Eudesmane-type sesquiterpene lactones inhibit multiple steps in the NF-κB signaling pathway induced by inflammatory cytokines

doi:10.1016/j.bmcl.2011.11.029

Bioorganic & Medicinal Chemistry Letters

Volume 22, Issue 1, 1 January 2012, Pages 207-211

https://doi.org/10.1016/j.bmcl.2011.11.029 Get rights and content

Abstract

Inflammatory cytokines, such as interleukin-1α (IL-1α) and tumor necrosis factor-α (TNF-α), induce the intracellular signaling pathway leading to the activation of nuclear factor κB (NF-κB). A series of eudesmane-type sesquiterpene lactones possessing an α-methylene γ-lactone group and/or an α-bromo ketone group were synthesized and evaluated for their inhibitory effects on the NF-κB-dependent gene expression and signaling pathway. Our present study reveals that eudesmane-type α-methylene γ-lactones and α-bromo ketones inhibit multiple steps in the NF-κB signaling pathway induced by IL-1α and TNF-α.

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Acknowledgment

This work was supported in part by a Grant-in-Aid for Scientific Research (KAKENHI) from Japan Society for the Promotion of Science (JSPS).

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Cited by (21)

Alantolactone derivatives inhibit the tumor necrosis factor α-induced nuclear factor κB pathway by a different mechanism from alantolactone
2024, European Journal of Pharmacology
Alantolactone is a eudesmane-type sesquiterpene lactone that exerts various biological effects, including anti-inflammatory activity. In the present study, screening using the RIKEN Natural Products Depository chemical library identified alantolactone derivatives that inhibited the expression of intercellular adhesion molecule-1 (ICAM-1) on human umbilical vein endothelial cells stimulated with proinflammatory cytokines and Toll-like receptor ligands. In human lung adenocarcinoma A549 cells stimulated with tumor necrosis factor-α (TNF-α), six alantolactone derivatives inhibited ICAM-1 expression in a dose-dependent manner and at IC₅₀ values of 13–21 μM, whereas that of alantolactone was 5 μM. Alantolactone possesses an α-methylene-γ-lactone moiety, whereas alantolactone derivatives do not. In the nuclear factor κB (NF-κB) signaling pathway, alantolactone prevented the TNF-α-induced phosphorylation and degradation of the inhibitor of NF-κB α (IκBα) protein, and its downstream signaling pathway. In contrast, alantolactone derivatives neither reduced TNF-α-induced IκBα degradation nor the nuclear translocation of the NF-κB subunit RelA, but inhibited the binding of RelA to the ICAM-1 promoter. The inhibitory activities of alantolactone and alantolactone derivatives were attenuated by glutathione. These results indicate that alantolactone derivatives inhibit the TNF-α-induced NF-κB pathway by a different mechanism from alantolactone.
Syntheses and structure-activity relationship study of santamarine, douglanine, dihydrosantamarine and four series of 1-/3-oxygenated eudesman-12,6α-olides
2022, Tetrahedron
Citation Excerpt :
Deacetalization of 29 with 50% aqueous acetic acid at refluxing temperature gave 30 in 83% yield. Selective reduction of the C-1 carbonyl group of 30 with LiAl(t-BuO)3H afforded the desired β-alcohol, dihydrosantamarine 31 [12] and the corresponding α-alcohol 32 in 85% and 7% yield, respectively. Acetylation of 31 with Ac2O in pyridine in the presence of DMAP gave 33 in 93% yield.
Herein, we report the syntheses and structure-activity relationships of Santamarine, Douglanine, dihydrosantamarine, 1-oxygenated and 3-oxygenated eudesman-12,6α-lactones. The anti-inflammatory and anti-cancer activities were measured by the inhibition on induction of intercellular adhesion molecule (ICAM-1), killing function of cytotoxic T lymphocytes (CTLs), and cytotoxic activities to cell lines (VA-13, HepG-2, and WI-38), respectively. α-Methylene-γ-lactones 13 with a 1-oxo-2-en moiety showed significant inhibition toward ICAM-1(IC₅₀ 12.8 μM), the killing function of CTLs (IC₅₀ 11.0 μM) and the VA-13 cell line (IC₅₀ 2.84 μM), 21 with α-bromo-ketone moiety showed significant inhibition to VA-13(IC₅₀ 1.85 μM). Both 13 ((cell viability)/(inhibitory activity of ICAM-1) = 6.0-fold, WI-38/VA-13 = 1.28-fold) and 21 (WI-38/VA-13 = 1.28-fold) were within safety satisfaction. To conclude, the α,β-unsaturated-ketone and α-bromo-ketone moieties were essential for α-methylene-eudesman-12,6α-olides' anti-inflammatory and anti-cancer activities.
α-Conidendrin inhibits the expression of intercellular adhesion molecule-1 induced by tumor necrosis factor-α in human lung adenocarcinoma A549 cells
2021, European Journal of Pharmacology
α-Conidendrin is a lignan isolated from Taxus wallichiana and other species. In the present study, we demonstrated that α-conidendrin inhibited the cell-surface expression of intercellular adhesion molecule-1 (ICAM-1) induced by tumor necrosis factor-α (TNF-α) at an IC₅₀ value of 40–60 μM in human lung adenocarcinoma A549 cells. α-Conidendrin decreased ICAM-1 protein and mRNA expression levels at concentrations of 40–100 μM in TNF-α-stimulated A549 cells. The TNF-α-induced mRNA expression of vascular cell adhesion molecule-1, E-selectin, and cyclooxygenase-2 was also reduced by α-conidendrin. In the TNF-α-induced nuclear factor κB (NF-κB) signaling pathway, α-conidendrin did not influence the translocation of the NF-κB subunit RelA from the cytoplasm to the nucleus at concentrations up to 100 μM. A chromatin immunoprecipitation assay revealed that α-conidendrin at 100 μM reduced the binding of RelA to the ICAM-1 promoter in response to a stimulation with TNF-α. Collectively, these results indicated that α-conidendrin interfered with the DNA binding of RelA to the ICAM-1 promoter, thereby reducing ICAM-1 transcription.
Recent developments in the anti-inflammatory potential of sesquiterpene lactones and their semisynthetic analogs
2019, Discovery and Development of Anti-inflammatory Agents from Natural Products
Sesquiterpene lactones (SLs), a special class of naturally occurring biologically active natural products, are widely distributed in numerous genera of the family Asteraceae (Compositae). Moreover, their availability has been confirmed in certain other angiosperm families. Their wide structural diversity and potential biological activities reported against various diseases, such as anticancer, antimalarial, antimicrobial, antiviral, anti-inflammatory, antitubercular, hepatoprotective, antiulcer, antioxidant, anti-HIV, antidiabetic, antipyretic, antidiarrheal, antidepressant, antihelminthic, antitrypanosomal, and antifeedant, have attracted a great deal of attention from medicinal chemists around the globe. Some of them have been encountered as potential drugs for treating various diseases. Various report have confirmed that most structurally diverse biologically potent SLs have emerged as potential anti-inflammatory agents. This chapter focuses on a comprehensive account of SLs as anti-inflammatory agents.
Isolation of eudesmanes from Pluchea odorata and evaluation of their effects on cancer cell growth and tumor invasiveness in vitro
2017, Phytochemistry
Citation Excerpt :
Several studies provide evidence for the effects of eudesmanes on various kinases and their specific and unspecific mode of action. As an example, it was shown that eudesmane-type sesquiterpenes can inhibit the release of the adhesion molecule ICAM-1, which is a prerequisite for CCID-formation (Kopf et al., 2013; Viola et al., 2013a), by suppressing multiple steps in the NF-κB pathway such as the IκB kinase (Chun et al., 2012; Li et al., 2014; Tamura et al., 2012). Furthermore, eudesmanes inhibit metastasis through NF-κB and phosphatidylinositide 3-kinase related pathways and subsequent regulation of urokinase-type plasminogen activator and diverse matrix metalloproteinases (Nakabayashi and Shimizu, 2012; Shi et al., 2014; Weidle et al., 2015).
The traditionally used Central American medicinal plant Pluchea odorata, known as an anti-inflammatory and cancer cell growth-inhibiting remedy, was subjected to bioassay-guided isolation. Structure elucidation by 1D- and 2D-NMR and MS techniques supported by ECD and UV spectroscopic data revealed seven structurally previously undescribed and eight known eudesmane-type sesquiterpenes. Furthermore, one previously undescribed and one known phytol-like alcohol were identified. All compounds were tested for their cytotoxicity in cancer cells and for their anti-invasive effects. Among the eudesmanes, 3α-(2′,3′-epoxy-2′-methylbutyryloxy)-4α-hydroxy-11-hydroperoxy-eudesm-6-en-8-one exhibited the most potent cytotoxic activity with an IC₅₀ value of 8.8 μM (after 48 h). Also in an in vitro model measuring the tumor-triggered breaching of the adjacent lymph endothelial cell barrier (3S*,4R*,5S*,10S*,2′R*,3′R*)-3-(2′,3′-epoxy-2′-methylbutyryloxy)-4,7-dihydroxy-eudesm-11-en-8-one (IC₇₅ = 47 μM) and (3S*,4R*,5R*,10S*,2′R*,3′R*)-3-(2′,3′-epoxy-2′-methylbutyryloxy)-4-acetyloxy-6-methoxy-11-hydroxy-eudesm-6-en-8-one (IC₇₅ = 73 μM) showed inhibitory activities. Furthermore, preliminary structure-activity relationships (SARs) of the eudesmanes were developed.
Sesquiterpene Lactones: Structural Diversity and Perspectives as Anti-Inflammatory Molecules
2016, Studies in Natural Products Chemistry
Citation Excerpt :
IκBα degradation can be blocked by α,β-unsaturated carbonyl moieties of α-methylene-γ-lactones, which react with thiol groups of critical cysteine (Cys-179) in the IKK by Michael-type addition [90,91]. On the other hand, the prevention of nuclear translocation or DNA-binding of NF-κB occurs by alkylation of the critical cysteine residues (Cys38) in the DNA-binding domain of the p65 subunit of NF-κB [91,92]. Atractylenolide III (1), artemisinin (2), costunolide (3), and parthenolide (4) are some examples of SLs that can modulate inflammation by targeting NF-κB activation.
Sesquiterpene lactones (SLs) are secondary metabolites of several plants. Varied plants, commonly consumed in our diet or used to prepare beverages such as medicinal teas, present important pharmacological properties as a consequence of the occurrence of SLs. The anti-inflammatory mechanisms of SLs include inhibition of the production of cytokines, lipid mediators and other related molecules, modulation of pro- and antioxidant contents, and regulation of intracellular signaling pathways. These mechanisms targeted by SLs are involved in several inflammatory diseases; thus, it is possible that these molecules could reduce and/or help to control inflammatory diseases and their symptoms. In this chapter, we will focus on the anti-inflammatory effects of SLs from natural sources and the mechanisms of action involved in such effects. The chemical aspects of SLs and the most common plants that contain these metabolites, and the structural components responsible for their potent anti-inflammatory activity will also be addressed.

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^†: Present address: 22-20 Keiwa-machi, Taihaku-ku, Sendai 982-0823, Japan.

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Eudesmane-type sesquiterpene lactones inhibit multiple steps in the NF-κB signaling pathway induced by inflammatory cytokines

Abstract

Graphical abstract

Section snippets

Acknowledgment

Cell

Immunopharmacology

Bioorg. Med. Chem. Lett.

J. Biol. Chem.

Chem. Biol.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Life Sci.

Biochem. Pharmacol.

Nat. Rev. Immunol.

Nature

FEBS J.

Nat. Rev. Drug Disc.

J. Antibiot.