recently, meroterpenoids featuring a benzo-fused ten-membered ring skeleton have attracted considerable attention for their unique scaffolds and diverse post-modifications. Bioactivity evaluations have revealed that nearly half of these compounds (32 of 66) exhibit cytotoxicity with half-maximal inhibitory concentrations below 10 μM, and therefore have great potential as drug development candidates, particularly in cancer therapy. However, a systematic summary of this subclass remains lacking. Herein, we summarize benzo-fused ten-membered ring meroterpenoids reported between 1980 and 2024, including their sources, structural diversity, bioactivities, and biosynthetic pathways, to provide comprehensive insights to guide further studies on meroterpenoids.

Keywords

Benzo-fused ten-membered ring meroterpenoids / Structural diversity / Cytotoxic activity / Biosynthetic pathway / Natural product drug leads

References

[1] Pfütze S, Charria-Girón E, Schulzke E, Toshe R, Khonsanit A, Franke R, et al.: Depicting the Chemical Diversity of Bioactive Meroterpenoids Produced by the Largest Organism on Earth. Angewandte Chemie 2024, 63: e202318505.

[2] Barras BJ, Ling T, Rivas F: Recent Advances in Chemistry and Antioxidant/Anticancer Biology of Monoterpene and Meroterpenoid Natural Product. Molecules 2024, 29: 279.

[3] Yin X, Feng T, Li Z-H, Dong Z-J, Li Y, Liu JK: Highly Oxygenated Meroterpenoids from Fruiting Bodies of the Mushroom Tricholoma terreum . Journal of Natural Products 2013, 76: 1365-1368.

[4] Wang Y, Zhu Y, Xiao L, Ge L, Wu X, Wu W, et al.: Meroterpenoids Isolated from Arnebia euchroma (Royle) Johnst. and Their Cytotoxic Activity in Human Hepatocellular Carcinoma Cells . Fitoterapia 2018, 131: 236-244.

[5] Qin G, Guo P, Wang Q, Nikolovski G, Wang W, Xuan L: Two Novel Meroterpenoids with a 6/10/5 Tricyclic System Containing a Pyran-4-one Ring from Arnebia euchroma . Tetrahedron Letters 2024, 151: 155318.

[6] Yan H-W, Zhao L-H, Zhang X, Yang Y-N, Yuan X, Zhang P-C: Photoinduced Irreversible Intramolecular Proton Transfer of Arnebinones B, D, and E: The Case of Photoenolization at the p-Benzoquinone-CH₂/CH-π System . Journal of Natural Products 2021, 84: 2981-2989.

[7] Yan H-W, Yang Y-N, Zhang X, Jiang J-S, Yuan X, Feng Z-M, et al.: Eight New Arnebinol B-based Meroterpenoids with Planar Chirality in the Constrained 6/10/5 Tricyclic Skeleton from Arnebia euchroma and Their Cytotoxicities . Bioorganic Chemistry 2022, 128: 106091.

[8] Sun Z, Chen D, Li L, Hou Y, Chen M, Huang G, et al.: Clavipyrrine A, a Unique Polycyclic Nitrogenous Meroterpenoid with Promising Anti-glioma Effects Isolated from the Fungus Clitocybe clavipes . Bioorganic Chemistry 2021, 117: 105468.

[9] Cassinelli G, Lanzi C, Pensa T, Gambetta RA, Nasini G, Cuccuru G, et al.: Clavilactones, a Novel Class of Tyrosine Kinase Inhibitors of Fungal Origin. Biochemical Pharmacology 2000, 59: 1539-1547.

[10] Hai P, Jia H, Luo Z, Fan H, He Y, Li X, et al.: Meroterpenoids with Anti-triple Negative Breast Cancer and Antimicrobial Activities from Arnebia euchroma . Fitoterapia 2024, 179: 106234.

[11] Kitazaki T, Oka M, Nakamura Y, Tsurutani J, Doi S, Yasunaga M, et al.: Gefitinib, an EGFR Tyrosine Kinase Inhibitor, Directly Inhibits the Function of P-glycoprotein in Multidrug Resistant Cancer Cells . Lung Cancer 2005, 49: 337-343.

[12] Fujimoto H, Nakayama Y, Yamazaki M: Identification of Immunosuppressive Components of a Mushroom, Lactarius flavidulus . Chemical & Pharmaceutical Bulletin 1993, 41: 654-658.

[13] Lei Q-J, Lyu J, Ma G-X, Sun Z-C, Xu X-D, Wei H, et al.: Chemical Constituents from Clitocybe clavipes and Their Antitumor Activities . China Journal of Chinese Materia Medica 2024, 49: 2947-2952.

[14] Harms K, Paomephan P, Boonpratuang T, Choeyklin R, Boonchird C, Surup F: ent-Clavilactone J and Its Quinone Derivative, Meroterpenoids from the Fungus Resupinatus sp. Journal of Natural Products 2023, 86: 2580-2584.

[15] Chen R, Zhang F, Chen S, Chi X: Checklist of National Key Protected Wild Plants on the Qinghai-Tibetan Plateau. Biodiversity Data Journal 2023, 11: e103289.

[16] Larrosa I, Da Silva MI, Gómez PM, Hannen P, Ko E, Lenger SR, et al.: Highly Convergent Three Component Benzyne Coupling: The Total Synthesis of ent-clavilactone B. Journal of the American Chemical Society 2006, 128: 14042-14043.

[17] Takao K-I, Mori K, Kasuga K, Nanamiya R, Namba A, Fukushima Y, et al.: Total Synthesis of Clavilactones. The Journal of Organic Chemistry 2018, 83: 7060-7075.

[18] Jiang Y, Xiao Z, Du L, Suo Y, Zhang X, Wang W: Cyclization Diversity of Meroditerpenoids from Endophytic Fungi of Medicinal Plants Driven by Synthetic Biology Strategies. Science of Traditional Chinese Medicine 2025, 3: 81-86.

[19] Li R, Wang J, Han Y, Dai Z: Compound Danshen Yeast 1.0. Science of Traditional Chinese Medicine 2024, 2: 303-311.

[20] Yang E, Yao Y, Su H, Sun Z, Gao S-S, Sureram S, et al.: Two Cytochrome P450 Enzymes Form the Tricyclic Nested Skeleton of Meroterpenoids by Sequential Oxidative Reactions. Journal of the American Chemical Society 2024, 146: 11457-11464.

[21] Gómez F, Quijano L, Calderón J, Ríos T: Terpenoids Isolated from Wigandia kunthii . Phytochemistry 1980, 19: 2202-2203.

[22] Arnone A, Cardillo R, Meille SV, Nasini G, Tolazz M: Secondary Mould Metabolites. Part 47. Isolation and Structure Elucidation of Clavilactones A-C, New Metabolites from the Fungus Clitocybe clavipes . Journal of the Chemical Society, Perkin Transactions 1, 1994, 2165-2168.

[23] Hou Y, Li Q, Chen M, Wu H, Yang J, Sun Z, et al.: Novel Geranylhydroquinone Derived Meroterpenoids from the Fungus Clitocybe clavipes and Their Cytotoxic Activity . Fitoterapia 2022, 161: 105251.

[24] Takahashi A, Kusano G, Ohta T, Nozoe S: Revised Structures of Flavidulos, Constituents of Lactarius flavidulus IMAI, and the Structure of Flavidulol D . Chemical and Pharmaceutical Bulletin 1993, 41: 2032-2033.

[25] Wang L, Li F, Liu X, Chen B, Yu K, Wang M-K: Meroterpenoids and a Naphthoquinone from Arnebia euchroma and Their Cytotoxic Activity . Planta Medica 2015, 81: 320-326.

[26] Merlini L, Nasini G, Scaglioni L, Cassinelli G, Lanzi C: Structure Elucidation of Clavilactone D: An Inhibitor of Protein Tyrosine Kinases. Phytochemistry 2000, 53: 1039-1041.

[27] Sun Z, Zhu NL, Zhou M, Huo XW, Wu H, Tian Y, et al.: Clavipines A-C, Antiproliferative Meroterpenoids with a Fused Azepine Skeleton from the Basidiomycete Clitocybe clavipes . Organic Chemistry Frontiers 2019, 6: 3759-3765.

[28] Zhaocui S, Xudong X, Hanqiao L, Xinyi X, Guoxu M, Leiling S: Five New Meroterpenoids from the Fruiting Bodies of the Basidiomycete Clitocybe clavipes with Cytotoxic Activity . Molecules 2019, 24: 4015.

[29] Sun Z, Ma Y, Zhang J, Ma G, Wu H, Shi L, et al.: Four Meroterpenoids with Novel Aminoglycoside Moiety from the Basidiomycete Clitocybe clavipes with Cytotoxic Activity . Molecules 2023, 28: 5456.

[30] Dettrakul S, Surerum S, Rajviroongit S, Kittakoop P: Biomimetic Transformation and Biological Activities of Globiferin, a Terpenoid Benzoquinone from Cordiaglobifera . Journal of Natural Products 2009, 72: 861-865.

[31] Takahashi A, Kusano G, Ohta T, Nozoe S: The Constituents of Lactarius flavidulus IMAI . Chemical & Pharmaceutical Bulletin 1988, 36: 2366-2370.

[32] Vargas Gallego JC . Isolation and Identification of Secondary Metabolites in Leaves from Wigandia urens (Hydrophyllaceae) . Scientia et technica, 2012, 17: 197-202.

[33] Madarshahi FS, Taghizadeh SF, Rezaee R, Azizi M, Asili J, Karimi G: Fungicidal and Anti-aflatoxin Activity of Four Meroterpenoids Isolated from Arnebia euchroma Root . Toxicological & Environmental Chemistry 2022, 104: 263-279.

[34] Silva AK, Pinto FCL, Canuto K, Braz-Filho R, Silva RAC, Santos FA, et al.: Anti-Inflammatory Meroterpenoids of Cordia glazioviana (Boraginaceae) . Journal of the Brazilian Chemical Society 2021, 32: 1424-1434.

[35] Wan H, Li J, Zhang K, Zou X, Ge L, Zhu F, et al.: A New Meroterpenoid Functions as an Anti-tumor Agent in Hepatoma Cells by Downregulating mTOR Activation and Inhibiting EMT. Scientific Reports 2018, 8: 13152.

[36] Toscano RA, Quijano L, Gómez F, García-Pérez G, Rios T: Structure of Wigandol. Acta Crystallographica Section C Crystal Structure Communications 1992, 48: 2000-2002.

[37] Jiang M, Wu Z, Liu L, Chen S: The Chemistry and Biology of Fungal Meroterpenoids (2009-2019). Organic & Biomolecular Chemistry 2021, 19: 1644-1704.

[38] Miyazaki S, Sasazawa Y, Mogi T, Suzuki T, Yoshida K, Dohmae N, et al.: Identification of Seco-clavilactone B as a Small-molecule Actin Polymerization Inhibitor. FEBS Letters 2016, 590: 1163-1173.

[39] Wang S, Wang R, Liu T, Lv C, Liang J, Kang C, et al.: CYP76B74 Catalyzes the 3’’-Hydroxylation of Geranylhydroquinone in Shikonin Biosynthesis. Plant Physiology 2019, 179: 402-414.

[40] Mito K . Overexpression and Functional Analysis of a Membrane-bound Aromatic Prenyltransferase LePGT-1 in Lithospermum erythrorhizon . Uji City, Kyoto, Japan: Sustainable humanosphere: bulletin of Research Institute for Sustainable Humanosphere Kyoto University; 2006, 2: 41- 41.

[41] Yang E, Yao Y, Liu Y, Sun Z, Shi T, Pan Y, et al.: A Gatekeeper Residue Controls Aromatic Acceptor Specificity of the PHB-Type UbiA Prenyltransferases. ACS Catalysis 2023, 13: 13717-13728.

[42] Lu H, Wang S, Gu T, Sun L, Wang Y: Roles of the Fungal-Specific Lysine Biosynthetic Pathway in the Nematode-Trapping Fungus Arthrobotrys oligospora Identified through Metabolomics Analyses . Journal of Fungi 2023, 9: 206.

[43] Zhang H, Li Z, Zhou S, Li S-M, Ran H, Song Z, et al.: A Fungal NRPS-PKS Enzyme Catalyses the Formation of the Flavonoid Naringenin. Nature Communications 2022, 13: 6361.

[44] Wang R, Liu C, Lyu C, Sun J, Kang C, Ma Y, et al.: The Discovery and Characterization of AeHGO in the Branching Route from Shikonin Biosynthesis to Shikonofuran in Arnebia euchroma . Frontiers in Plant Science 2023, 14: 1160571.

[45] Bureau J-A, Oliva ME, Dong Y, Ignea C: Engineering Yeast for the Production of Plant Terpenoids Using Synthetic Biology Approaches. Natural Product Reports 2023, 40: 1822-1848.

[46] Zhang N, Li X, Zhou Q, Zhang Y, Lv B, Hu B, et al.: Self-controlled In silico Gene Knockdown Strategies to Enhance the Sustainable Production of Heterologous Terpenoid by Saccharomyces cerevisiae . Metabolic Engineering 2024, 83: 172-182.

[47] Wang J, Ji X, Yi R, Li D, Shen X, Liu Z, et al.: Heterologous Biosynthesis of Terpenoids in Saccharomyces cerevisiae . Biotechnology Journal 2025, 20: e202400712.

[48] Wang S, Shi L, Wang R, Liu C, Wang J, Shen Y, et al.: Characterization of Arnebia euchroma PGT Homologs Involved in the Biosynthesis of Shikonin . Plant Physiology and Biochemistry 2023, 196: 587-595.

[49] Yang Y-L, Zhou H, Du G, Feng K-N, Feng T, Fu X-L, et al.: A Monooxygenase from Boreostereum vibrans Catalyzes Oxidative Decarboxylation in a Divergent Vibralactone Biosynthesis Pathway. Angewandte Chemie 2016, 55: 5463-5466.

[50] Enguita FJ, Leitão AL: Hydroquinone: Environmental Pollution, Toxicity, and Microbial Answers. BioMed Research International 2013, 2013: 542168.

[51] Navale GR, Dharne MS, Shinde SS: Metabolic Engineering and Synthetic Biology for Isoprenoid Production in Escherichia coli and Saccharomyces cerevisiae . Applied Microbiology and Biotechnology 2021, 105: 457-475.

[52] Wang Q, Quan S, Xiao H: Towards Efficient Terpenoid Biosynthesis: Manipulating IPP and DMAPP supply. Bioresources and Bioprocessing 2019, 6: 6.

[53] Forman V, Luo D, Kampranis SC, Stærk D, Møller BL, Pateraki I: Not All Cytochrome b5s are Created Equal: How a Specific CytB5 Boosts Forskolin Biosynthesis in Saccharomyces cerevisiae . Metabolic Engineering 2024, 86: 288-299.

[54] Zhang C, Wu J, Sun Q, Ding S, Tao H, He Y, et al.: De novo Production of Bioactive Sesterterpenoid Ophiobolins in Saccharomyces cerevisiae Cell Factories . Microbial Cell Factories 2024, 23: 129.

[55] Chen L, Xiao W, Yao M, Wang Y, Yuan Y: Compartmentalization Engineering of Yeasts to Overcome Precursor Limitations and Cytotoxicity in Terpenoid Production. Frontiers in Bioengineering and Biotechnology 2023, 11: 1132244.

[56] Gao Q, Xiao W . Advances in the Biosynthesis of Monoterpenes by Yeast. Synthetic Biology Journal, 2025, 6: 357-372.

[57] Pereira R, Mohamed ET, Radi MS, Herrgård MJ, Feist AM, Nielsen J, et al.: Elucidating Aromatic Acid Tolerance at Low pH in Saccharomyces cerevisiae Using Adaptive Laboratory Evolution . Proceedings of the National Academy of Sciences of the United States of America 2020, 117: 27954-27961.

[58] Zhou YJ, Hu Y, Zhu Z, Siewers V, Nielsen J: Engineering 1-Alkene Biosynthesis and Secretion by Dynamic Regulation in Yeast. ACS Synthetic Biology 2018, 7: 584-590.