The chemical structures and biological activities of marine terpenoids: a review and perspective from cheminformatics

Abstract

Marine terpenoids are a structurally diverse class of natural products produced by marine organisms, characterized by unique molecular architectures and notable biological activities. They play essential roles in ecological interactions and chemical defense, while also exhibiting promising therapeutic properties, including anti-inflammatory and anti-tumor effects. In this review, we compile 13 132 reported marine terpenoids, of which 2066 have documented biological activities, and provide a concise summary of their organismal origins, molecular scaffolds, and associated activities. Cheminformatics approaches are further applied to compare the chemical space of marine versus terrestrial terpenoids, highlighting their structural distinctiveness. Finally, we discuss promising directions for the discovery, utilization, and synthesis of marine terpenoids, with the goal of promoting comprehensive and sustainable exploration of these valuable marine resources.

Keywords

Terpenoids / Marine / Biological activity / Drug discovery / Cheminformatics

References

[1] Tetali SD. Terpenes and isoprenoids: a wealth of compounds for global use. Planta. 2019; 249(1):1-8. https://doi.org/10.1007/s00425-018-3056-x.

[2] Nagegowda DA, Gupta P. Advances in biosynthesis, regulation, and metabolic engineering of plant specialized terpenoids. Plant Sci. 2020;294:110457. https://doi.org/10.1016/j.plantsci.2020.110457.

[3] Li X, Ju J. Intracellularly driven chemical modifications of antimicrobial secondary metabolites: potent mechanisms of self-resistance. Pharm Sci Adv. 2024;2:100032. https://doi.org/10.1016/j.pscia.2023.100032.

[4] Gozari M, Alborz M, El-Seedi HR, et al. Chemistry, biosynthesis and biological activity of terpenoids and meroterpenoids in bacteria and fungi isolated from different marine habitats. Eur J Med Chem. 2021;210:112957. https://doi.org/10.1016/j.ejmech.2020.112957.

[5] Shikov AN, Flisyuk EV, Obluchinskaya ED, et al. Pharmacokinetics of marine-derived drugs. Mar Drugs. 2020; 18(11):557. https://doi.org/10.3390/md18110557.

[6] Molinski TF, Dalisay DS, Lievens SL, et al. Drug development from marine natural products. Nat Rev Drug Discov. 2009; 8(1):69-85. https://doi.org/10.1038/nrd2487.

[7] Zeng T, Chen Y, Jian Y, et al. Chemotaxonomic investigation of plant terpenoids with an established database (TeroMOL). New Phytol. 2022; 235(2):662-673. https://doi.org/10.1111/nph.18133.

[8] Cole TJ, Short KL, Hooper SB. The science of steroids. Semin Fetal Neonatal Med. 2019; 24(3):170-175. https://doi.org/10.1016/j.siny.2019.05.005.

[9] Russo D, Milella L.Analysis of meroterpenoids. Recent Advances in Natural Products Analysis. Amsterdam: Elsevier, 2020:477-501. https://doi.org/10.1016/b978-0-12-816455-6.00014-7.

[10] Shang J, Hu B, Wang J, et al. Cheminformatic insight into the differences between terrestrial and marine originated natural products. J Chem Inf Model. 2018; 58(6):1182-1193. https://doi.org/10.1021/acs.jcim.8b00125.

[11] Proksch P, Edrada R, Ebel R. Drugs from the seas-current status and microbiological implications. Appl Microbiol Biotechnol. 2002; 59(2):125-134. https://doi.org/10.1007/s00253-002-1006-8.

[12] Papon N, Copp BR, Courdavault V. Marine drugs: Biology, pipelines, current and future prospects for production. Biotechnol Adv. 2022;54:107871. https://doi.org/10.1016/j.biotechadv.2021.107871.

[13] Gross H, König GM. Terpenoids from marine organisms: unique structures and their pharmacological potential. Phytochem Rev. 2006; 5(1):115-141. https://doi.org/10.1007/s11101-005-5464-3.

[14] Caplan S, Zheng B, Dawson-Scully K, et al. Pseudopterosin A: protection of synaptic function and potential as a neuromodulatory agent. Mar Drugs. 2016; 14(3):55. https://doi.org/10.3390/md14030055.

[15] Ahmed AF, Wu MH, Wang GH, et al. Eunicellin-based diterpenoids, australins A-D, isolated from the soft coral Cladiella australis. J Nat Prod. 2005; 68(7):1051-1055. https://doi.org/10.1021/np0500732.

[16] Chao CH, Chou KJ, Huang CY, et al. Steroids from the soft coral sinularia crassa. Mar Drugs. 2012; 10(2):439-450. https://doi.org/10.3390/md10020439.

[17] Van Minh C, Nam NH, Thao NP, et al. Diterpenoid constituents from Sinularia maxima. J Chem. 2015; 53(2e): 9-12. https://doi.org/10.15625/0866-7144.2015-2e-003.

[18] Wu Q, Li XW, Li H, et al. Bioactive polyoxygenated cembranoids from a novel Hainan chemotype of the soft coral Sinularia flexibilis. Bioorg Med Chem Lett. 2019; 29(2):185-188. https://doi.org/10.1016/j.bmcl.2018.12.004.

[19] Zhu SH, Yu DD, Su MZ, et al. Oxygenated cembrane diterpenes from the South China Sea soft coral Sinularia tumulosa. Chem Biodivers. 2023; 20(7):e202300589. https://doi.org/10.1002/cbdv.202300589.

[20] Li Y, Li S, Cuadrado C, et al. Polyoxygenated anti-inflammatory biscembranoids from the soft coral Sarcophyton tortuosum and their stereochemistry. Chin Chemical Lett. 2021; 32(1):271-276. https://doi.org/10.1016/j.cclet.2020.11.037.

[21] Burks JE, van der Helm D, Chang CY, et al. The crystal and molecular structure of briarein A, a diterpenoid from the Gorgonian Briareum abestinum. Acta Crystallogr B Struct Crystallogr Cryst Chem. 1977; 33(3):704-709. https://doi.org/10.1107/s0567740877004518.

[22] Huynh TH, Liu CJ, Liu YH, et al. Briavioids E-G, newly isolated briarane-diterpenoids from a cultured octocoral briareum violaceum. Mar Drugs. 2023; 21(2):124. https://doi.org/10.3390/md21020124.

[23] Schmitz FJ, Schulz MM, Siripitayananon J, et al. New diterpenes from the Gorgonian solenopodium excavatum. J Nat Prod. 1993; 56(8):1339-1349. https://doi.org/10.1021/np50098a018.

[24] Bloor SJ, Schmitz FJ, Hossain MB, et al. Diterpenoids from the Gorgonian solenopodium stechei. J Org Chem. 1992; 57(4):1205-1216. https://doi.org/10.1021/jo00030a031.

[25] Groweiss A, Look SA, Fenical W. Solenolides, new antiinflammatory and antiviral diterpenoids from a marine octocoral of the genus Solenopodium. J Org Chem. 1988; 53(11):2401-2406. https://doi.org/10.1021/jo00246a001.

[26] Luo ZW, Yin FC, Wang XB, et al. Progress in approved drugs from natural product resources. Chin J Nat Med. 2024; 22(3): 195-211.10.1016/S1875-5364(24)60582-0.

[27] Zheng LG, Chang YC, Hu CC, et al. Fragilides K and L, new briaranes from the Gorgonian coral junceella fragilis. Molecules. 2018; 23(7):1510. https://doi.org/10.3390/molecules23071510.

[28] Yang J, Zhang S, Qia SH, et al. Briarane-type diterpenoids from the China Gorgonian coral Subergorgia reticulata. Biochem Syst Ecol. 2007; 35(11):770-773. https://doi.org/10.1016/j.bse.2007.06.003.

[29] Bahl A, Jachak SM, Palaniveloo K, et al. 2-acetoxyverecynarmin C, a new briarane COX inhibitory diterpenoid from Pennatula aculeata. Nat Prod Commun. 2014; 9(8):1934578X1400900820. https://doi.org/10.1177/1934578x1400900820.

[30] Sun JF, Yang B, Zhou XF, et al. A new briarane-type diterpenoid from the South China Sea GorgonianDichotella gemmacea. Nat Prod Res. 2015; 29(9):807-812. https://doi.org/10.1080/14786419.2014.987774.

[31] Pinto AC, Pizzolatti MG, de A Epifanio R, et al. The isolation of novel diterpenoids, including a C 40 bis-diterpenoid, from the Brazilian plant Vellozia magdalenae (Velloziaceae). Tetrahedron. 1997; 53(6):2005-2012. https://doi.org/10.1016/s0040-4020(96)01183-0.

[32] Zhang BY, Wang H, Luo XD, et al. Bisyinshanic acids a and B, two novel diterpene dimers from the roots of Euphorbia yinshanica. Helv Chim Acta. 2012; 95(9):1672-1679. https://doi.org/10.1002/hlca.201200092.

[33] Zhu C, Xu B, Adpressa DA, et al. Discovery and biosynthesis of a structurally dynamic antibacterial diterpenoid. Angew Chem Int Ed. 2021; 60(25):14163-14170. https://doi.org/10.1002/anie.202102453.

[34] Li Z, Xu B, Kojasoy V, et al. First trans-eunicellane terpene synthase in bacteria. Chem. 2023; 9(3):698-708. https://doi.org/10.1016/j.chempr.2022.12.006.

[35] Li J, Chen B, Fu Z, et al. Discovery of a terpene synthase synthesizing a nearly non-flexible eunicellane reveals the basis of flexibility. Nat Commun. 2024;15:5940. https://doi.org/10.1038/s41467-024-50209-z.

[36] Scesa PD, Lin Z, Schmidt EW. Ancient defensive terpene biosynthetic gene clusters in the soft corals. Nat Chem Biol. 2022; 18(6):659-663. https://doi.org/10.1038/s41589-022-01027-1.

[37] Kennard O, Watson DG, et al.di Sanseverino LR, Chemical studies of marine invertebrates IV. Terpenoids LXII. Eunicellin, a diterpenoid of the Gorgonian. X-ray diffraction analysis of Eunicellin dibromide. Tetrahedron Lett. 1968; 9(24):2879-2884. https://doi.org/10.1016/s0040-4039(00)75652-8.

[38] Li G, Dickschat JS, Guo YW. Diving into the world of marine 2, 11-cyclized cembranoids: a summary of new compounds and their biological activities. Nat Prod Rep. 2020; 37(10):1367-1383. https://doi.org/10.1039/D0NP00016G.

[39] Ciavatta ML, Manzo E, Mollo E, et al. Tritoniopsins A-D, cladiellane-based diterpenes from the South China Sea nudibranch Tritoniopsis elegans and its prey Cladiella krempfi. J Nat Prod. 2011; 74(9):1902-1907. https://doi.org/10.1021/np200342k.

[40] Mancini I, Guella G, Zibrowius H, et al. A novel type of a second epoxy bridge in eunicellane diterpenes: isolation and characterization of massileunicellins A-C from the GorgonianEunicella cavolinii. Helv Chim Acta. 1999; 82(10):1681-1689. https://doi.org/10.1002/(sici)1522-2675(19991006)82:101681::aid-hlca1681>3.0.co;2-9. doi:10.1002/(sici)1522-2675(19991006)82:101681::aid-hlca1681>3.0.co;2-9.

[41] Roussis V, Fenical W, Vagias C, et al. Labiatamides A, B, and other eunicellan diterpenoids from the Senegalese gorgonian Eunicella labiata. Tetrahedron. 1996; 52(8):2735-2742. https://doi.org/10.1016/0040-4020(96)00010-5.

[42] Bioactive compounds from marine Gorgonian corals. Bioactive Natural Products.Amsterdam: Elsevier; 2012:325-351. https://doi.org/10.1016/b978-0-444-59530-0.00012-5.

[43] Huang YQ, Illias AM, Chen PJ, et al. 24-Dehydrohippuristanol, a cytotoxic spiroketal steroid from Isis hippuris. Tetrahedron Lett. 2023;123:154540. https://doi.org/10.1016/j.tetlet.2023.154540.

[44] Tanaka J, Trianto A, Musman M, et al. New polyoxygenated steroids exhibiting reversal of multidrug resistance from the Gorgonian Isis hippuris. Tetrahedron. 2002; 58(32):6259-6266. https://doi.org/10.1016/s0040-4020(02)00625-7.

[45] Yan X, Liu J, Leng X, et al. Chemical diversity and biological activity of secondary metabolites from soft coral genus sinularia since 2013. Mar Drugs. 2021; 19(6):335. https://doi.org/10.3390/md19060335.

[46] Savić MP, Sakač MN, Kuzminac IZ, et al. Structural diversity of bioactive steroid compounds isolated from soft corals in the period 2015-2020. J Steroid Biochem Mol Biol. 2022;218:106061. https://doi.org/10.1016/j.jsbmb.2022.106061.

[47] Huang CY, Liaw CC, Chen BW, et al. Withanolide-based steroids from the cultured soft coral Sinularia brassica. J Nat Prod. 2013; 76(10):1902-1908. https://doi.org/10.1021/np400454q.

[48] Alam M. Exploration of binding affinities of a 3β, 6β-diacetoxy-5α-cholestan-5-ol with human serum albumin: insights from synthesis, characterization, crystal structure, antioxidant and molecular docking. Molecules. 2023; 28(16):5942. https://doi.org/10.3390/molecules28165942.

[49] Seo Y, Rho JR, Cho KW, et al. Isolation of new steroidal hemiacetals from the Gorgonian Euplexaura anastomosans. J Nat Prod. 1996; 59(12):1196-1199. https://doi.org/10.1021/np960543f.

[50] Ioannou E, Abdel-Razik AF, Alexi X, et al. 9, 11-Secosterols with antiproliferative activity from the Gorgonian Eunicella cavolini. Bioorg Med Chem. 2009; 17(13):4537-4541. https://doi.org/10.1016/j.bmc.2009.05.004.

[51] Wang SK, Dai CF, Duh CY. Cytotoxic pregnane steroids from the Formosan soft coral Stereonephthya crystalliana. J Nat Prod. 2006; 69(1):103-106. https://doi.org/10.1021/np050384c.

[52] Wu IT, Fan YC, Lin GZ, et al. A new capnellene skeleton from the octocoral Capnella imbricata (Quoy & Gaimard, 1833). J Mol Struct. 2023;1271:133995. https://doi.org/10.1016/j.molstruc.2022.133995.

[53] Jean YH, Chen WF, Sung CS, et al. Capnellene, a natural marine compound derived from soft coral, attenuates chronic constriction injury-induced neuropathic pain in rats. British J Pharmacology. 2009; 158(3):713-725. https://doi.org/10.1111/j.1476-5381.2009.00323.x.

[54] Han X, Wang Q, Luo X, et al. Lemnalemnanes A-C, three rare rearranged sesquiterpenoids from the soft corals Paralemnalia thyrsoides and Lemnalia sp. Org Lett. 2022; 24(1):11-15. https://doi.org/10.1021/acs.orglett.1c03386.

[55] Xio YJ, Su JH, Tseng YJ, et al. Oxygenated eremophilane- and neolemnane-derived sesquiterpenoids from the soft coral lemnalia philippinensis. Mar Drugs. 2014; 12(8):4495-4503. https://doi.org/10.3390/md12084495.

[56] Keyzers RA, Gray CA, Schleyer MH, et al. Malonganenones A-C, novel tetraprenylated alkaloids from the Mozambique Gorgonian Leptogorgia gilchristi. Tetrahedron. 2006; 62(10):2200-2206. https://doi.org/10.1016/j.tet.2005.12.018.

[57] Clark PGK. Investigations into the H-D exchange of malonganenone B. Victoria University of Wellington Library. 2011. https://doi.org/10.26686/wgtn.16985386

[58] Su JH, Ahmed AF, Sung PJ, et al. Meroditerpenoids from a Formosan soft coral Nephthea chabrolii. J Nat Prod. 2005; 68(11):1651-1655. https://doi.org/10.1021/np050278a.

[59] Rizos SR, Peitsinis ZV, Koumbis AE. Total synthesis of enantiopure chabrolonaphthoquinone B via a stereoselective julia-kocienski olefination. J Org Chem. 2021; 86(15):10440-10454. https://doi.org/10.1021/acs.joc.1c01106.

[60] Yu HB, Chen HY, Duan S, et al. Bioactive scalarane-type sesterterpenoids from marine sources. Chem Biodivers. 2022; 19(5):e202200049. https://doi.org/10.1002/cbdv.202200049.

[61] Yu HB, Hu B, Ning Z, et al. Phyllofenones F-M, scalarane sesterterpenes from the marine sponge phyllospongia foliascens. Mar Drugs. 2023; 21(10):507. https://doi.org/10.3390/md21100507.

[62] Rueda A, Zubía E, Ortega MJ, et al. New cytotoxic metabolites from the SpongeCacospongia scalaris. J Org Chem. 1997; 62(5):1481-1485. https://doi.org/10.1021/jo961975y.

[63] Youssef DTA, Shaala LA, Emara S. Antimycobacterial scalarane-based sesterterpenes from the red sea sponge Hyrtios erecta. J Nat Prod. 2005; 68(12):1782-1784. https://doi.org/10.1021/np0502645.

[64] Somerville MJ, Hooper JNA, Garson MJ. Mooloolabenes A-E, norsesterterpenes from the Australian sponge Hyattella intestinalis. J Nat Prod. 2006; 69(11):1587-1590. https://doi.org/10.1021/np060244i.

[65] Piao SJ, Zhang HJ, Lu HY, et al. Hippolides A-H, acyclic manoalide derivatives from the marine sponge Hippospongia lachne. J Nat Prod. 2011; 74(5):1248-1254. https://doi.org/10.1021/np200227s.

[66] Abdjul DB, Yamazaki H, Kanno SI, et al. Furanoterpenes, new types of protein tyrosine phosphatase 1B inhibitors, from two Indonesian marine sponges, Ircinia and Spongia spp. Bioorg Med Chem Lett. 2017; 27(5):1159-1161. https://doi.org/10.1016/j.bmcl.2017.01.071.

[67] Shirley HJ, Jamieson ML, Brimble MA, et al. A new family of sesterterpenoids isolated around the Pacific Rim. Nat Prod Rep. 2018; 35(3):210-219. https://doi.org/10.1039/C7NP00049A.

[68] Wang W, Lee Y, Lee TG, et al. Phorone a and isophorbasone A, sesterterpenoids isolated from the marine sponge Phorbas sp. Org Lett. 2012; 14(17):4486-4489. https://doi.org/10.1021/ol3019874.

[69] Betancur-Galvis L, Zuluaga C, Arnó M, et al. Cytotoxic effect (on tumor cells) and in vitro antiviral activity against herpes simplex virus of synthetic spongiane diterpenes. J Nat Prod. 2002; 65(2):189-192. https://doi.org/10.1021/np010206t.

[70] Han GY, Sun DY, Liang LF, et al. Spongian diterpenes from Chinese marine sponge Spongia officinalis. Fitoterapia. 2018; 127:159-165. https://doi.org/10.1016/j.fitote.2018.02.010.

[71] Marcos IS, García N, Sexmero MJ, et al. Synthesis of (+)-agelasine C. A structural revision. Tetrahedron. 2005; 61(49):11672-11678. https://doi.org/10.1016/j.tet.2005.09.049.

[72] Rudi A, Kashman Y. Chelodane, barekoxide, and zaatirin—three new diterpenoids from the marine sponge chelonaplysilla erecta. J Nat Prod. 1992; 55(10):1408-1414. https://doi.org/10.1021/np50088a004.

[73] Vogel CV, Pietraszkiewicz H, Sabry OM, et al. Enantioselective divergent syntheses of several polyhalogenated Plocamium monoterpenes and evaluation of their selectivity for solid tumors. Angew Chem Int Ed. 2014; 53(45):12205-12209. https://doi.org/10.1002/anie.201407726.

[74] Du L, Zhou YD, Nagle DG.Inducers of hypoxic response: marine sesquiterpene quinones activate HIF-1. J Nat Prod. 2013; 76(6):1175-1181. https://doi.org/10.1021/np400320r.

[75] Mitome H, Nagasawa T, Miyaoka H, et al. Dactyloquinones C, D and E novel sesquiterpenoid quinones, from the Okinawan marine sponge, Dactylospongia elegans. Tetrahedron. 2002; 58(9):1693-1696. https://doi.org/10.1016/s0040-4020(02)00078-9.

[76] Alvi KA, Tenenbaum L, Crews P. Anthelmintic polyfunctional nitrogen-containing terpenoids from marine sponges. J Nat Prod. 1991; 54(1):71-78. https://doi.org/10.1021/np50073a002.

[77] Itoh T, Sica D, Djerassi C. Minor and trace sterols in marine invertebrates. Part 35. Isolation and structure elucidation of seventy-four sterols from the sponge Axinella cannabina. J Chem Soc Perkin Trans 1. 1983:147. https://doi.org/10.1039/p19830000147.

[78] Anjaneyulu ASR, Krishna Murthy MVR, Gowri PM. Novel epoxy steroids from the Indian Ocean soft CoralSarcophyton crassocaule. J Nat Prod. 2000; 63(1):112-118. https://doi.org/10.1021/np990205p.

[79] Mancini I, Guella G, Guerriero A, et al. Adriadysiolide, the first monoterpenoid isolated from a marine sponge. Helv Chim Acta. 1987; 70(8):2011-2018. https://doi.org/10.1002/hlca.19870700806.

[80] Wilson K, de Rond T, Burkhardt I, et al. Terpene biosynthesis in marine sponge animals. Proc Natl Acad Sci U S A. 2023; 120(9):e2220934120. https://doi.org/10.1073/pnas.2220934120.

[81] Li MY, Yang XB, Pan JY, et al. Granatumins A-G, limonoids from the seeds of a Krishna mangrove, Xylocarpus granatum. J Nat Prod. 2009; 72(12):2110-2114. https://doi.org/10.1021/np900625w.

[82] Shen L, Liao Q, Zhang M, et al. Limonoids with diverse structures of rings-A, B from the Thai mangrove, Xylocarpus moluccensis. Fitoterapia. 2020;147:104737. https://doi.org/10.1016/j.fitote.2020.104737.

[83] Cui J, Wu J, Deng Z, et al. Xylocarpins A-I, limonoids from the Chinese mangrove plant Xylocarpus granatum. J Nat Prod. 2007; 70(5):772-778. https://doi.org/10.1021/np060622j.

[84] Li MY, Yang SX, Pan JY, et al. Moluccensins A-G, phragmalins with a conjugated C-30 carbonyl group from a Krishna mangrove, Xylocarpus moluccensis. J Nat Prod. 2009; 72(9):1657-1662. https://doi.org/10.1021/np9003504.

[85] Huang Y, Hou P, Pan LW, et al. Oleanane-type triterpenoids from Sabia limoniacea and their anti-inflammatory activities. Bioorg Chem. 2024;151:107683. https://doi.org/10.1016/j.bioorg.2024.107683.

[86] Zhu S, Li Y, Yu B. Synthesis of betavulgaroside III, a representative triterpene seco-glycoside. J Org Chem. 2008; 73(13):4978-4985. https://doi.org/10.1021/jo800669h.

[87] Banno N, Akihisa T, Tokuda H, et al. Triterpene acids from the leaves of Perilla frutescensand their anti-inflammatory and antitumor-promoting effects. Biosci Biotechnol Biochem. 2004; 68(1):85-90. https://doi.org/10.1271/bbb.68.85.

[88] Wang JD, Li ZY, Guo YW. Secoatisane- and isopimarane-type diterpenoids from the Chinese mangrove Excoecaria agallocha L. Helv Chim Acta. 2005; 88(5):979-985. https://doi.org/10.1002/hlca.200590092.

[89] Waridel P, Wolfender JL, Lachavanne JB, et al. Ent-Labdane glycosides from the aquatic plant Potamogeton lucens and analytical evaluation of the lipophilic extract constituents of various Potamogeton species. Phytochemistry. 2004; 65(7):945-954. https://doi.org/10.1016/j.phytochem.2004.01.018.

[90] Pal M, Mishra T, Kumar A, et al. Biological evaluation of terrestrial and marine plant originated labdane diterpenes (a review). Pharm Chem J. 2016; 50(8):558-567. https://doi.org/10.1007/s11094-016-1490-2.

[91] Mao SC, Guo YW. A laurane sesquiterpene and rearranged derivatives from the Chinese red alga Laurencia okamurai yamada. J Nat Prod. 2006; 69(8):1209-1211. https://doi.org/10.1021/np0503810.

[92] Liu Z, Chen Y, Chen S, et al. Aspterpenacids a and B, two sesterterpenoids from a mangrove endophytic fungus Aspergillus terreus H010. Org Lett. 2016; 18(6):1406-1409. https://doi.org/10.1021/acs.orglett.6b00336.

[93] Sun Y, Ouyang J, Deng Z, et al. Structure elucidation of five new iridoid glucosides from the leaves of Avicennia marina. Magn Reson Chem. 2008; 46(7):638-642. https://doi.org/10.1002/mrc.2224.

[94] Jiang W, Kuang LS, Hou AJ, et al. Iridoid glycosides from Hedyotis corymbosa. Helv Chim Acta. 2007; 90(7):1296-1301. https://doi.org/10.1002/hlca.200790130.

[95] Klaiklay S, Rukachaisirikul V, Saithong S, et al. Trichothecenes from a soil-derived Trichoderma brevicompactum. J Nat Prod. 2019; 82(4):687-693. https://doi.org/10.1021/acs.jnatprod.8b00205.

[96] Shi ZZ, Liu XH, Li XN, et al. Antifungal and antimicroalgal trichothecene sesquiterpenes from the marine algicolous fungus Trichoderma brevicompactum A-DL-9-2. J Agric Food Chem. 2020; 68(52):15440-15448. https://doi.org/10.1021/acs.jafc.0c05586.

[97] Yamazaki H, Takahashi O, Kirikoshi R, et al. Epipolythiodiketopiperazine and trichothecene derivatives from the NaI-containing fermentation of marine-derived Trichoderma brevicompactum. J Antibiot. 2020; 73(8):559-567. https://doi.org/10.1038/s41429-020-0314-5.

[98] Shu HZ, Peng C, Bu L, et al. Bisabolane-type sesquiterpenoids: Structural diversity and biological activity. Phytochemistry. 2021;192:112927. https://doi.org/10.1016/j.phytochem.2021.112927.

[99] Guo ZY, Song WM, Xia GR, et al. Preparation, structure elucidation, and cytotoxic activity of amide derivatives of hydroxysydonic acid. Chem Nat Compd. 2021; 57(6):1029-1031. https://doi.org/10.1007/s10600-021-03542-4.

[100] Ge Y, Tang WL, Huang QR, et al. New enantiomers of a nor-bisabolane derivative and two new phthalides produced by the marine-derived fungus penicillium chrysogenum LD-201810. Front Microbiol. 2021;12:727670. https://doi.org/10.3389/fmicb.2021.727670.

[101] Yang X, Yu H, Ren J, et al. Sulfoxide-containing bisabolane sesquiterpenoids with antimicrobial and nematicidal activities from the marine-derived fungus Aspergillus sydowii LW09. JoF. 2023; 9(3):347. https://doi.org/10.3390/jof9030347.

[102] Du W, Yang Q, Xu H, et al. Drimane-type sesquiterpenoids from fungi. Chin J Nat Med. 2022; 20(10):737-748. https://doi.org/10.1016/s1875-5364(22)60190-0.

[103] Ma M, Ge H, Yi W, et al. Bioactive drimane sesquiterpenoids and isocoumarins from the marine-derived fungus Penicillium minioluteum ZZ1657. Tetrahedron Lett. 2020; 61(7):151504. https://doi.org/10.1016/j.tetlet.2019.151504.

[104] Liu YF, Yue YF, Feng LX, et al. Asperienes A-D, bioactive sesquiterpenes from the marine-derived fungus aspergillus flavus. Mar Drugs. 2019; 17(10):550. https://doi.org/10.3390/md17100550.

[105] Wang S, Li S, Chen Y, et al. A new phenylspirodrimane derivative from the deep-sea-derived fungus Stachybotrys chartarumFS705. Nat Prod Res. 2025; 39(9):2580-2586. https://doi.org/10.1080/14786419.2024.2305197.

[106] Ma X, Wu M, Chen Z, et al. Phenylspirodrimane with moderate reversal effect of multidrug resistance isolated from the deep-sea fungus stachybotrys sp.3A00409. Molecules. 2024; 29(7):1685. https://doi.org/10.3390/molecules29071685.

[107] Lin S, Huang J, Zeng H, et al. Distachydrimanes A-F, phenylspirodrimane dimers and hybrids with cytotoxic activity from the coral-derived fungus Stachybotrys chartarum. Chin Chem Lett. 2022; 33(10):4587-4594. https://doi.org/10.1016/j.cclet.2022.03.064.

[108] Guo X, Meng Q, Liu J, et al. Sclerotiamides C-H, notoamides from a marine Gorgonian-derived fungus with cytotoxic activities. J Nat Prod. 2022; 85(4):1067-1078. https://doi.org/10.1021/acs.jnatprod.1c01194.

[109] Kato H, Yoshida T, Tokue T, et al. Notoamides A-D: prenylated indole alkaloids isolated from a marine-derived fungus, Aspergillus sp. Angew Chem. 2007; 119(13):2304-2306. https://doi.org/10.1002/ange.200604381.

[110] Finefield JM, Kato H, Greshock TJ, et al. Biosynthetic studies of the notoamides: isotopic synthesis of stephacidin a and incorporation into notoamide B and sclerotiamide. Org Lett. 2011; 13(15):3802-3805. https://doi.org/10.1021/ol201284y.

[111] Zhang P, Li XM, Wang JN, et al. Prenylated indole alkaloids from the marine-derived fungus Paecilomyces variotii. Chin Chemical Lett. 2015; 26(3):313-316. https://doi.org/10.1016/j.cclet.2014.11.020.

[112] Choi BK, Trinh PTH, Lee HS, et al. New ophiobolin derivatives from the marine fungus Aspergillus flocculosus and their cytotoxicities against cancer cells. Mar Drugs. 2019; 17(6):346. https://doi.org/10.3390/md17060346.

[113] Wei H, Itoh T, Kinoshita M, et al. Cytotoxic sesterterpenes,6-epi-ophiobolin G and 6-epi-ophiobolin N, from marine derived fungus Emericella variecolor GF10. Tetrahedron. 2004; 60(28):6015-6019. https://doi.org/10.1016/j.tet.2004.05.021.

[114] Felder S, Kehraus S, Neu E, et al. Salimyxins and enhygrolides: antibiotic, sponge-related metabolites from the obligate marine myxobacterium Enhygromyxa salina. ChemBioChem. 2013; 14(11):1363-1371. https://doi.org/10.1002/cbic.201300268.

[115] Hinkley SF, Moore JA, Squillari J, et al. New atranones from the fungus Stachybotrys chartarum. Magnetic Reson Chem. 2003; 41(5):337-343. https://doi.org/10.1002/mrc.1186.

[116] Yang B, He Y, Lin S, et al. Antimicrobial dolabellanes and atranones from a marine-derived strain of the toxigenic fungus Stachybotrys chartarum. J Nat Prod. 2019; 82(7):1923-1929. https://doi.org/10.1021/acs.jnatprod.9b00305.

[117] Matulja D, Wittine K, Malatesti N, et al. Marine natural products with high anticancer activities. Curr Med Chem. 2020; 27(8):1243-1307. https://doi.org/10.2174/0929867327666200113154115.

[118] Chen B, Qiu P, Xu B, et al. Cytotoxic and antibacterial isomalabaricane terpenoids from the sponge Rhabdastrella globostellata. J Nat Prod. 2022; 85(7):1799-1807. https://doi.org/10.1021/acs.jnatprod.2c00348.

[119] Chao CH, Wu YC, Wen ZH, et al. Steroidal carboxylic acids from soft coral Paraminabea acronocephala. Mar Drugs. 2013; 11(1):136-145. https://doi.org/10.3390/md11010136.

[120] Xio YJ, Su JH, Chen BW, et al. Oxygenated ylangene-derived sesquiterpenoids from the soft coral Lemnalia philippinensis. Mar Drugs. 2013; 11(10):3735-3741. https://doi.org/10.3390/md11103735.

[121] Sunassee SN, Ransom T, Henrich CJ, et al. Steroidal alkaloids from the marine sponge Corticium niger that inhibit growth of human colon carcinoma cells. J Nat Prod. 2014; 77(11):2475-2480. https://doi.org/10.1021/np500556t.

[122] Chen B, Li Y, Li W, et al. Antitumor activity and mechanism of terpenoids in seaweeds based on literature review and network pharmacology. Adv Biol. 2024; 8(3):2300541. https://doi.org/10.1002/adbi.202300541.

[123] Andrianasolo EH, France D, Cornell-Kennon S, et al. DNA methyl transferase inhibiting halogenated monoterpenes from the Madagascar red marine alga Portieria hornemannii. J Nat Prod. 2006; 69(4):576-579. https://doi.org/10.1021/np0503956.

[124] Smyrniotopoulos V, Firsova D, Fearnhead H, et al. Density functional theory (DFT)-aided structure elucidation of linear diterpenes from the Irish brown seaweed Bifurcaria bifurcata. Mar Drugs. 2021; 19(1):42. https://doi.org/10.3390/md19010042.

[125] Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005; 6(12):1191-1197. https://doi.org/10.1038/ni1276.

[126] González Y, Torres-Mendoza D, Jones GE, et al. Marine diterpenoids as potential anti-inflammatory agents. Mediat Inflamm. 2015;2015:263543. https://doi.org/10.1155/2015/263543.

[127] Wu SL, Su JH, Wen ZH, et al. Simplexins A-I, eunicellin-based diterpenoids from the soft coral Klyxum simplex. J Nat Prod. 2009; 72(6):994-1000. https://doi.org/10.1021/np900064a.

[128] Lin MC, Chen BW, Huang CY, et al. Eunicellin-based diterpenoids from the Formosan soft coral Klyxum molle with inhibitory activity on superoxide generation and elastase release by neutrophils. J Nat Prod. 2013; 76(9):1661-1667. https://doi.org/10.1021/np400372v.

[129] Ghallab DS, Ibrahim RS, Mohyeldin MM, et al. Marine algae: a treasure trove of bioactive anti-inflammatory compounds. Mar Pollut Bull. 2024;199:116023. https://doi.org/10.1016/j.marpolbul.2023.116023.

[130] Liu M, Li W, Chen Y, et al. Fucoxanthin: a promising compound for human inflammation-related diseases. Life Sci. 2020;255:117850. https://doi.org/10.1016/j.lfs.2020.117850.

[131] Liu X, Xin J, Sun Y, et al. Terpenoids from marine sources: a promising avenue for new antimicrobial drugs. Mar Drugs. 2024; 22(8):347. https://doi.org/10.3390/md22080347.

[132] Ying Z, Li XM, Yang SQ, et al. New polyketide and sesquiterpenoid derivatives from the Magellan seamount-derived fungus Penicillium rubens AS-130. Chem Biodivers. 2023; 20(4):e202300229. https://doi.org/10.1002/cbdv.202300229.

[133] Wang J, Liu L, Hong LL, et al. New bisabolane-type phenolic sesquiterpenoids from the marine sponge Plakortis simplex. Chin J Nat Med. 2021; 19(8):626-631. https://doi.org/10.1016/s1875-5364(21)60062-6.

[134] Li Y, Jian YJ, Xu F, et al. Five new terpenoids from Viburnum odoratissimum var. sessiliflorum. Chin J Nat Med. 2023; 21(4):298-307. https://doi.org/10.1016/S1875-5364(23)60438-8.

[135] Yi M, Lin S, Zhang B, et al. Antiviral potential of natural products from marine microbes. Eur J Med Chem. 2020;207:112790. https://doi.org/10.1016/j.ejmech.2020.112790.

[136] Fang W, Lin X, Zhou X, et al. Cytotoxic and antiviral nitrobenzoyl sesquiterpenoids from the marine-derived fungus Aspergillus ochraceus Jcma1F17. Med Chem Commun. 2014; 5(6):701-705. https://doi.org/10.1039/C3MD00371J.

[137] Abdjul DB, Yamazaki H, Takahashi O, et al. Two new protein tyrosine phosphatase 1B inhibitors, hyattellactones A and B, from the Indonesian marine sponge Hyattella sp. Bioorg Med Chem Lett. 2015; 25(4):904-907. https://doi.org/10.1016/j.bmcl.2014.12.058.

[138] Liang LF, Gao LX, Li J, et al. Cembrane diterpenoids from the soft coral Sarcophyton trocheliophorum Marenzeller as a new class of PTP1B inhibitors. Bioorg Med Chem. 2013; 21(17):5076-5080. https://doi.org/10.1016/j.bmc.2013.06.043.

[139] Chao CH, Huang LF, Yang YL, et al. Polyoxygenated steroids from the Gorgonian Isis hippuris. J Nat Prod. 2005; 68(6):880-885. https://doi.org/10.1021/np050033y.

[140] Bordeleau ME, Mori A, Oberer M, et al. Functional characterization of IRESes by an inhibitor of the RNA helicase eIF4A. Nat Chem Biol. 2006; 2(4):213-220. https://doi.org/10.1038/nchembio776.

[141] Ran GJ, Wang P, Wang HK, et al. Beautoide A, an anti-osteoclastogenic sterol from Beauveria sp. NBUF 147 associated with an Irciniidae sponge from the marine mesophotic zone. Chem Biodivers. 2024; 21(12):e202401689. https://doi.org/10.1002/cbdv.202401689.

[142] Chen J, Jia Y, Sun Y, et al. Global marine microbial diversity and its potential in bioprospecting. Nature. 2024; 633(8029):371-379. https://doi.org/10.1038/s41586-024-07891-2.

[143] Tao H, Lauterbach L, Bian G, et al. Discovery of non-squalene triterpenes. Nature. 2022; 606(7913):414-419. https://doi.org/10.1038/s41586-022-04773-3.

[144] Li Z, Xu B, Alsup TA, et al. Cryptic isomerization in diterpene biosynthesis and the restoration of an evolutionarily defunct P450. J Am Chem Soc. 2023; 145(41):22361-22365. https://doi.org/10.1021/jacs.3c09446.

[145] Paoli L, Ruscheweyh HJ, Forneris CC, et al. Biosynthetic potential of the global ocean microbiome. Nature. 2022; 607(7917):111-118. https://doi.org/10.1038/s41586-022-04862-3.

[146] Nambisan P. Biodiversity and sharing of biological resources. In: P. Nambisan (Ed.). An introduction to ethical, safety and intellectual property rights issues in biotechnology. Academic Press, 2017;189-209. https://doi.org/10.1016/b978-0-12-809231-6.00008-9.

[147] Gao B, Huang Y, Peng C, et al. High-throughput prediction and design of novel conopeptides for biomedical research and development. BioDesign Res. 2022;2022:9895270. https://doi.org/10.34133/2022/9895270.