Four new diarylheptanoids and two new terpenoids from the fruits of Alpinia oxyphylla and their anti-inflammatory activities

Abstract

Four previously unreported diarylheptanoids (1a/1b−2a/2b), one undescribed sesquiterpenoid (8), one new diterpenoid (12), and twelve known analogs were isolated from the fruits of Alpinia oxyphylla. The structural elucidation of these compounds was achieved through a comprehensive analysis of spectroscopic data, single-crystal X-ray diffraction, electronic circular dichroism (ECD), and modified Mosher’s method. Enantiomeric mixtures (1a/1b, 2a/2b, 3a/3b, 4a/4b, and 5a/5b) were separated on a chiral column using acetonitrile-water mixtures as eluents. Among them, compounds 3a/3b and 4a/4b were isolated as optically pure enantiomers in the initial chiral separation. Furthermore, most of the isolates were evaluated for their inhibitory effects against the production of nitric oxide (NO) and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW264.7 macrophages. Interestingly, 2 and 4 showed significant inhibitory activities against NO production with IC₅₀ values of 33.65 and 9.88 μmol·L⁻¹ (hydrocortisone: IC₅₀ 34.26 μmol·L⁻¹), respectively. Additionally, they also partially reduced the secretion of IL-6.

Keywords

Alpinia oxyphylla / Diarylheptanoids / Terpenoids / Structural elucidation / Anti-inflammatory activity

References

[1] PharmacopoeiaofthePeople’sRepublicofChina(Part1)[S]. Beijing: China Medical Science Press; 2020.

[2] Dar MY, Shah WA, Rather MA, et al. Chemical composition, in vitro cytotoxic and antioxidant activities of the essential oil and major constituents of Cymbopogon jawarancusa (Kashmir)[J]. Food Chem, 2011, 129(4): 1606-1611.

[3] Thapa P, Lee YJ, Nguyen TT, et al. Eudesmane and eremophilane sesquiterpenes from the fruits of Alpinia oxyphylla with protective effects against oxidative stress in adipose-derived mesenchymal stem cells[J]. Molecules, 2021, 26(6): 1762.

[4] Bian QY, Wang SY, Xu LJ, et al. Two new antioxidant diarylheptanoids from the fruits of Alpinia oxyphylla[J]. J Asian Nat Prod Res, 2013, 15(10): 1094-1099.

[5] He B, Xu F, Yan T, et al. Tectochrysin from Alpinia Oxyphylla Miq. alleviates Aβ(1-42) induced learning and memory impairments in mice[J]. Eur J Pharmacol, 2019, 842: 365-372.

[6] Ji ZH, Zhao H, Liu C, et al. In-vitro neuroprotective effect and mechanism of 2β-hydroxy-δ-cadinol against amyloid β-induced neuronal apoptosis[J]. Neuroreport, 2020, 31(3): 245-250.

[7] Han Y, Wu J, Liu Y, et al. Therapeutic effect and mechanism of polysaccharide from Alpiniae oxyphyllae fructus on urinary incontinence[J]. Int J Biol Macromol, 2019, 128: 804-813.

[8] Su MS, Xu L, Gu SG, et al. Therapeutic effects and modulatory mechanism of Alpiniae oxyphyllae fructus in chronic intermittent hypoxia induced enuresis in rats[J]. Sleep Breath, 2020, 24(1): 329-337.

[9] Zhang T, Qiu J, Wu X, et al. Schizonepeta tenuifolia with Alpinia Oxyphylla alleviates atopic dermatitis and improves the gut microbiome in Nc/Nga mice[J]. Pharmaceutics, 2020, 12(8): 722.

[10] Fang L, Yan Y, Xu Z, et al. Tectochrysin ameliorates murine allergic airway inflammation by suppressing Th2 response and oxidative stress[J]. Eur J Pharmacol, 2021, 902: 174100.

[11] Yoo E, Lee J, Lertpatipanpong P, et al. Anti-proliferative activity of A. Oxyphylla and its bioactive constituent nootkatone in colorectal cancer cells[J]. BMC Cancer, 2020, 20(1): 881.

[12] Dong J, Zhou M, Qin Q, et al. Structurally diverse new eudesmane sesquiterpenoids with anti-inflammatory activity from the fruits of Alpinia oxyphylla[J]. Bioorg Chem, 2023, 134: 106431.

[13] Liu T, Wu H, Jiang H, et al. Echingridimer A, an oxaspiro dimeric sesquiterpenoid with a 6/6/5/6/6 fused ring system from Echinops grijsii and aphicidal activity evaluation[J]. J Org Chem, 2019, 84(17): 10757-10763.

[14] Staerk D, Skole B, Jørgensen FS, et al. Isolation of a library of aromadendranes from Landolphia dulcis and its characterization using the VolSurf approach[J]. J Nat Prod, 2004, 67(5): 799-805.

[15] Macías FA, Simonet AM, Pacheco PC, et al. Natural and synthetic podolactones with potential use as natural herbicide models[J]. J Agric Food Chem, 2000, 48(7): 3003-3007.

[16] Xin M, Guo S, Zhang W, et al. Chemical constituents of supercritical extracts from Alpinia officinarum and the feeding deterrent activity against tribolium castaneum[J]. Molecules, 2017, 22(4): 647.

[17] Honmore VS, Kandhare AD, Kadam PP, et al. Diarylheptanoid, a constituent isolated from methanol extract of Alpinia officinarum attenuates TNF-α level in Freund’s complete adjuvant-induced arthritis in rats[J]. J Ethnopharmacol, 2019, 229: 233-245.

[18] Sun DJ, Zhu LJ, Zhao YQ, et al. Diarylheptanoid: a privileged structure in drug discovery[J]. Fitoterapia, 2020, 142: 104490.

[19] Kuo YH, Shiu LL. Two new sesquiterpenes, 12-hydroxy-α-longipinene and 15-hydroxyacora-4(14),8-diene, from the heartwood of Juniperus chinensis LINN. var. tsukusiensis MASAM[J]. Chem Pharm Bull, 1996, 44: 1758-1760.

[20] Hikino H, Suzuki N, Takemoto T. Sesquiterpenoids. XIV. aynthesis of cyperolone and 3-epi-cyperolone[J]. Chem Pharm Bull, 1967, 15(9): 1395-1404.

[21] Weng Y, Yu X, Li J, et al. Abietane diterpenoids from Lycopodium complanatum[J]. Fitoterapia, 2018, 128: 135-141.

[22] Qin DP, Li HB, Pang QQ, et al. Structurally diverse sesquiterpenoids from the aerial parts of Artemisia annua (Qinghao) and their striking systemically anti-inflammatory activities[J]. Bioorg Chem, 2020, 103: 104221.

Funding

Programs Foundation for Leading Talents in National Administration of Traditional Chinese Medicine of China "Qihuang scholars" Project and Basic Research Program Natural Science Fund-Frontier Leading Technology Basic Research Special Project(SBK2023050003)