Kaemphenolide: a cyclobutane-bearing phenylpropanoid from Kaempferia galanga L. with nitric oxide inhibitory activity

doi:10.1007/s13659-025-00547-2

Natural Products and Bioprospecting ›› 2025, Vol. 15 ›› Issue (6): 68-68.DOI: 10.1007/s13659-025-00547-2

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Kaemphenolide: a cyclobutane-bearing phenylpropanoid from Kaempferia galanga L. with nitric oxide inhibitory activity

Syarifatul Mufidah^1,2, Yusaku Miyamae³, Hiroyuki Fuchino^4,5, Nobuo Kawahara^4,6

1. Master’s/Doctoral Program in Life Science Innovation, University of Tsukuba, Tsukuba, Japan;
2. Faculty of Pharmacy, Universitas Ahmad Dahlan, Yogyakarta, Indonesia;
3. Institute of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan;
4. Research Center for Medicinal Plant Resources, National Institutes of Biomedical Innovation, Health and Nutrition, Tsukuba, Japan

Received:2025-07-13 Online:2026-01-12
Contact: Yusaku Miyamae Email:E-mail:miyamae.yusaku.fw@u.tsukuba.ac.jp
Supported by:
This research was supported by INPEX Scholarship Foundation.

Kaemphenolide: a cyclobutane-bearing phenylpropanoid from Kaempferia galanga L. with nitric oxide inhibitory activity

Syarifatul Mufidah^1,2, Yusaku Miyamae³, Hiroyuki Fuchino^4,5, Nobuo Kawahara^4,6

1. Master’s/Doctoral Program in Life Science Innovation, University of Tsukuba, Tsukuba, Japan;
2. Faculty of Pharmacy, Universitas Ahmad Dahlan, Yogyakarta, Indonesia;
3. Institute of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan;
4. Research Center for Medicinal Plant Resources, National Institutes of Biomedical Innovation, Health and Nutrition, Tsukuba, Japan

通讯作者: Yusaku Miyamae Email:E-mail:miyamae.yusaku.fw@u.tsukuba.ac.jp
基金资助:
This research was supported by INPEX Scholarship Foundation.

Abstract

Abstract: An undescribed phenylpropanoid dimer featuring a rare cyclobutane ring was isolated from the rhizomes of Kaempferia galanga L., a medicinal plant traditionally used in Southeast Asia for its anti-inflammatory and therapeutic properties. Kaemphenolide (1), along with five known constituents, was obtained by separations of methanolic extract using chromatography. The presence of a cyclobutane ring within the phenylpropanoid scaffold represents an unusual structural motif among natural products and underscores the chemical uniqueness of this molecule. To evaluate its biological relevance, 1 was tested for its ability to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The compound exhibited anti-inflammatory activity, with an IC₅₀ value of 23.1 ± 6.40 μM.

Key words: Phenylpropanoid, Cyclobutane, Kaempferia galanga, Anti-inflammation

摘要： An undescribed phenylpropanoid dimer featuring a rare cyclobutane ring was isolated from the rhizomes of Kaempferia galanga L., a medicinal plant traditionally used in Southeast Asia for its anti-inflammatory and therapeutic properties. Kaemphenolide (1), along with five known constituents, was obtained by separations of methanolic extract using chromatography. The presence of a cyclobutane ring within the phenylpropanoid scaffold represents an unusual structural motif among natural products and underscores the chemical uniqueness of this molecule. To evaluate its biological relevance, 1 was tested for its ability to inhibit nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The compound exhibited anti-inflammatory activity, with an IC₅₀ value of 23.1 ± 6.40 μM.

关键词: Phenylpropanoid, Cyclobutane, Kaempferia galanga, Anti-inflammation

Syarifatul Mufidah, Yusaku Miyamae, Hiroyuki Fuchino, Nobuo Kawahara. Kaemphenolide: a cyclobutane-bearing phenylpropanoid from Kaempferia galanga L. with nitric oxide inhibitory activity[J]. Natural Products and Bioprospecting, 2025, 15(6): 68-68.

References

[1] Kumar A. Phytochemistry, pharmacological activities and uses of traditional medicinal plant Kaempferia galanga L.—an overview. J Ethnopharmacol. 2020;253:112667.
[2] Hashiguchi A, San M, Duangsodsri TT, Kusano Kazuo M, Watanabe N. Biofunctional properties and plant physiology of Kaempferia spp: status and trends. J Funct Foods. 2022;92:105029.
[3] Khairullah Aswin R, Sholikhah TI, Ansori ANM, Hanisia RH, Puspitarani GA, Fadholly A, et al. Medicinal importance of Kaempferia galanga L. (Zingiberaceae): a comprehensive review. J Herbmed Pharmacol. 2021;10(3):281-8.
[4] Sulaiman MR, Zakaria ZA, Daud IA, Ng FN, Ng YC, Hidayat MT. Antinociceptive and anti-inflammatory activities of the aqueous extract of Kaempferia galanga leaves in animal models. J Nat Med. 2008;62(2):221-7.
[5] Srivastava N, Mishra S, Iqbal H, Chanda D, Shanker K. Standardization of Kaempferia galanga L. rhizome and vasorelaxation effect of its key metabolite ethyl p-methoxycinnamate. J Ethnopharmacol. 2021;271:113911.
[6] Ridtitid W, Sae-wong C, Reanmongkol W, Wongnawa M. Antinociceptive activity of the methanolic extract of Kaempferia galanga Linn. in experimental animals. J Ethnopharmacol. 2008;118(2):225-30.
[7] Liu H, Chen Y, Hu Y, Zhang W, Zhang H. Protective effects of an alcoholic extract of Kaempferia galanga L. rhizome on ethanol-induced gastric ulcer in mice. J Ethnopharmacol. 2024;325:117845.
[8] Surya R, Romulo A, Nurkolis F, Kumalawati DA. Natural products in beverages. Cham: Springer; 2025. p. 307-39.
[9] Wang SY, Zhao H, Xu H, Han X, Wu Y. Kaempferia galanga L.: Progresses in phytochemistry, pharmacology, toxicology and ethnomedicinal uses. Front Pharmacol. 2021;12:675350.
[10] Ferrer JL, Austin MB, Stewart C, Noel JP. Structure and function of enzymes involved in the biosynthesis of phenylpropanoids. Plant Physiol Biochem. 2008;46(3):356-70.
[11] Zhu Y, Chen L, Zeng J, Xu J, Hu H, He X, et al. Six new phenylpropanoids from Kaempferia galanga L. and their anti-inflammatory activity. Fitoterapia. 2024;176:106028.
[12] Yang P, Jia Q, Song S, Huang X. [2 + 2]-Cycloaddition-derived cyclobutane natural products: structural diversity, sources, bioactivities, and biomimetic syntheses. Nat Prod Rep. 2023;40(6):1094-129.
[13] Van der Kolk MR, Janssen MACH, Rutjes FPJT, Blanco-Ania D. Cyclobutanes in small-molecule drug candidates. Chem Med Chem. 2022;17(9):20.
[14] Li J, Gao K, Bian M, Ding H. Recent advances in the total synthesis of cyclobutane-containing natural products. Org Chem Front. 2019;7(1):136-54.
[15] Namyslo JC, Kaufmann DE. The application of cyclobutane derivatives in organic synthesis. Chem Rev. 2003;103(4):1485-538.
[16] Schrader A, Jakupovic J, Baltes W. Photochemical reaction products of 4-methoxycinnamic acid-3′-methylbutyl ester. Tetrahedron Lett. 1994;35(8):1169-72.
[17] Yang XW, Li YL, Li SM, Shen YH, Tian JM, Zhu ZJ, et al. Mono- and sesquiterpenoids, flavonoids, lignans, and other miscellaneous compounds of Abies georgei. Planta Med. 2010;77:742-8.
[18] Boruwa J, Borah JC, Kalita B, Barua NC. Highly regioselective ring opening of epoxides using NaN₃: a short and efficient synthesis of (-)-cytoxazone. Tetrahedron Lett. 2004;45(39):7355-8.
[19] Umar MI, Asmawi MZ, Sadikun A, Atangwho I, Yam M, Altaf R, et al. Bioactivity-guided isolation of ethyl-p-methoxycinnamate, an anti-inflammatory constituent, from Kaempferia galanga L. extracts. Molecules. 2012;17(7):7.
[20] Gadgoli C, Mishra SH. Antihepatotoxic activity of p-methoxy benzoic acid from Capparis spinosa. J Ethnopharmacol. 1999;66(2):187-92.
[21] Wang JS, Wu K, Yin C, Li K, Huang Y, Ruan J, et al. Cage-confined photocatalysis for wide-scope unusually selective [2 + 2] cycloaddition through visible-light triplet sensitization. Nat Commun. 2020;11(1):4675.
[22] Tiz DB, Tofani G, Vicente FA, Likozar B. Chemical synthesis of monolignols: traditional methods, recent advances, and future challenges in sustainable processes. Antioxidants. 2024;13(11):1387.
[23] Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454:7203.
[24] Bogdan C. Nitric oxide and the immune response. Nat Immunol. 2001;2(10):907-16.
[25] Othman R, Ibrahim H, Mohd MA, Awang K, Gilani AH, Mustafa MR. Vasorelaxant effects of ethyl cinnamate isolated from Kaempferia galanga on smooth muscles of the rat aorta. Planta Med. 2002;68:655-7.
[26] Umar MI, Asmawi MZ, Sadikun A, Majid AMS, Alsuede FS, Hassan LEA, et al. Ethyl-p-methoxycinnamate isolated from Kaempferia galanga inhibits inflammation by suppressing interleukin-1, tumor necrosis factor-α, and angiogenesis by blocking endothelial functions. Clinics. 2014;69(2):134-44.
[27] Fuchino H, Fukui N, Iida O, Wada H, Kawahara N. Inhibitory effect of black ginger (Kaempferia parviflora) constituents on nitric oxide production. J Food Chem Safety. 2018;25:152-9.
[28] Miyazawa S, Sakai M, Omae Y, Ogawa Y, Shigemori H, Miyamae Y. Anti-inflammatory effect of covalent PPARγ ligands that have a hybrid structure of GW9662 and a food-derived cinnamic acid derivative. Biosci Biotechnol Biochem. 2024;88(10):1136-43.

Kaemphenolide: a cyclobutane-bearing phenylpropanoid from Kaempferia galanga L. with nitric oxide inhibitory activity

Kaemphenolide: a cyclobutane-bearing phenylpropanoid from Kaempferia galanga L. with nitric oxide inhibitory activity

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