Lirispirolides A−L, a new class of sesquiterpene-monoterpene heterodimers with anti-neuroinflammatory activity from the rare medicinal plant Liriodendron chinense

Abstract

Lirispirolides A−L (1−12), twelve novel sesquiterpene-monoterpene heterodimers featuring distinctive carbon skeletons, were isolated from the branches and leaves of Chinese tulip tree [Liriodendron chinense (L. chinense)], a rare medicinal and ornamental plant endemic to China. The structural elucidation was accomplished through comprehensive spectroscopic analyses, quantum-chemical calculations, and X-ray crystallography. These heterodimers exhibit a characteristic 2-oxaspiro[4.5]decan-1-one structural motif, biosynthetically formed through intermolecular [4 + 2]-cycloaddition between a germacrane-type sesquiterpene and an ocimene-type monoterpene. The majority of the isolated compounds demonstrated significant anti-neuroinflammatory effects in lipopolysaccharide (LPS)-induced BV-2 microglial cells by reducing the production of pro-inflammatory mediators, specifically tumor necrosis factor-α (TNF-α) and nitric oxide (NO). Further investigation revealed that the lirispirolides’ inhibition of NO release correlated with decreased messenger ribonucleic acid (mRNA) expression of inducible NO synthase (iNOS).

Keywords

Liriodendron chinense / Magnoliaceae / Lirispirolides / Sesquiterpene-monoterpene heterodimers / Anti-neuroinflammation

References

[1] Xia N, Liu Y, Hans PN. Flora of China. Beijing: Science Press. 2008;7:48-91.

[2] Jiangsu New Medical College. A Dictionary of the Traditional Chinese Medicine. Shanghai Science and Technology Press. 1986:1157-1628.

[3] Ministry of Ecology and Environment of the People’s Republic of China. List of Red Species of Biodiversity in China: Higher Plants Volume. 2023-05-19. https://www.mee.gov.cn/xxgk2018/xxgk/xxgk01/202305/t20230522_1030745.html.

[4] Cho HM, Park EJ, Park YJ, et al. Sesquiterpene lactone and its unique proaporphine hybrids from Magnolia grandiflora L. and their anti-inflammatory activity. Phytochemistry. 2022;200:113211. https://doi.org/10.1016/j.phytochem.2022.113211.

[5] He YH, Li QX, Wu YF, et al. Liriogerphines A-D, a class of sesquiterpene‐alkaloid hybrids from the rare Chinese tulip tree plant. J Org Chem. 2022; 87(10):6927-6933. https://doi.org/10.1021/acs.joc.2c00318.

[6] He YH, Xiang H, Li QX, et al. Liriogerphines E-U, further unique sesquiterpene-alkaloid hybrids from the rare Chinese tulip tree. Phytochemistry. 2024;218:13956. https://doi.org/10.1016/j.phytochem.2023.113956.

[7] Xu KL, Li C, Li CJ, et al. Oligomeric phenylpropanoids having new skeletons and hypoglycemic activity from Magnolia officinalis var. biloba. Org Chem Front. 2021; 8(17):4833-4838. https://doi.org/10.1039/D1QO00795E.

[8] Xu KL, Ma J, Li C, et al. P-menthane-based meroterpenoids with neuroprotective effects from the bark of Magnolia officinalis var. biloba. Tetrahedron. 2022;123:132964. https://doi.org/10.1016/j.tet.2022.132964.

[9] Li C, Li CJ, Ma J, et al. Magterpenoids A-C, three polycyclic meroterpenoids with PTP1B inhibitory activity from the bark of Magnolia officinalis var. biloba. Org Lett. 2018; 20(12):3682-3686. https://doi.org/10.1021/acs.orglett.8b01476.

[10] Li C, Li CJ, Ma J, et al. Magmenthanes A-H: eight new meroterpenoids from the bark of Magnolia officinalis var. biloba. Bioorg Chem. 2019;88:102948. https://doi.org/10.1016/j.bioorg.2019.102948.

[11] Hu X, Sui X, Wang Y, et al. Sesquiterpene-neolignans from Manglietia hookeri. Nat Prod Res. 2016; 30(13):1477-1483. https://doi.org/10.1080/14786419.2015.1110703.

[12] Ninh PT, Ha CTT, Thai TH, et al. Chevalierinol A and B, two new neolignan sesquiterpenoids from Magnolia chevalieri. Nat Prod Res. 2021; 35(21):3745-3751. https://doi.org/10.1080/14786419.2020.1736061.

[13] Tietze LF, Bell HP, Chandrasekhar S. Natural product hybrids as new leads for drug discovery. Angew Chem Int Ed. 2003; 42(34):3996-4028. https://doi.org/10.1002/anie.200200553.

[14] Walsh CT, Fischbach MA. Natural products version 2.0: connecting genes to molecules. J Am Chem Soc. 2010; 132(8):2469-2493. https://doi.org/10.1021/ja909118a.

[15] Yang XW, Grossman RB, Xu G. Research progress of polycyclic polyprenylated acylphloroglucinols. Chem Rev. 2018; 118(7):3508-3558. https://doi.org/10.1021/acs.chemrev.7b00551.

[16] Liu B, Fu S, Zhou C. Naturally occurring [4 + 2] type terpenoid dimers: sources, bioactivities and total syntheses. Nat Prod Rep. 2020; 37(12):1627-1660. https://doi.org/10.1039/C9NP00037B.

[17] Wang GQ. Compilation of Countrywide Herbal Medicine of China..Vol. II. Beijing: People’s Medical Publishing House. 2014.

[18] Fu LK, Jin JM. China Plant Red Data Book. Rare and Endangered Plants I. Beijing: Science Press. 1992.

[19] Phan KL. Liriodendron chinense. The IUCN Red List of Threatened Species. 2015:e.T31284A2803363. https://www.iucnredlist.org/species/31284/2803363.

[20] National Forestry and Grassland Administration. List of National Key Protected Wild Plants. 2021-09-07. https://www.gov.cn/zhengce/zhengceku/2021-09/09/content_5636409.htm.

[21] Wu YF, Zhao ZY, Yang MJ, et al. Pentacyclic triterpenoids as potential ACL inhibitors from the rare medicinal plant Semiliquidambar cathayensis. Fitoterapia. 2024;176:106018. https://doi.org/10.1016/j.fitote.2024.106018.

[22] Dong Y, Liang D, Huang JJ, et al. Sesquiterpenes with quinone reductase-inducing activity from Lirodendron chinense. Nat Prod Commun. 2009; 4(4):467-468.

[23] Doskotch RW, Jr Keely SL, Hufford CD, et al. New sesquiterpene lactones from Liriodendron tulipifera. Phytochemistry. 1975; 14(3):769-773. https://doi.org/10.1016/0031-9422(75)83032-9.

[24] Andersson PG, Bäckvall JE. Synthesis of furanoid terpenes via an efficient palladium-catalyzed cyclization of 4,6-dienols. J Org Chem. 1991; 56(18):5349-5353. https://doi.org/10.1021/jo00018a027.

[25] Rücker G, Mayer R, Manns D. α- and β-Myrcene hydroperoxide from Artemisia annua. J Nat Prod. 1987; 50(2):287-289. https://doi.org/10.1021/np50050a038.

[26] Bruhn T, Schaumloffel A, Hemberger Y, et al. SpecDis: quantifying the comparison of calculated and experimental electronic circular dichroism spectra. Chirality. 2013; 25(4):243-249. https://doi.org/10.1002/chir.22138.

[27] Marcarino MO, Cicetti S, Zanardi MM, et al. A critical review on the use of DP4+ in the structural elucidation of natural products: the good, the bad and the ugly. A practical guide. Nat Prod Rep. 2022; 39(1):58-76. https://doi.org/10.1039/D1NP00030F.

[28] Xiong J, Zhou PJ, Jiang HW, et al. Forrestiacids A and B, pentaterpene inhibitors of ACL and lipogenesis: extending the limits of computational NMR methods in the structure assignment of complex natural products. Angew Chem Int Ed. 2021; 60(41):22270-22275. https://doi.org/10.1002/anie.202109082.

[29] Chen FY, He ML, Xu LL, et al. Lindenane sesquiterpenoid monomers and oligomers: chemistry and pharmacological activities. Phytochemistry. 2023;215:113866. https://doi.org/10.1016/j.phytochem.2023.113866.

[30] Wang XJ, Xin JL, Xiang H, et al. Holotrichones A and B, potent anti-leukemic lindenane-type sesquiterpene trimers with unprecedented complex carbon skeletons from a rare Chloranthus species. Chin Chem Lett. 2024;35:109682. https://doi.org/10.1016/j.cclet.2024.109682.

[31] Son SR, Kim GJ, Choi YJ, et al. Patriniaterpenes A-D: unveiling the unique structure and antioxidant properties of monoterpene-sesquiterpene conjugates from Patrinia scabra. Org Chem Front. 2023; 10(17):4320-4328. https://doi.org/10.1039/D3QO00835E.

[32] Langat MK, Crouch NR, Nuzillard JM, et al. Pseudopulchellol: a unique sesquiterpene-monoterpene derived C-25 terpenoid from the leaves of Croton pseudopulchellus Pax (Euphorbiaceae). Phytochem Lett. 2018; 23:38-40. https://doi.org/10.1016/j.phytol.2017.11.008.

[33] Kim JH, Kim HK, Jeon SB, et al. New sesquiterpene-monoterpene lactone, artemisolide, isolated from Artemisia argyi. Tetrahedron Lett. 2002; 43(35):6205-6208. https://doi.org/10.1016/s0040-4039(02)01315-1.

[34] Su BN, Takaishi Y, Tori M, et al. Macrophyllols A and B, two unusual novel sesquiterpene and monoterpene dimers from the bark of Inula macrophylla. Org Lett. 2000; 2(4):493-496. https://doi.org/10.1021/ol990401n.

[35] Herz W, Pethtel KD, Raulais D. Isoflavones, a sesquiterpene lactone-monoterpene adduct and other constituents of Gaillardia species. Phytochemistry. 1991; 30(4):1273-1279. https://doi.org/10.1016/s0031-9422(00)95216-6.

[36] Bohlmann F, Mathur R, Jakupovic J, et al. Furanoheliangolides and other compounds from Calea hymenolepis. Phytochemistry. 1982; 21(8):2045-2048. https://doi.org/10.1016/0031-9422(82)83040-9.

[37] Appendino G, Taglialatela-Scafati O, Romano A, et al. Genepolide, a sesterpene γ-lactone with a novel carbon skeleton from mountain wormwood (Artemisia umbelliformis). J Nat Prod. 2009; 72(3):340-344. https://doi.org/10.1021/np800468m.

[38] Gao L, Su C, Du X, et al. FAD-dependent enzyme-catalysed intermolecular [4 + 2] cycloaddition in natural product biosynthesis. Nat Chem. 2020; 12(7):620-628. https://doi.org/10.1038/s41557-020-0467-7.

[39] Candelario-Jalil E, Dijkhuizen RM, Magnus T. Neuroinflammation, stroke, blood-brain barrier dysfunction, and imaging modalities. Stroke. 2022; 53(5):1473-1486. https://doi.org/10.1161/STROKEAHA.122.036946.

[40] Stuckey SM, Ong LK, Collins-Praino LE, et al. Neuroinflammation as a key driver of secondary neurodegeneration following stroke. Int J Mol Sci. 2021; 22(23):13101. https://doi.org/10.3390/ijms222313101.

[41] Troubat R, Barone P, Leman S, et al.Neuroinflammation and depression: a review. Eur J Neurosci. 2021; 53(1):151-171. https://doi.org/10.1111/ejn.14720.

[42] Dhapola R, Hota SS, Sarma P, et al. Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimer’s disease. Inflammopharmacology. 2021; 29(6):1669-1681. https://doi.org/10.1007/s10787-021-00889-6.

[43] Ibrahim MA, Na M, Oh J, et al. Significance of endangered and threatened plant natural products in the control of human disease. Proc Natl Acad Sci U S A. 2013; 110(42):16832-16837. https://doi.org/10.1073/pnas.1311528110.

[44] Zhu F, Qin C, Tao L, et al. Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting. Proc Natl Acad Sci U S A. 2011; 108(31):12943-12948. https://doi.org/10.1073/pnas.1107336108.

[45] Wang XJ, Yu SZ, Xin JL, et al. Further terpenoids from the Chloranthaceae plant Chloranthus multistachys and their anti-neuroinflammatory activities. Fitoterapia. 2022;156:105068. https://doi.org/10.1016/j.fitote.2021.105068.