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Quantitative Structure−Activity Relationship of Sesquiterpene Lactones as Inhibitors of the Transcription Factor NF-κB
Abstract
Sesquiterpene lactones (SLs) are the active compounds of a variety of traditionally used medicinal plants from the Asteraceae family. They are known to possess a considerable antiinflammatory activity in different inflammation models. They inhibit the transcription factor NF-kappaB probably by alkylating cysteine38 in the DNA binding domain of the p65 subunit. Here we investigate a set of 103 different sesquiterpene lactones representing 6 structural groups (44 germacranolides, 16 heliangolides, 22 guaianolides, 9 pseudoguaianolides, 2 hypocretenolides, 10 eudesmanolides) for their NF-kappaB inhibiting properties and the resulting IC(100)-values were submitted to a QSAR study. Properties important for the inhibition potency are discussed for the whole data set and for subsets of the different structural classes.
... From what was demonstrated in the aforementioned studies, the interactions between the SLs and the target proteins are stabilized by alkyl bonds through the α-methylene-γ-lactone, as well as van der Waals forces through other functional groups present in the structure. In fact, the cytotoxicity of the SLs greatly depends on the number of alkylating centers; nonetheless, molecular conformation and noncovalent interactions before alkylation may also be determinant variables [91]. ...
... An important SAR study comprising of a set of 103 SLs belonging to different structural subclasses was reported by Siedle et al. [91], shedding some light on which molecular descriptors best described the ability of the compounds to prevent NF-κB DNA-binding activity. When considering the whole set of SLs, the number of α,β-unsaturated carbonyl functions and, in particular, the presence of an α-methylene-γ-lactone, were the most relevant variables [91]. ...
... An important SAR study comprising of a set of 103 SLs belonging to different structural subclasses was reported by Siedle et al. [91], shedding some light on which molecular descriptors best described the ability of the compounds to prevent NF-κB DNA-binding activity. When considering the whole set of SLs, the number of α,β-unsaturated carbonyl functions and, in particular, the presence of an α-methylene-γ-lactone, were the most relevant variables [91]. Nonetheless, when smaller sets of structurally related SLs were considered, the differential importance of certain molecular features was underlined. ...
Inflammation is a crucial and complex process that reestablishes the physiological state after a noxious stimulus. In pathological conditions the inflammatory state may persist, leading to chronic inflammation and causing tissue damage. Sesquiterpene lactones (SLs) are composed of a large and diverse group of highly bioactive plant secondary metabolites, characterized by a 15-carbon backbone structure. In recent years, the interest in SLs has risen due to their vast array of biological activities beneficial for human health. The anti-inflammatory potential of these compounds results from their ability to target and inhibit various key pro-inflammatory molecules enrolled in diverse inflammatory pathways, and prevent or reduce the inflammatory damage on tissues. Research on the anti-inflammatory mechanisms of SLs has thrived over the last years, and numerous compounds from diverse plants have been studied, using in silico, in vitro, and in vivo assays. Besides their anti-inflammatory potential, their cytotoxicity, structure–activity relationships, and pharmacokinetics have been investigated. This review aims to gather the most relevant results and insights concerning the anti-inflammatory potential of SL-rich extracts and pure SLs, focusing on their effects in different inflammatory pathways and on different molecular players.
... This anti-inflammatory activity was maintained in vivo using Freund's adjuvant arthritis rat model. A novel phthalide-based butyrolactone (Entry 2) [25,26] and two natural productscalcaratarin D (Entry 3) [27] and a sesquiterpene lactone (Entry 4) [28]-were also reported to inhibit activity of the NF-κB signaling pathway and showed anti-inflammatory activity. Among them, the in vivo activity of the first butyrolactone (Entry 2) was evaluated against the adjuvant arthritis rat. ...
... A biological evaluation showed that butyrolactone-1 derivatives display inhibitory activity of protein tyrosine phosphatase 1B (PTP1B) which is a promising therapeutic target of type 2 diabetes. [27] 4 (3aR,4R,9aS,9bR)-6,9-Dimethyl-3-methylene-2,7-dioxo-2,3,3a,4,5,7,9a,9b-octahydroazuleno [4,5-b]furan-4-yl methacrylate NF-κB inhibition (IC100 = 10 μM) Natural (Viguiera gardneri) [28] (3aR,4R,9aS,9bR)-6,9-Dimethyl-3-methylene-2,7-dioxo-2,3,3a,4,5,7,9a,9boctahydroazuleno [4,5-b]furan-4-yl methacrylate NF-κB inhibition (IC 100 = 10 µM) Natural (Viguiera gardneri) [28] ...
... A biological evaluation showed that butyrolactone-1 derivatives display inhibitory activity of protein tyrosine phosphatase 1B (PTP1B) which is a promising therapeutic target of type 2 diabetes. [27] 4 (3aR,4R,9aS,9bR)-6,9-Dimethyl-3-methylene-2,7-dioxo-2,3,3a,4,5,7,9a,9b-octahydroazuleno [4,5-b]furan-4-yl methacrylate NF-κB inhibition (IC100 = 10 μM) Natural (Viguiera gardneri) [28] (3aR,4R,9aS,9bR)-6,9-Dimethyl-3-methylene-2,7-dioxo-2,3,3a,4,5,7,9a,9boctahydroazuleno [4,5-b]furan-4-yl methacrylate NF-κB inhibition (IC 100 = 10 µM) Natural (Viguiera gardneri) [28] ...
γ-Butyrolactone, a five-membered lactone moiety, is one of the privileged structures of diverse natural products and biologically active small molecules. Because of their broad spectrum of biological and pharmacological activities, synthetic methods for γ-butyrolactones have received significant attention from synthetic and medicinal chemists for decades. Recently, new developments and improvements in traditional methods have been reported by considering synthetic efficiency, feasibility, and green chemistry. In this review, the pharmacological activities of natural and synthetic γ-butyrolactones are described, including their structures and bioassay methods. Mainly, we summarize recent advances, occurring during the past decade, in the construction of γ-butyrolactone classified based on the bond formation in γ-butyrolactone between (i) C5-O1 bond, (ii) C4-C5 and C2-O1 bonds, (iii) C3-C4 and C2-O1 bonds, (iv) C3-C4 and C5-O1 bonds, (v) C2-C3 and C2-O1 bonds, (vi) C3-C4 bond, and (vii) C2-O1 bond. In addition, the application to the total synthesis of natural products bearing γ-butyrolactone scaffolds is described.
... TNF-α is a key pro-inflammatory cytokine [73]. Compound 48 was found to decrease TNF-α-induced inflammation in Jurkat cells through inhibiting the NF-κB pathway [46,74]. In particular, compound 48 directly alkylates the p65 subunit of NF-κB at Cys38 and Cys120 [46], and might be used to treat acute T cell leukemia. ...
... Compound 48 was found to decrease TNF-α-induced inflammation in Jurkat cells through inhibiting the NF-κB pathway [46,74]. In particular, compound 48 directly alkylates the p65 subunit of NF-κB at Cys38 and Cys120 [46], and might be used to treat acute T cell leukemia. COX-2 is an enzyme responsible for inflammation and pain [75]. ...
Inflammation is an essential part of the immune response to injury and infection. Emerging evidence indicates that long-term low-grade inflammation is positively correlated with many diseases, such as cancer, metabolic disorders, and cardiovascular diseases. Due to common anti-inflammatory drugs are suitable for treating acute inflammation and cause severe adverse effects, new safe and effective drug candidates are urgently needed for treating chronic inflammation. Plants of the Asteraceae family have been widely used in traditional medicines for relieving fever symptoms and killing pathogens. The anti-inflammatory properties of sesquiterpenoids from plants in the Asteraceae family have attracted increasing attention in recent decades because of their structural complexity and potent bioactivities. Herein, we provide a comprehensive and up-to-date summary of sesquiterpenoids from the Asteraceae family with anti-inflammatory properties, including their drug likeness and druggability, as analyzed with the SwissADME and ADMETlab online tools. In the future, some sesquiterpenoids might serve as therapeutic agents to treat inflammation-associated diseases.
... Arnica montana is in high demand in the pharmaceutical industry due to the medicinal property of its secondary metabolites (basically sesquiterpene lactones) which are concentrated mainly in the flowers (Kriplani et al. 2017). Together with their anti-inflammatory action (Siedle et al. 2004), sesquiterpene lactones have many interesting activities that protect the plant against dangerous environmental stressors (e.g. UV radiation and extreme temperature) and herbivory (Zidorn 2010). ...
... atlantica (Perry et al. 2009;Schmiderer et al. 2018). These SLs are the main metabolites that confer anti-inflammatory properties to the A. montana (Siedle et al. 2004). The anti-inflammatory action of H esters is greater than that of DH esters, but DH esters are less allergenic and, therefore, more valued in the pharmaceutical industry (Lass et al. 2008;Vera et al. 2014). ...
Iberian populations of Arnica montana L. (Asteraceae) represent a valuable resource both for conservation and pharmaceutical industry. Previous genetic analyses pointed out the presence of different genetic groups, but a wide region is still genetically unexplored. In order to fill this scientific gap, the present study analysed a wider sampling area along the northern Iberian Peninsula. Nuclear (i.e. microsatellite loci) and plastid DNA (cpDNA) molecular markers were used to assess the levels of genetic diversity and the population structure in 16 locations, eight analysed for the first time in the present study and eight representative of the different genetic groups previously identified. The two divergent cpDNA groups previously described were found, but their distribution was extended and refined. Thus, one of the groups (suggested as ancestral) was predominantly distributed in adjacent zones of the Cantabrian coasts while the other (more related to Central-European populations) was predominant in inner Cantabrian regions and Pyrenees. Genetic diversity with microsatellite loci (He = 0.280) was in accordance with the figures previously described, with a high level of population differentiation (FST > 0.500) identifying the presence of up to five population genetic units. Genetic and geographical distances were not related (no isolation-by-distance pattern identified), suggesting an important effect of genetic drift. Finally, due to the conservation and evolutionary interest of the populations analysed, different management actions useful for the maintenance of wild A. montana resources are provided.
... Such activity could be heavily attributed to the presence of high levels of sesquiterpene compounds which are basically found in leaf extracts ( (Cafarchia et al., 2002). Several previous studies showed that sesquiterpenes compounds provide a wide range of therapeutic treatment options ( (Siedle et al., 2004;Crespo-Ortiz and Wei, 2012;Ivanescu et al., 2015). One of their studied effects is their antimicrobial efficacy against a wide range of microorganisms ( (Siedle et al., 2004;Crespo-Ortiz and Wei, 2012). ...
... Several previous studies showed that sesquiterpenes compounds provide a wide range of therapeutic treatment options ( (Siedle et al., 2004;Crespo-Ortiz and Wei, 2012;Ivanescu et al., 2015). One of their studied effects is their antimicrobial efficacy against a wide range of microorganisms ( (Siedle et al., 2004;Crespo-Ortiz and Wei, 2012). Several types of bacteria were shown to be sensitive on sesquiterpenes, include Escherichia Coli, Bacillus subtilis, Staphylococcus aureus and bacteroids fragilis ((Anke and Sterner, 1991;Aljancic et al., 1999;Cho et al., 2003;Lin et al., 2003;Fortuna et al., 2011). ...
... Sesquiterpene lactones are a group of secondary metabolites of plants exerting various physiological activities such as anti-tumor, antimicrobial, anti-inflammatory, and anti-obesity effects (Cho et al., 2000;Galvis et al., 2011;Konstantinopoulou et al., 2003;Rabe et al., 2015). The physiological activity of sesquiterpene lactones is mostly mediated by the α,ß-unsaturated carbonyl structures, such as an α-methylene-γ-lactone group (αMγl), which irreversibly alkylates enzymes, transcription factors and other proteins (Arantes et al., 2011;Schmidt, 2006;Siedle et al., 2004). In particular, in the aspect of anti-inflammatory effect, αMγl of sesquiterpene lactone inhibits the inflammatory response by alkylating the p65, a subunit of NF-κB (Rüngeler et al., 1999). ...
... Furthermore, we identified that EST inhibited the LPS-induced phosphorylation of NF-κB and MAPK like other sesquiterpene lactones (Koo et al., 2001;Lyss et al., 1997;Mathema et al., 2012;Wang et al., 2017). It is known that the α,ß-unsaturated carbonyl structure of sesquiterpene lactone interacts with specific proteins to exert various physiological effects (Siedle et al., 2004). Representatively, parthenolide specifically inhibits IκB kinase (Kwok et al., 2001) and helenalin selectively inhibits p65, one of the NF-κB subunits (Lyß et al., 1998). ...
Background: Previously, we found that the water extract of Artermisia scoparia Waldst. & Kit suppressed the cytokine production of lipopolysaccharide (LPS)-stimulated macrophages and alleviated carrageenan-induced acute inflammation in mice. Artemisia contains various sesquiterpene lactones and most of them exert immunomodulatory activity.
Purpose: In the present study, we investigated the immunomodulatory effect of estafiatin (EST), a sesquiterpene lactone derived from A. scoparia, on LPS-induced inflammation in macrophages and mouse sepsis model.
Study design and methods: Murine bone marrow-derived macrophages (BMDMs) and THP-1 cells, a human monocytic leukemia cell line, were pretreated with different doses of EST for 2 h, followed by LPS treatment. The gene and protein expression of pro-inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and inducible nitric oxide synthase (iNOS) were measured by quantitative real-time polymerase chain reaction (qPCR) and Western blot analysis. The activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) was also evaluated at the level of phosphorylation. The effect of EST on inflammatory cytokine production, lung histopathology, and survival rate was assessed in an LPS-induced mice model of septic shock. The effect of EST on the production of cytokines in LPS-stimulated peritoneal macrophages was evaluated by in vitro and ex vivo experiments and protective effect of EST on cecal ligation and puncture (CLP) mice was also assessed.
Results: The LPS-induced expression of IL-6, TNF-α, and iNOS was suppressed at the mRNA and protein levels in BMDMs and THP-1 cells, respectively, by pretreatment with EST. The half-maximal inhibitory concentration (IC50) of EST on IL-6 and TNF-α production were determined as 3.2 μM and 3.1 μM in BMDMs, 3 μM and 3.4 μM in THP1 cells, respectively. In addition, pretreatment with EST significantly reduced the LPS-induced phosphorylation p65, p38, JNK, and ERK in both cell types. In the LPS-induced mice model of septic shock, serum levels of IL-6, TNF-α, IL-1β, CXCL1, and CXCL2 were lower in EST-treated mice than in the control animals. Histopathology analysis revealed that EST treatment ameliorated LPS-induced lung damage. Moreover, while 1 of 7 control mice given lethal dose of LPS survived, 3 of 7 EST-treated (1.25 mg/kg) mice and 5 of 7 EST-treated (2.5 mg/kg) mice were survived. Pretreatment of EST dose-dependently suppressed the LPS-induced production of IL-6, TNF-α and CXCL1 in peritoneal macrophages. In CLP-induced mice sepsis model, while all 6 control mice was dead at 48 h, 1 of 6 EST-treated (1.25 mg/kg) mice and 3 of 6 EST-treated (2.5 mg/kg) mice survived for 96 h.
Conclusion: These results demonstrated that EST exerts anti-inflammatory effects on LPS-stimulated macrophages and protects mice from sepsis. Our study suggests that EST could be developed as a new therapeutic agent for sepsis and various inflammatory diseases.
... Thus, it seems that an increasing number of recent studies demonstrated the activation of Nrf2 by sesquiterpene lactones like onopordopicrin but how these molecules can activate Nrf2 is still not well understood. It is believed that the methylene-G-lactone group of sesquiterpene lactones is the main responsible for biological activities as anti-inflammatory [35,61], cytotoxic [34] or antitrypanosomal [34]. Indeed, the methylene-G-lactone group can react as a thia-Michael acceptor. ...
... The 2-(hydroxymethyl)acrylate side chain represents a second Michael acceptor site in the structure of onopordopicrin. This chain seems to be important for activities [34,61], but it appears to be less reactive than the methylene-G-lactone group in NMR-based cysteamine assay [35]. For onopordopicrin, thia-addition is observed quickly and only on the methylene-G-lactone group, whereas for carmanin, a sesquiterpene without lactone, the addition was made on the 2-(hydroxymethyl)acrylate side chain very slowly [35]. ...
El Khatib N., Morel M., Hugon G., Rapior S., Carnac G. et Saint N.
Identification of a sesquiterpene lactone from Arctium lappa leaves with antioxidant activity in primary human muscle cells. Molecules Special Issue Antioxidants from Natural Sources: Separation and
Characterization, 26 (5), 1328 (2021). doi:10.3390/molecules26051328. hal-03157239 ____
Many pathologies affecting muscles (muscular dystrophies, sarcopenia, cachexia, renal insufficiency, obesity, diabetes type 2, etc.) are now clearly linked to mechanisms involving oxidative stress. In this context, there is a growing interest in exploring plants to find new natural antioxidants to prevent the appearance and the development of these muscle disorders. In this study, we investigated the antioxidant properties of Arctium lappa leaves in a model of primary human muscle cells exposed to H2O2 oxidative stress. We identified using bioassay-guided purification, onopordopicrin, a sesquiterpene lactone as the main molecule responsible for the antioxidant activity of A. lappa leaf extract. According to our findings, onopordopicrin inhibited the H2O2 -mediated loss of muscle cell viability, by limiting the production of free radicals and abolishing DNA cellular damages. Moreover, we showed that onopordopicrin promoted the expression of the nuclear factor-erythroid-2-related factor 2 (Nrf2) downstream target protein heme oxygenase-1 (HO-1) in muscle cells. By using siRNA, we demonstrated that the inhibition of the expression of Nrf2 reduced the protective effect of onopordopicrin, indicating that the activation of the Nrf2/HO-1 signaling pathway mediates the antioxidant effect of onopordopicrin in primary human muscle cells. Therefore, our results suggest that onopordopicrin may be a potential therapeutic molecule to fight against oxidative stress in pathological specific muscle disorders. ______ Keywords: Arctium lappa L.; burdock leaves; antioxidant; onopordopicrin; human myoblasts
... Regression models are widely used to predict specific activity values from known information on chemical structures such as molecular descriptors and fingerprints. [44][45][46] This method covers the relationship between relatively confined groups of compounds and specific targets. Discriminant models have been employed to predict whether a compound will exhibit activity or not, and are often applicable to compounds with more diverse structures. ...
Computational approaches to drug development are rapidly growing in popularity and have been used to produce significant results. Recent developments in information science have expanded databases and chemical informatics knowledge relating to natural products. Natural products have long been well-studied, and a large number of unique structures and remarkable active substances have been reported. Analyzing accumulated natural product knowledge using emerging computational science techniques is expected to yield more new discoveries. In this article, we discuss the current state of natural product research using machine learning. The basic concepts and frameworks of machine learning are summarized. Natural product research that utilizes machine learning is described in terms of the exploration of active compounds, automatic compound design, and application to spectral data. In addition, efforts to develop drugs for intractable diseases will be addressed. Lastly, we discuss key considerations for applying machine learning in this field. This paper aims to promote progress in natural product research by presenting the current state of computational science and chemoinformatics approaches in terms of its applications, strengths, limitations, and implications for the field.
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... SLs are the most important secondary metabolites responsible for the anti-inflammatory properties of the Arnica plant [49]. The anti-inflammatory activity of H esters is much greater than that of DH esters, but DH esters are less sensitizing and are, therefore, more valued in the pharmaceutical industry. ...
Arnica montana is a valuable plant with high demand on the pharmaceutical and cosmetic market due to the presence of helenalin (H) and 11α, 13-dihydrohelenalin (DH) sesquiterpene lactones (SLs), with many applications and anti-inflammatory, anti-tumor, analgesic and other properties. Despite the great importance of these compounds for the protection of the plant and their medicinal value, the content of these lactones and the profile of the compounds present within individual elements of florets and flower heads have not been studied so far, and attempts to localize these compounds in flower tissues have also not been conducted. The three studied Arnica taxa synthesize SLs only in the aerial parts of plants, and the highest content of these substances was found in A. montana cv. Arbo; it was lower in wild species, and a very small amount of H was produced by A. chamissonis. Analysis of dissected fragments of whole inflorescences revealed a specific distribution pattern of these compounds. The lactones content in single florets increased from the top of the corolla to the ovary, with the pappus calyx being a significant source of their production. Histochemical tests for terpenes and methylene ketones indicated the colocalization of lactones with inulin vacuoles.
... The lactone groups are the cyclic ester of organic acid with the most stable structure; they are five-membered (gamma lactone). They are known to have various biological activities including anticancer, antifungal, and antibacterial [2][3][4][5][6], and are found in andrographolide and its derivatives, including 14-deoxy-11,12-didehydroandrographolide, neoandrographolide, and andrograpanin ( Figure 1) [7]. Andrographolide has been widely studied, including, A. paniculata has been classified by traditional Chinese medicine as a safe and nontoxic medicine [17]. ...
Andrographis paniculata is widely used as a traditional medicine in Asian countries. It has been classified as a safe and non-toxic medicine by traditional Chinese medicine. The investigation of the biological activities of A. paniculata is still focused on the crude extract and isolation of its main active compound, andrographolide, and its derivatives. However, the use of andrographolide alone has been shown to exacerbate unwanted effects. This highlights the importance of developing a fraction of A. paniculata with enhanced efficacy as an herbal-based medicine. In this study, the extraction and fractionation of A. paniculata, followed by quantitative analysis using high-performance liquid chromatography coupled with a DAD detector, were established to quantify the andrographolide and its derivative in each fraction. Biological activities, such as antioxidant, anticancer, antihypertensive, and anti-inflammatory activities, were evaluated to study their correlations with the quantification of active substances of A. paniculata extract and its fractions. The 50% methanolic fraction of A. paniculata exhibited the best cytotoxic activities against CACO-2 cells, as well as the best anti-inflammatory and antihypertensive activities compared to other extracts. The 50% methanolic fraction also displayed the highest quantification of its main active compound, andrographolide, and its derivatives, 14-deoxy-11,12-didehydroandrographolide, neoandrographolide, and andrograpanin, among others.
... Costunolide exerts its anticancer effect by inhibiting the activation of NFκB pathway and nuclear translocation of p50/p65 NFκB subunits in glioma and breast cancer cells [17,18]. Sesquiterpene lactones prevent NFκB activation by alkylating Cys38 in the p65 subunit, and by blocking IκB phosphorylation [19,20]. A variety of signaling pathways, such as AKT phosphorylation, the Wnt-/β-catenin pathway, JNK activation, mTOR, ROS mediated Ras signaling, microtubule assembly, and the STAT3 pathway are inhibited by costunolide [21][22][23][24]. ...
The epithelial cell adhesion molecule (EpCAM) is considered an essential proliferation signature in cancer. In the current research study, qPCR induced expression of EpCAM was noted in acute lymphoblastic leukemia (ALL) cases. Costunolide, a sesquiterpene lactone found in crepe ginger and lettuce, is a medicinal herb with anticancer properties. Expression of EpCAM and its downstream target genes (Myc and TERT) wasdownregulated upon treatment with costunolide in Jurkat cells. A significant change in the telomere length of Jurkat cells was not noted at 72 h of costunolide treatment. An in silico study revealed hydrophobic interactions between EpCAM extracellular domain and Myc bHLH with costunolide. Reduced expression of NFκB, a transcription factor of EpCAM, Myc, and TERT in costunolide-treated Jurkat cells, suggested that costunolide inhibits gene expression by targeting NFκB and its downstream targets. Overall, the study proposes that costunolide could be a promising therapeutic biomolecule for leukemia.
... Phytochemicals that inhibit the activation of TLR4, may ameliorate obesity associated symptoms. It has been welldocumented that molecules with the α, β-unsaturated carbonyl groups can react with biological nucleophiles such as a sulfhydryl group (thiol group) by a Michael addition (Figure 2) (26)(27)(28). Phytochemicals with α, β-unsaturated carbonyl groups including withaferin A, kaempferide, isoliquiritigenin and curcumin were reported to ameliorate obesity and related metabolic symptoms by the suppression of TLR4. ...
The consumption of phytochemicals, bioactive compounds in fruits and vegetables, has been demonstrated to ameliorate obesity and related metabolic symptoms by regulating specific metabolic pathways. This review summarizes the progress made in our understanding of the potential of phytochemicals as metabolic signals: we discuss herein selected molecular mechanisms which are involved in the occurrence of obesity that may be regulated by phytochemicals. The focus of our review highlights the regulation of transcription factors toll like receptor 4 (TLR4), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), the peroxisome proliferator-activated receptors (PPARs), fat mass and obesity-associated protein (FTO) and regulation of microRNAs (miRNA). In this review, the effect of phytochemicals on signaling pathways involved in obesity were discussed on the basis of their chemical structure, suggesting molecular mechanisms for how phytochemicals may impact these signaling pathways. For example, compounds with an isothiocyanate group or an α, β-unsaturated carbonyl group may interact with the TLR4 signaling pathway. Regarding Nrf2, we examine compounds possessing an α, β-unsaturated carbonyl group which binds covalently with the cysteine thiols of Keap1. Additionally, phytochemical activation of PPARs, FTO and miRNAs were summarized. This information may be of value to better understand how specific phytochemicals interact with specific signaling pathways and help guide the development of new drugs to combat obesity and related metabolic diseases.
... Compounds 1 and 2, as well as other sesquiterpene lactones, are known to inhibit the NF-B stress response in human cells, which is critical for the survival of leukemia cells, and it has been suggested that this protein is involved in their mechanism of action [37,61,62]. In this mechanistic explanation, the sesquiterpene lactones interact with NF-B via a nucleophilic attack by way of an ↵, -unsaturated exocyclic double bond [63]. ...
A method to identify anticancer compounds in plants was proposed based on the hypothesis that these compounds are primarily present in plants to provide them with an ecological advantage over neighboring plants and other competitors. According to this view, identifying plants that contain compounds that inhibit or interfere with the development of other plant species may facilitate the discovery of novel anticancer agents. The method was developed and tested using Magnolia grandiflora, Gynoxys verrucosa, Picradeniopsis oppositifolia, and Hedyosmum racemosum, which are plant species known to possess compounds with cytotoxic activities. Plant extracts were screened for growth inhibitory activity, and then a thin-layer chromatography bioautography assay was conducted. This located the major antileukemic compounds 1, 2, 4, and 5 in the extracts. Once the active compounds were located, they were extracted and purified, and their structures were determined. The growth inhibitory activity of the purified compounds showed a significant correlation with their antileukemic activity. The proposed approach is rapid, inexpensive, and can easily be implemented in areas of the world with high biodiversity but with less access to advanced facilities and biological assays.
... Structurally, 1 contains γ-lactone ring as the most important pharmacophore while other units like epoxide, α-methylene, cadinane ring, steric and conformational constraints only ameliorate activity of the molecule [32]. As a consequence, α-methylene moiety easily tends to react with Michael donors like sulphydryl (-SH) groups of cysteine, glutathione, proteins, and enzymes [33][34][35][36]. ...
A library of new spiroisoxazoline analogues of arteannuin B was synthesized through 1, 3-dipolar cycloaddition in stereoselective fashion and consequently screened for anti-inflammatory activity in RAW 264.7 macrophage cells. Three potent analogues (8i, 8 m, and 8n) were found to attenuate the LPS induced release of cytokines IL-6 and TNF-α more potently than the parent molecule. Also, the inhibition of LPS induced nitric oxide production in these cells show moderate to high efficacy. None of the three potent molecules have altered the viability of RAW 264.7 cells following 48 h incubation suggesting that the inhibition of cytokines and nitric oxide production exhibited in the cells was not due to toxicity. In addition, these compounds exhibit an IC50 range of 0.17 µM-1.57 µM and 0.09 µM-0.35 µM for the inhibition of IL-6 release and nitric oxide production respectively. The results disclose potent inhibition of pro-inflammatory mediators which are encouraging and warrant further investigations to develop new therapeutic agents for inflammatory diseases.
... The ability to inhibit enzymes makes SLs promising agents for antitumor therapy. Among the most significant targets of SLs are the transcription factor NF-κB [3], pharnesyl transferase, and the enzymes of the primary metabolism, including the glycolysis [4]. At the same time, SLs have some disadvantages that limit their application as antitumor agents: (1) SLs also act on other tissues, which leads to toxic effects at therapeutic doses; (2) in the course of time, liver enzymes restore the unsaturated bond at the lactone ring of SLs, which results in a loss of activity; and (3) SLs are often hydrophobic substances with low bioaccessibility. ...
... Many lactones present a wide range of desired biological properties [8,9] and the molecular mechanisms of their actions were, in many cases, investigated. The most important mechanism induced by terpenoid lactones is inhibition of the expression of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) which is directly related to antiinflammatory and anticancer activities [10,11]. Parthenolide inhibits NF-κB by alkylation of Cys-38 in p65, Helenalin A by p65 alkylation, costunolide, triptolide and nepalolide A by IκB phosphorylation, artemisinin, triptolide, and ginkgolides by DNA binding, artemisolide by IKKβ inhibition on Cys-179, ergolide and zerumbone by IκB degradation, and elephantopins by IKK inhibition [11]. ...
Terpenoids with lactone moieties have been indicated to possess high bioactivity. Certain terpenoid lactones exist in nature, in plants and animals, but they can also be obtained by chemical synthesis. Terpenoids possessing lactone moieties are known for their cytotoxic, anti-inflammatory, antimicrobial, anticancer, and antimalarial activities. Moreover, one terpenoid lactone, artemisinin, is used as a drug against malaria. Because of these abilities, there is constant interest in new terpenoid lactones that are both isolated and synthesized, and their biological activities have been verified. In some cases, the activity of the terpenoid lactone is specifically connected to the lactone moiety. Recent works have revealed that new terpenoid lactones can demonstrate such functions and are thus considered to be potential active agents against many diseases.
... These molecules are, primarily, extracted from plants belonging to the Asteraceae family (daisies, asters) [11]. These class of molecules has immunomodulatory effects such as inhibition of NFκB and COX-2 and reducing inflammatory responses in cancer cells [12,13]. 7-hydroxy frullanolide (7HF) is one such sesquiterpene lactone that has been reported to have certain immunomodulatory effects. ...
Sesquiterpene lactones are a class of anti-inflammatory molecules obtained from plants belonging to the Asteraceae family. In this study, the effects of 7-hydroxy frullanolide (7HF), a sesquiterpene lactone, in inhibiting CD4+ T cell and peritoneal macrophage responses were investigated. 7HF, in a dose dependent manner, lowers CD69 upregulation, IL2 production and CD4+ T cell cycling upon activation with the combination of anti-CD3 and anti-CD28. Further mechanistic studies demonstrated that 7HF, at early time points, increases intracellular Ca2+ amounts, over and above the levels induced upon activation. The functional relevance of 7HF-induced Ca2+ increase was confirmed using sub-optimal amounts of BAPTA, an intracellular Ca2+ chelator, which lowers lactate and rescues CD4+ T cell cycling. In addition, 7HF lowers T cell cycling with the combination of PMA and Ionomycin. However, 7HF increases CD4+ T cell cycling with sub-optimal activating signals: only PMA or anti-CD3. Furthermore, LPS-induced nitrite and IL6 production by peritoneal macrophages is inhibited by 7HF in a Ca2+-dependent manner. Studies with Ca2+ channel inhibitors, Ruthenium Red and 2-Aminoethoxydiphenyl borate, lowers the inhibitory effects of 7HF on CD4+ T cell and macrophage responses. In silico studies demonstrated that 7HF binds to Ca2+ channels, TRPV1, IP3R and SERCA, which is mechanistically important. Finally, intraperitoneal administration of 7HF lowers serum inflammatory cytokines, IFNγ and IL6, and reduces the effects of DSS-induced colitis with respect to colon length and colon damage. Overall, this study sheds mechanistic light on the anti-inflammatory potential of 7HF, a natural plant compound, in lowering immune responses.
... These molecules are, primarily, extracted from plants belonging to the Asteraceae family (daisies, asters) [11]. These class of molecules has immunomodulatory effects such as inhibition of NFκB and COX-2 and reducing inflammatory responses in cancer cells [12,13]. 7-hydroxy frullanolide (7HF) is one such sesquiterpene lactone that has been reported to have certain immunomodulatory effects. ...
Deaths due to the ongoing COVID-19 pandemic vary (3-1681 deaths/million and mortality rates 0.71-14.54%) and are far greater in some countries compared to others. This observation led us to perform epidemiological analysis, using data in the public domain, to study the correlation of COVID-19 with the prevalence and vaccination strategies for two respiratory pathogens: flu and tuberculosis (TB). Countries showing more than 1000 COVID-19 deaths were selected at three time points during the ongoing pandemic: 17 May, 1 October and 31 December 2020. The major findings of this study that are broadly consistent at all three time points are: First, countries with high flu deaths negatively correlate with COVID-19 deaths/million. Second, TB incidences and deaths negatively correlate with COVID-19 deaths/million. Countries displaying high TB and flu deaths (Nigeria, Ethiopia, Myanmar, Indonesia, India) display lower COVID-19 deaths/million compared to countries with low TB and flu deaths (Italy, Spain, USA, France). Third, countries with greater flu vaccination display lower flu incidences but higher COVID-19 deaths/million and mortality rates. On the other hand, Bacillus Calmette Guerin (BCG) vaccination negatively correlates with Covid-19 deaths/million. Fourth, countries with only BCG, but no flu, vaccination show delayed and lower number of COVID-19 deaths/million compared to countries with flu, but no BCG, vaccination. Fifth, countries with high BCG vaccination coverage as well as high TB deaths display the lowest COVID-19 deaths/million. The implications of this global study are discussed with respect to the roles of respiratory infections and vaccinations in lowering COVID-19 deaths.
... Sesquiterpenes lactones have attracted much scientific attention because of their functional diversity and abundance, and they are important taxonomic markers in the family Asteraceae to which the genus Parthenium belongs [8,9]. Sesquiterpenes lactones display antimicrobial, antifeedant, growth-modifying and allelopathic activities [10,11], a virtue of to their high reactivity. This is likely related to the α-methylene moiety [8,10], a functional group that the guayulins lack. ...
The guayulins are a family of sesquiterpene compounds that consist of an isoprenoid nucleus substituted either by trans-cinnamic or p-anisic acid, and are present only in the resinous fraction of the rubber plant guayule (Parthenium argentatum, Gray). While the natural role of the guayulins remains enigmatic, they may serve as a defense function against other plants or herbivores by virtue of the accumulation of cinnamic acid. Prior research has suggested seasonal variation in guayulin content, which has been shown to decrease as winter arrives in two different varieties. In the present study, the effect of guayulins has been evaluated in 13 different accessions cultivated under the same conditions during autumn. A general reduction in guayulin content was found in the stems from all varieties between the September and November harvest, which was accompanied by an increase in the resin content. With respect to individual guayulins, while guayulin A was the most prominent member during most of the year, guayulin C had more prominence when temperature started to decrease. In this seasonal period, the production of each member of the guayulin family in the leaves was very balanced.
... However, beyond the cytotoxic effects, interactive activity of STLs with signaling physiological molecules such as NF-κB (Siedle et al., 2004), interleukins or TNF-α have attracted increasing notice in medical research (Kim & Choi, 2019). ...
Sunflower, Helianthus annuus, is one of the world’s most important oil crops and sunflower oil is esteemed for its high content of unsaturated fatty acids and the occurrence of relatively high amounts of vitamin E and phytosterols. Reports on other secondary metabolites are rare, but recently identified bioactive sesquiterpene lactones in non-germinated sunflower seeds suggested their existence in sunflower oil. Chromatographic combined with mass spectrometric analysis now showed the presence of costunolide, dehydrocostuslactone, 8-epixanthatin and tomentosin in samples of commercially available oils and allowed quantification of the sesquiterpene lactones. Implications of these results for the use of sunflower oil in nutrition and cosmetics are discussed.
... This specific activity of 11β,13-dihydrolactucin may arise as, unlike other SLs, it does not effectively form cysteine conjugates and is available to interact with target proteins. Indeed, the capacity of SLs to react with molecules containing cysteine is reported to be mainly due to the presence of α,β-unsaturated carbonyl groups with the presence of an α-methylene-γ-lactone ring enhancing the reaction rate [51]. 11β,13-dihydrolactucin lacks the αmethylene-γ-lactone ring and therefore may not readily form these conjugates. ...
Cichorium intybus L. has recently gained major attention due to large quantities of health-promoting compounds in its roots, such as inulin and sesquiterpene lactones (SLs). Chicory is the main dietary source of SLs, which have underexplored bioactive potential. In this study, we assessed the capacity of SLs to permeate the intestinal barrier to become physiologically available, using in silico predictions and in vitro studies with the well-established cell model of the human intestinal mucosa (differentiated Caco-2 cells). The potential of SLs to modulate inflammatory responses through modulation of the nuclear factor of activated T-cells (NFAT) pathway was also evaluated, using a yeast reporter system. Lactucopicrin was revealed as the most permeable chicory SL in the intestinal barrier model, but it had low anti-inflammatory potential. The SL with the highest anti-inflammatory potential was 11β,13-dihydrolactucin, which inhibited up to 54% of Calcineurin-responsive zinc finger (Crz1) activation, concomitantly with the impairment of the nuclear accumulation of Crz1, the yeast orthologue of human NFAT.
... Figure 22 shows some representative examples of ring-fused lactones. This interesting medicinal profile is fascinating, and several synthetic efforts have been made towards the synthesis of this heterocyclic core [540][541][542][543][544]. ...
Heterocycles, heteroaromatics and spirocyclic entities are ubiquitous components of a wide plethora of synthetic drugs, biologically active natural products, marketed pharmaceuticals and agrochemical targets. Recognizing their high proportion in drugs and rich pharmacological potential, these invaluable structural motifs have garnered significant interest, thus enabling the development of efficient catalytic methodologies providing access to architecturally complex and diverse molecules with high atom-economy and low cost. These chemical processes not only allow the formation of diverse heterocycles but also utilize a range of flexible and easily accessible building units in a single operation to discover diversity-oriented synthetic approaches. Alkynoates are significantly important, diverse and powerful building blocks in organic chemistry due to their unique and inherent properties such as the electronic bias on carbon–carbon triple bonds posed by electron-withdrawing groups or the metallic coordination site provided by carbonyl groups. The present review highlights the comprehensive picture of the utility of alkynoates (2007–2019) for the synthesis of various heterocycles (> 50 types) using transition-metal catalysts (Ru, Rh, Pd, Ir, Ag, Au, Pt, Cu, Mn, Fe) in various forms. The valuable function of versatile alkynoates (bearing multifunctional groups) as simple and useful starting materials is explored, thus cyclizing with an array of coupling partners to deliver a broad range of oxygen-, nitrogen-, sulfur-containing heterocycles alongside fused-, and spiro-heterocyclic compounds. In addition, these examples will also focus the scope and reaction limitations, as well as mechanistic investigations into the synthesis of these heterocycles. The biological significance will also be discussed, citing relevant examples of drug molecules highlighting each class of heterocycles.
Graphic Abstract
This review summarizes the recent developments in the synthetic methods for the synthesis of various heterocycles using alkynoates as readily available starting materials under transition-metal catalysis.
... According to the records of the European and China Pharmacopoeia (Wang et al., 2017), alantolactone possesses a wide range of biological properties, such as anti-inflammatory, antibacterial, antifungal and immunomodulatory activities. Chemically, alantolactone belongs to sesquiterpene lactones including the a-methylene-glactone group, which may potentially predispose to delayed hypersensitivity (Dupuis et al., 1980;Warshaw and Zug, 1996), but also exerts strong anti-inflammatory effects by interaction with NF-kB transcription factor (Siedle et al., 2004). Chun et al. reported the anti-inflammatory properties of alantolactone and proved that alantolactone at 10 µM suppresses inducible nitric oxide and cyclooxygenase 2 (COX-2) expression by down-FIGURE 9 | The influence of alantolactone on p65 NF-kB concentration after S. aureus infection. ...
Aim of the Study
Phagocytosis is a crucial element of innate immune defense involved in bacterial killing. The aim of our study was to evaluate the influence of alantolactone on phagocytosis and cytokines release by THP1-derived macrophages. We assessed whether antimicrobial compound alantolactone (a sesquiterpene lactone present in Inula helenium L.) is able to stimulate immune functions of macrophages by increase of S. aureus uptake, phagosome acidification and further stimulation of phago-lysosomes formation. Simultaneously, we tested influence of alantolactone on cytokines/chemokines production and p65 NF-κB concentration. The activity of alantolactone was compared with clarithromycin at concentration 20 µM.
Methods
The cytotoxicity of alantolactone as well as S. aureus uptake, pH of phagosomes and phago-lysosomes fusion were analysed with flow cytometry. Reactive oxygen species and superoxide production were evaluated spectrophotometrically. The efficiency of phagocytosis was evaluated via quantifying viable bacteria (CFU). The effect on p65 protein concentration and cytokine production by macrophages were measured by enzyme-linked immunosorbent assay (ELISA).
Results
Alantolactone enhanced phagocytosis via increase of S. aureus uptake, acidification of phagosomes, and later stimulation of phago-lysosomes fusion. Alantolactone treatment resulted in ROS and superoxide production decrease. Furthermore, alantolactone inhibited production of pro-inflammatory cytokines TNF-α, IL-1β, IL-6, and IL-8 as well as decreased p65 concentration, the subunit responsible for NF-κB activation and cytokine production and simultaneously stimulated release of anti-inflammatory mediators (IL-10 and TGF-β).
Conclusion
Results of our study indicate that alantolactone enhances clearance of S. aureus, and simultaneously modulates immune response, preventing collateral damage of the surrounding tissues. Considering the importance of phagocytosis in the pathogen killing, alantolactone may have a great potential as the supportive treatment of S. aureus infections. Further in vivo studies are warranted to confirm this hypothesis.
... As far as the antiviral mode of action of artemisinin-derived compounds is concerned, we and others previously reported on signaling effects. NF-κB-dependent signaling was shown to be modulated by artesunate and related compounds, with an inhibitory activity specifically focused on the main target NF-κB RelA/p65 [16,27,[52][53][54][55][56][57]. Interestingly, an inhibitory effect of ART and related compounds has already been demonstrated on the HCMV immediate-early gene expression and the pre-incubation of compounds before HCMV infection increases the inhibitory efficacy [15,16]. ...
Human cytomegalovirus (HCMV) is a major human pathogen associated with severe pathology. Current options of antiviral therapy only partly satisfy the needs of a well-tolerated long-term treatment/prophylaxis free from drug-induced viral resistance. Recently, we reported the strong antiviral properties in vitro and in vivo of the broad-spectrum anti-infective drug artesunate and its optimized derivatives. NF-κB signaling was described as a targeting mechanism and additional target proteins have recently been identified. Here, we analyzed the autofluorescent hybrid compound BG95, which could be utilized for intracellular visualization by confocal imaging and a tracking analysis in virus-infected primary human fibroblasts. As an important finding, BG95 accumulated in mitochondria visualized by anti-prohibitin and MitoTracker staining, and induced statistically significant changes of mitochondrial morphology, distinct from those induced by HCMV infection. Notably, mitochondrial membrane potential was found substantially reduced by BG95, an effect apparently counteracting efficient HCMV replication, which requires active mitochondria and upregulated energy levels. This finding was consistent with binding properties of artesunate-like compounds to mitochondrial proteins and thereby suggested a new mechanistic aspect. Combined, the present study underlines an important role of mitochondria in the multifaceted, host-directed antiviral mechanism of this drug class, postulating a new mitochondria-specific mode of protein targeting.
... The many species of Asteraceae (226), Fabaceae (194), Euphorbiaceae (85) and Lamiaceae (79) reported for medicinal purposes in the 28 studies (Table 4.3 in the Supplementary Material) reflect the floristic representation of these plant families in the region (see Bye and Linares, 2015, p. 394). The use consensus of Asteraceae is on digestive (D; 54% spp./19.5% use-records) and inflammatory skin disorders (S; 47.8% spp./ 12.8% use-records) but the characteristic presence of cytotoxic sesquiterpene lactones in this family can lead to allergenic reactions (Siedle et al., 2004). The family with the highest share of species for skin disorders in the MAMPDB are the Solanaceae (66.2% spp./20.8% ...
The quality of health care in Mesoamerica is influenced by its rich cultural diversity and characterized by social inequalities. Especially indigenous and rural communities confront diverse barriers to accessing formal health services, leading to often conflicting plurimedical systems. Fostering integrative medicine is a fundamental pillar for achieving universal health coverage (UHC) for marginalized populations. Recent developments toward health sovereignty in the region are concerned with assessing the role of traditional medicines, and particularly herbal medicines, to foster accessible and culturally pertinent healthcare provision models. In Mesoamerica, as in most regions of the world, a wealth of information on traditional and complementary medicine has been recorded. Yet these data are often scattered, making it difficult for policy makers to regulate and integrate traditionally used botanical products into primary health care. This critical review is based on a quantitative analysis of 28 survey papers focusing on the traditional use of botanical drugs in Mesoamerica used for the compilation of the “Mesoamerican Medicinal Plant Database” (MAMPDB), which includes a total of 12,537 use-records for 2188 plant taxa. Our approach presents a fundamental step toward UHC by presenting a pharmacological and toxicological review of the cross-culturally salient plant taxa and associated botanical drugs used in traditional medicine in Mesoamerica. Especially for native herbal drugs, data about safety and effectiveness are limited. Commonly used cross-culturally salient botanical drugs, which are considered safe but for which data on effectiveness is lacking constitute ideal candidates for treatment outcome studies.
... Herbal drugs containing mucilage and used for oral and respiratory problems (e.g., derived from Malvaceae and Cetraria islandica (L.) Ach., Parmeliaceae) show redundancy for their soothing quality (Bruneton 1999;Hänsel and Sticher 2007;Wagner et al. 2007). Sesquiterpene lactones are known at the same time for their anti-inflammatory, cytotoxic, and allergenic properties, owing their activity to the α-methylene-γ-lactone moiety, which is able to alkylate nucleophiles of biomolecules by a Michael-type addition, especially cysteine sulfhydryl residues of proteins in general and specifically pro-inflammatory nuclear factor-kappa B, leading to undesirable cytotoxicity (Siedle et al. 2004). This is probably the reason why sesquiterpene lactone-rich herbal drugs from Asteraceae are frequently used as topical anti-inflammatory drugs (Moujir et al. 2020) and show a certain degree of redundancy. ...
The cross-cultural exchange of plant resources between societies across the globe added to the diversification of medicinal floras and pharmacopeias. Understanding how and why people select plants for medicine is still a common focus and topic addressed by the interdisciplinary research fields of ethnobotany, anthropology, ethnopharmacology, ethnomedicine, pharmacy, phytochemistry, and pharmacognosy. Here, we scrutinize recently reviewed ethnobotanical theories and hypotheses, which focus on the selection of plants as medicine by putting them into historical, ecological, and pharmacological perspective. We contextualize the availability, versatility, and diversification hypotheses, often presented in association with the inclusion of non-native species or imported herbal drugs into medicinal floras or ethnopharmacopeias. We also discuss the relevance of the concept of utilitarian redundancy and the apparency hypothesis, as well as the appropriateness of various statistical models applied for assessing non-random plant selection. It appears that the concept of utilitarian redundancy has been applied in a too reductionist and uncritical way, while the apparency theory is conceptually inconsistent and contradictive allowing for multiple interpretations. While the availability, versatility, and diversification hypotheses are not contextualized historically, they are used to explain retrospectively deliberate and well-documented human activities and cultural developments. Therefore, considering the cultural history and the pharmacology of plants is essential for the formulation of hypotheses related to the selection of plants as medicine and food. Ecological research questions applied to human-plant relationships should consider the historical impact of human culture as a framework and confounder to be integrated into the analysis.
Graphical abstract
https://rdcu.be/b5Gte
... These two SL types (i.e. H and DH) are the main compounds responsible for anti-inflammatory properties of A. montana extracts (Siedle et al. 2004). ...
Arnica montana (Asteraceae) is a herbaceous species with high interest for pharmaceutical industry due its anti-inflammatory properties. However, commercial collection in wild, habitat loss, abandonment of land, reforestation and the ongoing climate change threaten the conservation of the species throughout its natural distribution. Galicia (north-western Spain) is one of the main flower suppliers, but no legislation on A. montana exploitation is currently applied. In order to assess the genetic status and population structure in this region, 27 locations were genotyped for 14 microsatellite loci and sequenced for 2 plastid DNA (cpDNA) markers. The relationship of environmental, biochemical and morphological variables with genetic differentiation was also evaluated. Two different cpDNA groups previously described were found. One of them was widely distributed while the other was restricted to heathlands of the O Courel Mountains. The percentage of clonality was low (< 10%). Genetic diversity based on microsatellites (He = 0.245) was lower than in Central European populations, with high levels of population differentiation (FST = 0.441), suggesting strong effects of genetic drift. Bayesian clustering methods revealed the presence of four genetically distinct population units, one of them corresponding to the O Courel Mountains group described by cpDNA analysis. Environmental and biochemical factors were related to genetic differentiation, suggesting local adaptation. Necessary conservation measures include the overdue implementation of the Habitats Directive by the Galician Regional Administration, establishing sustainable harvesting regimes, and aim to conserve genetic variation in these endangered populations at the southern range edge.
... The beneficial health effects of sesquiterpene lactones seem to be of potentially major interest especially their anti-inflammatory effect, and reported gastric cytoprotective properties [101,102]. Hyperglycemia is responsible for an inflammatory status through the activation of NF-κB signaling, which is involved in the synthesis of cytokines such as TNFα [103,104]. The suppressive action of sesquiterpene lactones on the degradation of the I-κB (inhibitor of NF-κB) reduces the activation of glucose-stimulated NF-κB [105]. ...
The prevalence of metabolic syndrome (METS) directly correlates with the prevalence of obesity, and it is associated with several other risk factors. Among them, chronic inflammation, oxidative stress and insulin resistance might be reduced in order to delay the progression of METS. The first management of METS involves physical exercises and a suitable diet. Many Asteraceae are plants commonly consumed. The bitter Asteraceae known for their health effect are traditionally used as bitter drinks. Their particularly rich contents in sesquiterpene lactones and hydroxy-cinnamic acids mainly in caffeoyl derivatives, confer to these plants good anti-METS potential. These compounds are known for their antioxidant, anti-inflammatory and insulin sensitizing effects and confer to bitter Asteraceae the potential to be good candidate products to delay METS. Keywords: Metabolic syndrome, Bitter Asteraceae, Hydroxycinnamic acids, Chicoric acid, Chlorogenic acid
... In addition to the primary targets of SLs which were exposed thiol groups in proteins, the activity of SLs may also be influenced by other factors, including molecular geometry, lipophilicity, and the chemical environment of the target sulfhydryl groups. The anti-inflammatory SLs focusing on their effects has been explained by mechanisms of action such as inhibition of the nuclear factor-kB, reactive oxygen, and nitrogen species, cytokines, and lipid mediators, probably by alkylating cysteine-38 in the DNA binding domain of the p65 subunit [27,28]. According to the literature, inuviscolide, the main anti-inflammatory SL possessing 8,12 guaianolide skeleton from I. viscosa, was reported having significant topical anti-inflammatory effect against acute inflammation by in vivo model. ...
The aerial parts of Chrysophthalmum montanum (DC.) Boiss. (Asteraceae) is traditionally used for wound healing, as well as for the treatment of common cold, sinusitis, and other inflammatory diseases. The objectives of this study were to identify potential anti-inflammatory effects of the methanol extract, and its different polarity subextracts (n-hexane, chloroform, n-butanol, and remaining aqueous), and guaianolide-type sesquiterpene lactones [6α-acetoxy-4α-hydroxy-1βH-guaia-9.11(13)-dien-12.8α-olide (1), 6α-acetoxy-4α-hydroxy-9β.10β-epoxy-1βH-guaia-11(13)-en-12.8α-olide (2), 4α,6α-dihydroxy-1β,5α,7αH-guaia-9(10),11(13)-dien-12,8α-olide (3), and (4α,5α,8β,10β)-4,10-dihydroxy-1,11(13)-guaidien-12,8-olide (4)] from the aerial parts of C. montanum. In order to evaluate the anti-inflammatory activity of C. montanum, carrageenan- and PGE2-induced hind paw edema, and acetic acid-induced increase in capillary permeability mice models were used. The methanol extract, the chloroform subextract, and compounds 3, and 4 were shown to possess anti-inflammatory activity in in vivo models at 100 mg/kg dose. The results provide a biological, and phytochemical basis for the traditional use of C. montanum aerial parts for inflammatory conditions in Turkish folk medicine.
Tanacetum Parthenium is a herbal medicinal plant which is known as feverfew. Asterace is the family of feverfew. It is traditionally applicable in the treatment of stomach aches, fever, arthritis, infertility, migraine, insect bites, menstruation problems, and labour pain during childbirth. Dioscorides was the first Greek physician to which uses feverfew extract for treatment of inflammation. Particularly among Greek and early European herbalists, feverfew plant has ancient historyfor traditionally used as common medicine. This plant is also known as "featherfew" due to its feathery leaves. The leaves have been used in medicinal preparation in past two decades for treatment of arthritis and migraine by both the British and Canadian government. The herbal plant of feverfew cultivated in large area of world that show medicinal importance. Plant grow substantially and show important strongly report in support of therapeutic uses. This aromatic plant look like yellow green leave and give bitter odour and give therapeutic active chemical constituents include pinenes flavonoid and glycoside. It shows various pharmacological properties, like antispasmodic, cardiotonic, anti-inflammatory, anti-cancer, and as an enema for worms. The colour of feverfew plant is yellow and bloom in October to July, which is also used in asthma, dizziness, nausea and vomiting. Parthenolide may experience an acid-induced cyclisation in the presence of excessive moisture, resulting in a sesquiterpene lactone of the guaianolide class, which is frequently present in feverfew. If the composition satisfies pharmacopoeial microbiological quality standards, microbial degradations are unlikely to have a significant impact.
Nine undescribed carotane sesquiterpenes and rare rearranged guaiane sesquiterpenoids ( 1‒9 ), along with two known analogues ( 10‒11 ), were obtained from the aerial parts of Daphne penicillata . Their structures and absolute configurations...
The traditional Chinese medicine Xanthium sibiricum Patrin ex Widder is used to treat wind-cold headache, nasal congestion, nasal discharge, allergic rhinitis, sinusitis, urticaria, and arthritis. Our previous studies found that sesquiterpene lactones, the main bioactive constituents of X. sibiricum, relieved airway inflammation in an asthma mouse model. To obtain active sesquiterpenes, five undescribed ones, including a pair of eremophilanes and three xanthanolides, together with eight known xanthanolides were isolated from X. sibiricum. Their structures were identified by IR, UV, HR-ESI-MS and NMR spectroscopic data, and their absolute configurations were determined by X-ray crystallographic diffraction analysis and the comparison between their experimental and calculated electronic circular dichroism. All isolated compounds were evaluated for their inhibitory effects on nitric oxide production, and Tnf-α, Il-1β, and Il-6 mRNA expression induced by lipopolysaccharide in the macrophage cell line RAW264.7. Further investigation showed that xanthsibiriolide and 11β-hydroxyl-13-chloro-8-epi-xanthatin exerted their anti-inflammatory effects by inhibiting the PI3K/AKT/mTOR signaling pathway. Analysis of the structure-activity relationships indicated that the α,β-unsaturated lactone ring and the 1,5-epoxide group might be the bioactive groups of xanthanolides, and these results provide a basis for further exploration of sesquiterpene-type lead compounds with anti-inflammatory activity.
Peritoneal fibrosis is a common complication of peritoneal dialysis (PD) with a complicated pathogenesis and limited treatments. Parthenolide (PTL), a recognized nuclear factor-κB (NF-κB) inhibitor extracted from Tanacetum balsamita, has been widely used to treat various inflammatory diseases and has been proven to improve peritoneal fibrosis in PD mice by selectively inhibiting the phosphorylation of Smad2/3. Transforming growth factor-β1 (TGF-β1), via Smad-dependent signaling, has a pivotal role in promoting pathogenic of fibrosis. To investigate whether PTL can inhibit peritoneal fibrosis, we affected the interaction between NF-κB and the TGF-β/Smad2/3 pathway. Long dwell peritoneal dialysis fluid (PDF) and peritoneum tissues were collected from continuous ambulatory peritoneal dialysis (CAPD) patients. PTL was administered intragastrically into a PD mouse model by daily infusion of 4.25% dextrose-containing PDF. Treated HMrSV5 cells or rat peritoneal mesothelial cells (RPMCs) were treated with high glucose(138 mM) at the same concentration as 2.5% dextrose-containing PDF and PTL. PD-related peritoneal fibrosis samples indicated an increase in inflammation, and PTL decreased the levels of inflammatory cytokines (L-6, TNF-α, and MCP-1). PTL inhibited high glucose-induced mesothelial-to-mesenchymal transition (MMT), as indicated by a reduced expression of fibrosis markers (fibronectin, collagen I, and α-SMA) and increased expression of the epithelial marker E-cadherin. PTL also significantly decreased TGF-β1 expression and the phosphorylation of IκBα and NF-κBp65. The changes in the levels of TGF-β1 expression and p-p65 or p65 showed similar trends according to western blot, immunohistochemistry, and immunofluorescence assays in vitro and in vivo. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were used to confirm that PTL regulates the transcription of TGF-β1 induced by high glucose through NF-κBp65. In summary, PTL induces a therapeutic effect in peritoneal fibrosis by inhibiting inflammation via the NF-κB/ TGF-β/Smad signaling axis.
Cancer has claimed the lives of millions of people around the world. The non-selective toxicity of current anticancer drugs and the increasing drug resistance of certain types of cancer are the major problems in the treatment of cancer. Affordability is another concern in cancer treatment. The number of new cases is expected to rise by double within the next two decades. Discovering new anticancer drugs with safe modes of action is thus urgently needed. Natural products have been well-known contributors to anticancer drugs. Among higher plants, species of Taxus, Vinca (Catharanthus), Camptotheca, Podophyllum, and Combretum are a few examples of successful plant sources of clinically used anticancer drugs. Further, some of the natural product-derived molecules like docetaxel, cabazitaxel, etoposide, teniposide, irinotecan, topotecan, vindesine, vinorelbine, epirubicin, idarubicin, eribulin, etc., are some of the successful clinical drugs. There are many more natural products or molecules of terrestrial/marine origin having potential anticancer activities. These are required to evaluate systematically and extensively to get another success story like many of the previous ones. This chapter describes the concise knowledge about cancer and detailed anticancer agents from different classes of phytochemicals like alkaloids, terpenoids, phenolics, steroids, and others. The mechanistic studies of active compounds and structure–activity relationship will also be highlighted.
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurological illness that affect people in their later years. Memory loss is the hallmark of Alzheimer’s disease, while dyskinesia, or loss of mobility, is associated with muscle rigidity and tremors in PD. Both diseases are unrelated, however they do have a few similarities associated to extrapyramidal abnormalities, particularly stiffness, which has been linked to concomitant PD in many AD patients. Increased levels of IL-1, IL-6, and TNF in the AD’s and PD’s patients can be regarded evidence of systemic inflammation associated with each of these neurodegenerative disorders. One of the primary variables in the progression of neurodegenerative disorders is oxidative stress. Many medicinal plants and their secondary metabolites have been claimed to be able to help people with neurodegenerative disorders like AD and PD. Anti-inflammatory, antioxidant, antiapoptotic, monoamine oxidase inhibition, acetylcholinesterase, and neurotrophic pursuits are among the major mechanisms identified by which phytochemicals exert their neuroprotective effects and potential maintenance of neurological health in old age. In regard to neurodegenerative disorders, numerable plant-based drugs like alkaloids, iridoids, terpenes, flavones are employed for the treatment. Structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) are used to investigate the link between bioactivity and chemical configuration of substances. The SAR and QSAR of natural plant components employed in AD and PD are discussed in the current review.
We have recently highlighting the role of spiro-isoxazoline arteannuin B derivatives in mediating proinflammatory cytokines like IL-6, TNfα and NO in vitro. In the present study, a series of new β-arylated arteannuin B analogues were synthesized through coupling with arylboroic acids and evaluated for their in vitro cytotoxic activity in a panel of six cancer cell lines. The binding efficiency was verified by docking of the original ligand within the active site of ATPase domain of GRP78 (PDB ID: 3LDL) at a resolution of 2.30 Å with the score energy of -8.07 kcal/mol. Among the new compounds 3a, 3b, 3d, 3i, 3j and 3n displayed potent cytotoxic potential with an IC50 from 2 to 18 µM and compound 3i was proven to be the most potent cytotoxic and anti-proliferative compound of all the six distinct cell lines. Compound 3i exhibited promising apoptosis inducing potential in breast cancer cells and stalled their wound healing properties and was effective in blocking the migration of cancer cells.
The pseudoguaianolide-type sesquiterpene lactone (SL) britannin (BRT), found in different Inula species, has been characterized as a potent anticancer agent acting via modulation of the transcription factor NFkB and the Nrf2-Keap1 signaling pathway. In addition, a BRT-induced down-regulation of the immune checkpoint PD-L1 (programmed cell death ligand 1) expressed on cancer cells has been evidenced. Here we have performed a docking analysis of the direct binding of BRT to the PD-L1 protein, both in its monomeric and dimeric state. BRT appears to form stable complexes with PD-L1, with a preference for the dimeric form, binding at the interface of the two monomers. The calculated empirical energy of interaction (ΔE) value reaches −63.1 kcal/mol for the BRT-PD-L1 dimer complex, not far from the value calculated with the reference PD-L1 ligand BMS-202 (ΔE = −73.4 kcal/mol) under identical conditions. We also studied the potential PD-L1 dimer binding of 15 pseudoguaianolide sesquiterpene lactones analogues to BRT, including helenalin, gaillardin, bigelovin, coronopilin, and others. The docking analysis predicted that the SL chamissonolide (CHM) can also form equally stable complexes with PD-L1 dimer (ΔE = −64.8 kcal/mol). Preliminary compound structure-PD-L1 binding relationships have been delineated. This computational study supports the proposed interaction of BRT with PD-L1 and provides a guidance to the design of novel PD-L1 binders incorporating a SL-like tricyclic core unit.
Carpesium divaricatum Sieb. & Zucc., a traditional medicinal plant used as an inflammation-relieving remedy, is a rich source of terpenoids. At least 40 germacrane-type sesquiterpene lactones, representatives of four different structural groups, were isolated from the plant. Cytotoxicity against cancer cells in vitro is the most frequently described biological activity of the compounds. However, little is known about the selectivity of the cytotoxic effect. The anti-inflammatory activity of the germacranolides is also poorly documented. The objective of the present study was to assess the cytotoxic activity of selected C. divaricatum germacranolides-derivatives of 4,5,8,9-tetrahydroxy-3-oxo-germacran-6,12-olide towards cancer and normal cell lines (including cells of different p53 status). Moreover, to assess the anti-inflammatory effect of the compounds, the release of four proinflammatory cytokines/chemokines (IL-1β, IL-8, TNF-α and CCL2) by lipopolysaccharide-stimulated human neutrophils was measured by ELISA. The investigated sesquiterpene lactones demonstrated nonselective activity towards prostate cancer (Du145 and PC3) and normal prostate epithelial cells (PNT2) as well as against melanoma cells (A375 and HTB140) and keratinocytes (HaCaT). Cytotoxic activity against osteosarcoma cells was independent of their p53 status. In sub-cytotoxic concentrations (0.5–2.5 µM) the studied compounds significantly decreased cytokine/chemokine release by lipopolysaccharide-stimulated human leukocytes.
Scope
Nuclear factor‐κB (NF‐κB) activation in macrophages aggravates atherosclerosis. Dietary plant secondary metabolites including sesquiterpene lactone lactucopicrin target multiple organs. This study was focused on the impact of lactucopicrin on NF‐κB activation in inflammated macrophages and atherogenesis in a mouse model of atherosclerosis.
Methods and Results
In LPS‐stimulated mouse bone marrow‐derived macrophages, lactucopicrin inhibited NF‐κB activation and concomitantly repressed the expression of IL‐1β, IL‐6 and tumor necrosis factor alpha. This effect was not due to modulation of inhibitor of NF‐κB kinases (IKK) α/β/γ and NF‐κB inhibitor α, and NF‐κB/p65 DNA binding activity. Instead, the lactucopicrin effect was reliant on the inhibition of cytoplasmic dynein‐mediated p65 transportation, a prerequisite step for p65 nuclear translocation. In high‐fat diet‐fed apolipoprotein E‐deficient mice, lactucopicrin consumption dose‐dependently reduced plaque area, inhibited plaque macrophage accumulation, attenuated plaque macrophage NF‐κB activation, and reduced both plaque and serum inflammatory burden. However, lactucopicrin consumption did not affect the levels of serum lipids and anti‐inflammatory cytokines (IL‐4, IL‐10 and transforming growth factor beta).
Conclusion
Dietary lactucopicrin inhibits atherogenesis in mice likely by its anti‐inflammatory property. These findings suggest that dietary supplementation with lactucopicrin is a promising strategy to inhibit atherosclerotic cardiovascular disease.
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α-Methylene-γ-lactones are present in ∼3% of known natural products, and compounds comprising this motif display a range of biological activities. However, this reactive lactone limits informed structure-activity relationships for these bioactive molecules. Herein, we describe chemically tuning the electrophilicity of the α-methylene-γ-lactone by replacement with an α-methylene-γ-lactam. Guaianolide analogues having α-methylene-γ-lactams are synthesized using the allenic Pauson-Khand reaction. Substitution of the lactam nitrogen with electronically different groups affords diverse thiol reactivity. Cellular NF-κB inhibition assays for these lactams were benchmarked against parthenolide and a synthetic α-methylene-γ-lactone showing a positive correlation between thiol reactivity and bioactivity. Cytotoxicity assays show good correlation at the outer limits of thiol reactivity but less so for compounds with intermediate reactivity. A La assay to detect reactive molecules by nuclear magnetic resonance and mass spectrometry peptide sequencing assays with the La antigen protein demonstrate that lactam analogues with muted nonspecific thiol reactivities constitute a better electrophile for rational chemical probe and therapeutic molecule design.
Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype to treat because there are no targeted therapies. Currently, chemotherapy is the only clinical option for TNBC despite development of resistance. New therapeutic agents with unique mechanisms of action are urgently needed; therefore, this study investigated the potential anti-TNBC effects of budlein A methylacrylate (BAM), a natural sesquiterpene lactone isolated from plants of the Helianthus genus. We discovered that BAM selectively suppressed and induced apoptosis TNBC cell growth versus other breast cancer or normal mammary epithelial cells. Mechanistically, BAM co-inhibited inhibitor of nuclear factor κBα (IκBα) kinase subunit β (IKKβ) and exportin-1 (XPO-1; chromosome region maintenance 1, CRM1), which are two dysregulated onco-related proteins in TNBC cells, by covalently modifying key functional cysteine residues (Cys179 of IKKβ, Cys528 of XPO-1). Dual inhibition led to the stabilization and nuclear retention of IκBα, impairment of NF-κB transcriptional activity, and consequent induction of TNBC cell apoptosis. In conclusion, this study provides evidence that co-inhibition of IKKβ and XPO-1 by BAM was effective against TNBC, demonstrating it as a representative new generation inhibitor with potential for TNBC treatment.
Sigesbeckia orientalis, more commonly referred to as Herba Sigesbeckiae or Xi Xian Cao in traditional Chinese medicine and hy thiêm in traditional Vietnamese medicine, is used in China and Vietnam to treat inflammatory diseases such as arthritis, rheumatism, and joint pain. In initial investigations, the dichloromethane extract from the aerial parts of S. orientalis showed distinct inhibitory effects on the release of interleukin-8 in human neutrophils. Therefore, the purpose of the present study was the phytochemical investigation of the bioactive dichloromethane extract and the in vitro analysis of the effects of the isolated compounds on interleukin-8, interleukin-1β, tumor necrosis factor-α, and monocyte chemoattractant protein 1 release, and surface expression of adhesion molecules (CD11a, CD11b, and CD62L) in lipopolysaccharide-stimulated human neutrophils to identify the active principle(s). The separation of the bioactive dichloromethane extract using various chromatographic techniques led to the isolation of nine compounds. Their chemical structures were elucidated from nuclear magnetic resonance and mass spectrometry data. One diterpene, 17(13 → 14)-abeo-ent-3S*,13S*,16-trihydroxystrob-8(15)-ene, was identified as a new natural product. Three germacranolide sesquiterpene lactones inhibited interleukin-8 production with IC50 values between 1.6 and 6.3 µM, respectively, and tumor necrosis factor-α production with IC50 values between 0.9 and 3.3 µM, respectively. Furthermore, they significantly inhibited interleukin-1β and monocyte chemoattractant protein 1 production and diminished the effects of lipopolysaccharide on the surface expression of the adhesion molecules CD11a, CD11b, and CD62L. These findings support the traditional use of S. orientalis in the treatment of inflammatory diseases.
INTRODUCTION: This thesis presents a panel of the anti-inflammatory, cytotoxic and antioxidant activities of nine plant species, which have been selected from Thai textbooks, in order to assess the traditional claims about the therapeutic potential and to select plants for further phytochemical research, of active compounds through bioassay-guided fractionation procedures. METHODS: Anti-inflammatory, Nuclear factor-kappa B (NF-κB) inhibitory effects on PMA-induced NF-κB activation in stably tranfected HeLa cells were determined by luciferase assay, and the effects on LPS-induced pro-inflammatory mediators prostaglandin E2 (PGE2), interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)α in primary monocytes were assessed by ELISA. Cytotoxic activities were examined against cervix cancer HeLa cells, human leukaemia CCRF-CEM cells and the multidrug-resistant CEM/ADR5000 cells using the MTT and XTT tests. However, as redox status has been linked with both inflammation and cancer, antioxidant effects were also assessed using the DPPH, lipid-peroxidation, and Folin- Ciocalteau methods. Phytochemical investigation of active compounds from the methanol extract of G. pseudochina var. hispida was carried out using Sephadex LH-20 column chromatography, TLC and HPLC as well as NMR and MS spectroscopic techniques. RESULTS: Among the nine species, the methanol extract of Gynura pseudochina var. hispida and the ethylacetate extract of Oroxylum indicum showed the most promising NF-κB-inhibitory effects with the lowest IC50 values (41.96 and 47.45 μg/ml, respectively). The ethyl acetate and methanol extracts of Muehlenheckia platyclada did not inhibit the NF-κB activation but effectively inhibited the release of IL-6, IL-1β and TNF-α with IC50 values ranging between 0.28 and 8.67 μg/ml. The petroleum ether extract of Pouzolzia indica was the most cytotoxic against CCRF-CEM cells and the multidrug resistant CEM/ADR5000 cells (9.75% and 10.48% viability, at 10 μg/ml, respectively). The ethylacetate extract of Rhinacanthus nasutus showed the most potent cytotoxicity against HeLa cells (IC50 3.63 μg/ml) and the methanol extract of R. nasutus also showed specific cytotoxicity against the multidrug resistant CEM/ADR5000 cells (18.72% viability at 10 μg/ml, p< 0.0001 compared to its cytotoxicity against CCRF-CEM cells). Moreover, the ethylacetate extract of O. indicum showed a high level of antioxidant activity by inhibiting lipid-peroxidation (IC50=0.08 μg/ml). As the most active anti-inflammatory species via the NF-κB signaling pathway, G. pseudochina var. hispida was selected for further investigation of active compounds. Through bioassay guided fractionation and isolation procedures, flavonoid glycosides; quercetin-rutinoside (rutin), dicaffeoylquinic acid derivatives and caffeoylquinic acid were isolated as the active NF-κB inhibitors. CONCLUSIONS: This thesis provides in vitro evidence for the use of the Thai plants, most importantly Gynura pseudochina var. hispida, Oroxyhm indicum and Muehlenheckia platyclada as Thai anti-inflammatory remedies. The active compounds isolated from the methanol extract of G. pseudochina var. hispida: the most potent NF-κB inhibitory extract, were identified as the known compounds quercetin-rutinoside and dicaffeoylquinic acid. Some of the results obtained might support the uses of the plants and are in agreement with previously reported literature, but some are in need of further investigation of either active compounds or their pharmacology. This finding provides a new insight for understanding the anti-inflammatory activities of a panel of traditionally used anti-inflammatory plants. The active compounds isolated from the methanol extract of G. pseudochina var. hispida: the most potent NF-κB inhibitory extract, were identified as the known compounds quercetin-rutinoside, dicaffeoylquinic acid and caffeoylquinic acid derivatives. The active compounds are reported from this genus for the first time.
Parthenolide is an important sesquiterpene lactone with potent anticancer activities. In order to further improve its biological activity, a series of parthenolide semicarbazone or thiosemicarbazone derivatives was synthesized and evaluated for their anticancer activity. Derivatives were tested in vitro against 5 human tumor cell lines, and many of these showed higher cytotoxicity than parthenolide. Five compounds were further studied for their antitumor activity in mice. The in vivo result indicated that compound 4d showed both promising antitumor activity against mice colon tumor and small side effects on immune systems. The cell apoptosis and cell cycle distribution of compound 4d were also studied. Molecular docking studies revealed multiple interactions between 4d and NF-κB. Our findings demonstrate the potential of semicarbazones as a promising type of compounds with anticancer activity.
Helichrysum plicatum DC. is widely used in folk medicine in treating a variety of health disorders. The aim of this study was to examine the influence of different extraction solvents on the chemical composition, antioxidant potential, and antimicrobial activities of H. plicatum. Aerial parts were separately extracted with ethanol, dichloromethane, and sunflower oil. The oil extract (OE) was re-extracted with acetonitrile. A total of 142 compounds were tentatively identified in ethanolic (EE), dichloromethane (DCME), and acetonitrile (ACNE) extracts using HPLC-DAD/ESI-ToF-MS. The dominant compound class in all extracts were α-pyrones, alongside flavonoids in EE, terpenoids in DCME and ACNE, and phloroglucinols in DCME. The antioxidant potential of the extracts was assessed by the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) assay. EE and DCME possessed the most potent radical scavenging capacity. Antimicrobial activity was investigated on eight bacterial, two yeast, and one fungal species. All extracts exhibited high antifungal and notable antibacterial activities compared to control substances, with DCME being the most potent. DCME exhibited stronger antimicrobial activity against P. aeruginosa than the standard chloramphenicol.
Investigation into the chemical diversity of Artemisia argyi led to the discovery of two new (1, 4) and four known (2-3, 5-6) sesquiterpenoids. The new structures were determined via extensive spectroscopic data, including IR, UV, MS, and NMR, and the absolute configurations of these compounds were elucidated by calculated ECD method. All isolates were tested for their inhibitory activity against NO production in RAW 264.7 macrophages, and the isolated sesquiterpenoids exhibited NO production inhibitory activity with IC50 values ranging from 1.91 to 36.52 μM.
A new parametric quantum mechanical molecular model, AM1 (Austin Model 1), based on the NDDO approximation, is described. In it the major weaknesses of MNDO, in particular failure to reproduce hydrogen bonds, have been overcome without any increase in computing time. Results for 167 molecules are reported. Parameters are currently available for C, H, O, and N.
In chronic inflammatory diseases, such as asthma, rheumatoid arthritis, inflammatory bowel disease, and psoriasis, several cytokines recruit activated immune and inflammatory cells to the site of lesions, thereby amplifying and perpetuating the inflammatory state.1 These activated cells produce many other mediators of inflammation. What causes these diseases is still a mystery, but the disease process results from an interplay of genetic and environmental factors. Genes, such as those for atopy in asthma and for HLA antigens in rheumatoid arthritis and inflammatory bowel disease, may determine a patient's susceptibility to the disease and the disease's severity, but environmental factors, often unknown, . . .
Sesquiterpene lactones are plant constituents often possessing a bitter taste which are common in most tribes of the Asteraceae (Compositae) and also are found in at least 14 other angiosperm families and to a limited extend in gymnosperms, liverworts and fungi.1 There are more than 4,000 known structures in this class of plant secondary metabolites, and the bioactivity of some of these compounds has been reviewed previously, e. g. by Picman,1 Ivie and Witzel,2 and Rodriguez, Towers, and Mitchell.3 Planta Medica has announced the planned publication of an updated review by Rodriguez. These reviews have reported a wide variety of biological effects, some of which are listed in Table 1. Sesquiterpene lactone mechanisms of action also have been investigated extensively, and some of their reported molecular targets include acid Phosphatase, aryl sulfatase, cathepsins, cyclooxygenase, DNA, DNA Polymerase, glycogen synthase, 5-lipoxygenase, phosphofructokinase, phospholipase A2, reduced glutathione, and thymidylate synthetase.1–3
As one of the largest groups of secondary plant metabolites, sesquiterpene lactones (STL) possess a broad variety of conspicuous biological activities directed towards all types of predating organisms. The majority of these compounds are believed to exert their activities by a common chemical mechanism of action, alkylation of biological macromolecules leading to decisive consequences on cellular function. An impressive number of enzymes and other essential macromolecules are known to be inhibited by STL, usually at very low concentrations. Such alkylant STL, therefore, are generally cytotoxic. Although many of them possess potentially useful activities, e.g. as therapeutic agents against inflammation and cancer, the low selectivity of these effects usually forbids utilization due to high unspecific toxicity. In addition to such alkylants which can be considered a non-specific and highly efficient chemical weapon against literally any organism that might be harmful to the plants, some less common representatives which exert toxicity by very specific molecular mechanisms, such as some strong inhibitors of intracellular calcium signalling and some highly potent GABA-antagonistic neurotoxins, are treated separately. The various aspects of sesquiterpene lactone toxicity from the general chemical basis via molecular targets and toxic effects at the cellular level to toxicity versus the different mammalian organ systems are outlined. Wherever possible, special attention is paid to relationships between chemical structure and bioactivity.
Based on results of a previous study on cytotoxicity of 21 helenanolide sesquiterpene lactones, a quantitative description of structure activity relationships is established. Different approaches (Free-Wilson type analysis and QSAR based on 33 molecular descriptors) led to similar results. Cytotoxicity is strongly dependent on the number and type of alkylating centers and on molecular conformation. A further factor is the number of H-bond accepters which is important for non-covalent interactions of the compounds with proteins preceding alkylation.
An extract of Calea lantanoides which inhibits larval development of Strongyloides stercoralis and three species of hookworms gave the heliangolide 15-deoxybudlein A.
Tanacetum chiliophyllum var. heimerlei afforded nine eudesmanolide and germacranolide type sesquiterpene lactones, two of them being new. The structures were elucidated by spectral methods.
From A. cordifolia, in addition to two known compounds, a sesquiterpene lactone, new as a natural compound, was identified. The structures were elucidated by spectroscopic methods.
Aerial parts of Tithonia diversifolia collected in São Paulo State afforded two new heliangolides in addition to the heliangolides tagitinin F and 1,2-epoxytagitinin C, one known guaianolide and the flavone hispidulin. Structures were established by spectroscopic studies. © 1997 Elsevier Science Ltd. All rights reserved
The aerial parts ofPicris altissima afforded in addition to dehydrocostus lactone, three closely related C-3 and C-10 oxygenated guaianolides, two of them were isolated for the first time from a plant source. The structures were determined on the basis of their spectral data.
Alcoholic extracts prepared form Arnicae flos, the collective name for flowerheads from Arnica montana and A. chamissonis ssp. foliosa, are used therapeutically as anti-inflammatory remedies. The active ingredients mediating the pharmacological effect are mainly sesquiterpene lactones, such as helenalin, 11 alpha,13-dihydrohelenalin, chamissonolid and their ester derivatives. While these compounds affect various cellular processes, current data do not fully explain how sesquiterpene lactones exert their anti-inflammatory effect. We show here that helenalin, and, to a much lesser degree, 11 alpha,13-dihydrohelenalin and chamissonolid, inhibit activation of transcription factor NF-kappa B. This difference in efficacy, which correlates with the compounds' anti-inflammatory potency in vivo, may be explained by differences in structure and conformation. NF-kappa B, which resides in an inactive, cytoplasmic complex in unstimulated cells, is activated by phosphorylation and degradation of its inhibitory subunit, I kappa B. Helenalin inhibits NF-kappa B activation in response to four different stimuli in T-cells, B-cells and epithelial cells and abrogates kappa B-driven gene expression. This inhibition is selective, as the activity of four other transcription factors, Oct-1, TBP, Spl and STAT 5 was not affected. We show that inhibition is not due to a direct modification of the active NF-kappa B heterodimer. Rather, helenalin modifies the NF-kappa B/I kappa B complex, preventing the release of I kappa B. These data suggest a molecular mechanism for the anti-inflammatory effect of sesquiterpene lactones, which differs from that of other nonsteroidal anti-inflammatory drugs (NSAIDs), indomethacin and acetyl salicylic acid.
Low-molecular phenolic cleavage products as well as dibenzofurans are obtained by treatment of polymeric polyphenols from Sargassum muticum and Pelvetia canaliculata (brown algae) with hot aqueous alkali. Similar degradation products were observed in the analogous treatment of model substances (1). Statements about certain structure elements of polymeric material can now be made from rules derived at that time. The polyphenol fraction from S. muticum seems to contain only phlorotannins of the fuhalol type and those from P. canaliculata, in addition to a large portion of non-cleavable substances, several compounds of the fucophlorethol type.
The aerial parts of Tanacetum praeteritum subsp. praeteritum afforded three new eudesmanolides and a new sesquiterpene ester, in addition to some known sesquiterpene lactones. The structures of the compounds were elucidated by spectral methods.
The aerial parts ofTanacetum densum subsp.sivasicum yielded, in addition to known compounds, a new sesquiterpene lactone, sivasinolide which showed antibacterial activity againstBacillus subtilis andKlebsiella pneumoniae. The structures were elucidated by spectral methods. Some sesquiterpene lactones were evaluated for their cytotoxic activity.
Investigation of Podachaenium eminens afforded nine sesquiterpene lactones (Sls) from which costunolide, 7-hydroxycostunolide, santamarin as well as 3-chlorodehydroleucodin are new for this plant and 3,4-dehydro-4-dehydroxypodachaenin (= 3-costoyloxydehydroleucodin) is found for the first time in nature. All isolated Sls were studied for their anti-inflammatory activity using the transcription factor NF-κB as a molecular target. NF-κB is involved in the synthesis of inflammatory mediators, such as cytokines and chemokines. Except for podachaenin, all compounds completely inhibited NF-κB DNA binding in an electrophoretic mobility shift assay at concentrations between 5 and 200 μM without showing any cytotoxic effects. 3,4-Epoxydehydroleucodin possessing an α-methylene-γ-butyrolactone and a second reactive structure element by its epoxy ring α,β to a carbonyl group was most active. Although the majority of the Sls tested in this study were monofunctional only low concentrations of 50 μM were often needed for complete inhibition. Possible reasons are discussed for this result.
Abbreviations
BSA:bovine serum albuminc.p.m.:counts per minuteDTT:dithiothreitolEDTA:ethylenediaminetetraacetic acidEGTA:ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acidFCS:fetal calf serumHEPES:N-[2-hydroxyethyl]piperazine-N′-[2-ethanesul-fonic acid]NP-40:nonylphenoxypolyethoxyethanolPBS:phosphate buffered salinePMSF:phenylmethanesulfonyl fluoridePoly (dI-dC):polydeoxyinosinicdeoxycytidylic acid, double-stranded alternating copolymer
Many sesquiterpene lactones (SLs) possess considerable anti-inflammatory activity. They inhibit the transcription factor NF-κB by selectively alkylating its p65 subunit probably by reacting with cysteine residues. Here we assayed 28 sesquiterpene lactones for their ability to inhibit NF-κB. The majority of the potent NF-κB inhibitors possess two reactive centers in form of an α-methylene-γ-lactone group and an α,β- or α,β,γ,δ-unsaturated carbonyl group. Based on computer molecular modelling we propose a molecular mechanism of action, which is able to explain the p65 selectivity of the SLs and the observed correlation of high activity with alkylant bifunctionality. A single bifunctional SL molecule can alkylate the cysteine residue (Cys 38) in the DNA binding loop 1 (L1) and a further cysteine (Cys 120) in the nearby E’ region. This cross link alters the position of tyrosine 36 and additional amino acids in such a way that their specific interactions with the DNA become impossible. We also created a model for monofunctional SLs.
In continuation of a previous QSAR study on the cytotoxicity of 20 sesquiterpene lactones (STLs) of the helenanolide type towards a mouse tumour cell line where a very strong correlation of activity with only two indicator variables encoding the nature of the present α,β-unsaturated carbonyl structure elements (cyclopentenone and α-methylene-γ-lactone structure) was found, it was the major goal of this study to establish a QSAR model for a set of STLs with wider structural variability. Cytotoxicity towards the human KB cervix carcinoma cell line was experimentally determined for a set of 40 STLs representing five different structural groups (2 germacranolides, 6 guaianolides, 23 pseudoguaianolides, 8 eudesmanolides and 1 carabranolide (cyclopropane type xanthanolide) and the resulting IC50 values were submitted to a QSAR study using the molecular modelling program MOE. As major result it could be shown that variance in STL cytotoxicity data can be explained to a high degree by electronic and surface properties. QSAR models of considerable internal and external predictivity could be obtained by PCR and PLS analysis of a descriptor set representing fractional accessible molecular surface areas (Q_frASAs). This set of descriptors is calculated by partitioning the molecular surface accessible to a spheric probe of radius 1.4 Å into fractions attributable to atoms within 14 charge intervals from −0.3 to 0.3 e. The applicability of such Q_frASA descriptors is validated by analysis of several sets of literature data, yielding QSAR models of good statistical quality. It is therefore assumed that Q_frASA descriptors may be of wider applicability in QSAR and QSPR.
Introduction Background for Molecular Connectivity Development of Molecular Connectivity Molecular Connectivity Approach Molecular Connectivity Method QSAR Applications of Molecular Connectivity Chi Indexes Characterization of Molecular Shape Background: Steric or Shape Influence Methods for Steric Quantification Model of Molecular Shape Based on Chemical Graph Theory Shape Infromation in the Kappa Values Encoding Atom Identity Kappa Index Values for Small Molecules Molecular Shape Quantitation General Applications Specific Application of Kappa Indexes Characterization of Skeletal Atoms, the Topological State
Aerial parts of Eremanthus arboreus furnished two new eremantholides, a hydroxy acid related to them and 5,7-dihydroxy-3′,4′-dimethoxyflavone.
The support vector machine, as a novel type of learning machine, for the first time, was used to develop a QSAR model of 57 analogues of ethyl 2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate (EPC), an inhibitor of AP-1 and NF-kappa B mediated gene expression, based on calculated quantum chemical parameters. The quantum chemical parameters involved in the model are Kier and Hall index (order3) (KHI3), Information content (order 0) (IC0), YZ Shadow (YZS) and Max partial charge for an N atom (MaxPCN), Min partial charge for an N atom (MinPCN). The mean relative error of the training set, the validation set, and the testing set is 1.35%, 1.52%, and 2.23%, respectively, and the maximum relative error is less than 5.00%.
In an earlier article 8 the need was demonstrated for atomic physicochemical properties for three dimensional structure directed quantitative structure-activity relationships, and it was shown how atomic parameters can be developed for successfully evaluating the molecular octanol-water partition coefficient, which is a measure of hydrophobicity. In this work we report more refined atomic values of octanol-water partition coefficients derived from nearly twice the number of compounds. Carbon, hydrogen, oxygen, nitrogen, sulfur and halogens are divided into 110 atom types of which 94 atomic values are evaluated from 830 molecules by least squares. These values gave a standard deviation of 0.470 and a correlation coefficient of 0.931. These parameters predicted the octanol-water partition coefficient of 125 compounds with a standard deviation of 0.520 and a correlation coefficient of 0.870. There is only a correlation coefficient of 0.432 between the atomic octanol-water partition coefficients and the atomic contributions to molar refractivity over the 93 atom types used for both the properties. This suggests that both parameters can be used simultaneously to model intermolecular interactions. We evaluated the CNDO/2 gross atomic charge distribution over several molecules to check the validity of our classification. We found that the charge density on the heteroatoms in conjugated systems is strongly affected by the presence of similar atoms in the conjugation which suggests it should be incorporated as a separate parameter in evaluating the partition coefficient. Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/38278/1/540090111_ftp.pdf
Die in Mittelamerika traditionell angewendete Bignoniaceae Arrabidaea chica, wurde mittels biologisch kontrollierter Fraktionierung phytochemisch untersucht. Aus dem Blattextrakt wurden 4 3-Desoxyanthocyanidine und 2 Flavonoide isoliert und in ihrer Struktur aufgeklärt. Es konnte gezeigt werden, dass 3-Desoxyanthocyanidine zur entzündungshemmenden Aktivität beitragen. Aus der Asteraceae Mikania micrantha wurden 2 Sesquiterpenlactone (SLs) vom Germacradiolid-Typ isoliert (IC100 NF-kB-DNA-Bindung 10 µM). 17 SLs wurden auf Hemmung der humanen Neutrophilen Elastase untersucht. Mit Bindungsstudien konnte postuliert werden dass OH-gruppen in der Nähe einer Carbonylgruppe für die Bindung an das aktive Zentrum von HNE wichtig sind. Bei Zimtsäurederivaten ist das Vorhandensein einer aromatischen o-Dihydroxygruppe zusammen mit einer lipophilen Struktur wichtig für die Aktivität. Sie bilden ein H-brückennetzwerk mit der katalytischen Triade aus. 8 SLs hemmen die Elastase-Freisetzung aus neutrophilen Granulocyten (IC50 2.5-30 µM). Von 103 auf Hemmung der NFkB-DNA-Bindung untersuchten SLs wurden energiarme Konformationen zur Berechnung von Deskriptoren verwendet. In einer QSAR-Untersuchung wurde mittels multipler linearer Regressionsanalyse die Aktivität mit den Deskriptoren korreliert. Dabei waren die Parameter wie die Anzahl und Art der a,b-unges. Carbonylstrukturen im Molekül entscheidend. Teilt man den Datensatz nach Strukturgruppen, so sind bei den flexibleren Strukturen die reaktivitätscodierenden und bei den starreren Molekülen die räumliche Gestalt und Verknüpfung codierenden Parameter wichtig.
Die vorgestellten Ergebnisse erweitern die Kenntnisse zum antiphlogistischen Wirkmechanismus und zu Struktur-Wirkungs-Beziehungen der SLs und stellen die traditionelle Anwendung von zwei mittelamerikanischen Arzneipflanzen auf eine wissenschaftliche Basis.
Die in Mittelamerika heimische Asteraceae Mikania cordifolia, deren Zubereitungen in der traditionellen Medizin bei verschiedenen entzündlichen Erkrankungen eingesetzt werden, wurde phytochemisch auf ihre Wirkstoffe hin untersucht. Aus den oberirdischen Teilen wurden 11 Sesquiterpenlactone vom Germacranolid-Typ und 4 vom Eudesmanolid-Typ isoliert. Die Strukturen der isolierten Verbindungen wurden unter Verwendung NMR-spektroskopischer und massenspektroskopischer Methoden aufgeklärt.
Diese Sesquiterpenlactone wurden in pharmakologisch-biologischen Testsystemen untersucht. Sie hemmten in Konzentrationen von 20 – 300 µM die Bindung der Transkriptionsfaktoren NF-kB, NF-AT und AP-1 an die DNA. Die untersuchten Transkriptionsfaktoren stellen zentrale Mediatoren im Immun- und Entzündungsgeschehen dar. Weitere, mit einem Germacranolid durchgeführte Unter-suchungen zeigten, dass auch die Freisetzung der Zytokine IL-1b, IL-6 und TNF-a sowie die Proliferation von T- und B-Lymphozyten gehemmt wurde.
Mit den Sesquiterpenlactonen Parthenolid und 4ß,15-Epoxymiller-9E-enolid wurden Experimente zum Wirkungsmechanismus der NF-AT/AP-1-Hemmung durchgeführt. Es konnte gezeigt werden, dass diese Naturstoffe nicht nur die im EMSA beobachtete DNA-Bindung von NF-AT, sondern auch die NF-AT abhängige Genexpression hemmen. Dieses erfolgt durch direkten Angriff von NF-AT und AP-1, indem vermutlich Aminosäuren in der DNA bindenden Region alkyliert werden.
Zwei verschiedene Tinkturen aus den Blüten der Asteraceae Arnica montana wurden auf ihre hemmende Aktivität gegenüber NF-kB und NF-AT sowie den Zytokinen IL-1b und TNF-a untersucht und ihre Hemmaktivitäten mit ihrem qualitativen und quantitativen Sesquiterpenlactongehalt korreliert.
Die vorgestellten Ergebnisse erweitern die bisherigen Erkenntnisse zum antiphlogistischen Wirkmechanismus der Sesquiterpenlactone und stellen die traditionelle Anwendung einer mittelamerikanischen und europäischen Arzneipflanze auf eine wissenschaftliche Basis.
Some sesquiterpene lactones and related compounds were tested for anti-inflammatory activity in rodents. In the edema-induced carrageenan inflammation screen, the alpha-methylene-gamma-lactone moiety of the sesquiterpene lactones was required for inhibitory activity. The 6-hydroxy group of helenalin also was required for potency. In the tenulin series, the 2,3-epoxy derivatives were marginally active. The same structure was required for inhibition of the writhing reflex. In the chronic adjuvant arthritic screen, compounds containing the alpha-methylene-gamma-lactone moiety, the beta-unsubstituted cyclopentenone ring, and the alpha-epoxy cyclopentenone system afforded significant inhibition at 2.5 mg/kg/day. The sesquiterpene lactones were marginally effective against induced pleurisy. The delayed hypersensitivity was suppressed by these agents whereas immunoglobulin synthesis was slightly stimulated. No delerious side effects were observed with these agents from the limited tests performed.
The isolation and structural elucidation of two new sesquiterpene lactones from the roots of Vernonia fexuosa Sims. were described. Vernoflexuoside and vernoflexin have been identified as guianolides with the structure I and V respectively.
The presence of an α-methylene-γ-lactone is essential for significant cytotoxic activity among the sesquiterpene lactones. The biological activity is enhanced by the presence of certain additional α,β-unsaturated carbonyl functions. In addition, the activity of these compounds increases with increasing lipophilicity, but does not appear to correlate with reactivity toward cysteine. Those sesquiterpenes with demonstrated in vivo antitumor activity have common features which set them apart from the majority of the sesquiterpene lactones.
Thiols are the most reactive nucleophilic reagents among the biological models investigated. They undergo "Michael-type" addition
to the polyfunctional sesquiterpene lactones. The rapid rates of reaction with L-cysteine were measured and the reaction products were characterized. Each addition of thiol successively decreased the cytotoxicity
of the adducts formed.
Sesquiterpene lactones containing an alpha-methylene-gamma-lactone moiety were shown to be potent inhibitors of carrageenan-induced edema and chronic adjuvant-induced arthritis in rodents at 2.5 mg/kg/day. The mode of action of sesquiterpene lactones as anti-inflammatory agents appeared to be at multiple sites; for example, at 5 X 10(-4) M, the sesquiterpene lactones effectively uncoupled the oxidative phosphorylation of human polymorphonuclear neutrophils and elevated the cyclic adenosine monophosphate levels of rat neutrophils and rat and mouse liver cells. Free and total lysosomal enzymatic activity was inhibited by these agents at 5 X 10(-4) M in both rat and mouse liver and rat and human neutrophils. Furthermore, the structure-activity relationships for the stabilization of lysosomal membrane for rat liver cathepsin activity followed the same structural requirement necessary for anti-inflammatory activity; i.e., the alpha-methylene-gamma-lactone moiety contributed the most activity, whereas the beta-unsubstituted cyclopentenone and alpha-epoxycyclopentanone contributed only minor activity. Human polymorphonuclear neutrophil chemotaxis was inhibited at low concentrations (i.e., 5 X 10(-5) and 5 X10(-6) M), whereas prostaglandin synthetase activity was inhibited at a higher concentration (i.e., 10(-3) M) by the sesquiterpene lactones.
NF-kappa B is a ubiquitous transcription factor. Nevertheless, its properties seem to be most extensively exploited in cells of the immune system. Among these properties are NF-kappa B's rapid posttranslational activation in response to many pathogenic signals, its direct participation in cytoplasmic/nuclear signaling, and its potency to activate transcription of a great variety of genes encoding immunologically relevant proteins. In vertebrates, five distinct DNA binding subunits are currently known which might extensively heterodimerize, thereby forming complexes with distinct transcriptional activity, DNA sequence specificity, and cell type- and cell stage-specific distribution. The activity of DNA binding NF-kappa B dimers is tightly controlled by accessory proteins called I kappa B subunits of which there are also five different species currently known in vertebrates. I kappa B proteins inhibit DNA binding and prevent nuclear uptake of NF-kappa B complexes. An exception is the Bcl-3 protein which in addition can function as a transcription activating subunit in th nucleus. Other I kappa B proteins are rather involved in terminating NF-kappa B's activity in the nucleus. The intracellular events that lead to the inactivation of I kappa B, i.e. the activation of NF-kappa B, are complex. They involve phosphorylation and proteolytic reactions and seem to be controlled by the cells' redox status. Interference with the activation or activity of NF-kappa B may be beneficial in suppressing toxic/septic shock, graft-vs-host reactions, acute inflammatory reactions, acute phase response, and radiation damage. The inhibition of NF-kappa B activation by antioxidants and specific protease inhibitors may provide a pharmacological basis for interfering with these acute processes.
Our previous reports indicate that the cytoprotective effect of helenalin and several sesquiterpene lactones is mediated through a Michael reaction between the sulfhydryl containing peptides of the gastric mucosa and Michael acceptors present in the sesquiterpene lactone molecules. In the present work the different alternative active sites in molecules containing up to three places which could act as viable Michael acceptors are evaluated. To do this, an extensive conformational and electronic study of helenalin and its derivatives was carried out. The experimental and theoretical results obtained show the gamma-lactone and cyclopentenone groups to be the biologically active places of the molecules under study, whereas tiglic and angelic substituents in these compounds show different behavior as Michael acceptors.
Ten sesquiterpene lactones and one sesquiterpene isolated from Tanacetum praeteritum subsp. praeteritum: 1 alpha, 6 alpha -dihydroxyisocostic acid methyl ester (2), 1 alpha-hydroxy-1-deoxoarglanine (3), douglanin (5), santamarin (6), reynosin (7), 1-epitatridin B (8), ludovicin A (10), armexin (12), armefolin (13), armexifolin (14), and 3 alpha-hydroxyreynosin (15) were tested against the human lung carcinoma cell line GLC4 and the colorectal cancer cell line COLO 320 as well as against the bacteria Bacillus subtilis, Staphylococcus aureus, Proteus mirabilis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus, beta-hemolytic Streptococcus, and the yeast Candida albicans. In addition, two germacranolides tatridin A (16) and tamirin (17) were included in the study. All compounds showed cytotoxic activity (IC50 = 124 microM) but most of them were not effective in the antimicrobial tests.
The potential inhibitory effect of 54 Mexican Indian medicinal plants on the activation of transcription factor NF-kappaB was studied. Band-shift experiments identified the ethanolic leaf extracts of Artemisia ludoviciana ssp. mexicana, Calea zacatechichi, and Polymnia maculata (all rich in sesquiterpene lactones) as inhibitors of NF-kappaB down to a concentration of 25 microg/ml. The sesquiterpene lactones isohelenin and parthenolide prevented NF-kappaB activation completely as low as 5 microM. Treatment of HeLa cells with leaf extract of A. ludoviciana ssp. mexicana, isohelenin and parthenolide prevented the induction of transcription on the IL-6 promoter. These experiments identify the eudesmanolide and germacranolide type of sesquiterpene lactones as potent non-antioxidant inhibitors of NF-kappaB. All plants active in the NF-kappaB assay also showed a delay in the onset of capillary reactions of the allantois membrane in a physiological model for anti-inflammatory activity - the HET-CAM assay.
The reactivity of the two potential Michael addition sites of the helenanolide-type sesquiterpene lactone helenalin towards the physiological thiols glutathione (GSH) and cysteine (cys) in aqueous solution was investigated by 1H NMR spectroscopic experiments. In the presence of one molar equivalent of GSH, the reaction was shown to occur with high regio- and stereoselectivity at the beta-position of C-2 in the cyclopentenone ring. Addition to the exocyclic methylene group at the lactone ring was found to occur in the presence, of GSH in molar ratios over 1:1, but proceeded at a rate 10 times smaller than at C-2 leading to the 2 beta,13(11 beta)-bis-glutathionyl adduct. In contrast, addition of free cys highly favoured the exocyclic methylene group. Addition of GSH to the cyclopentenone of 11 alpha, 13-dihydrohelenalin (plenolin) showed the same characteristics as observed with helenalin while 2 alpha-acetoxy-2,3-dihydro-4 beta H-helenalin (chamissonolide) did not form an adduct when incubated with an equimolar amount of GSH. Explanations for the observed differences in reactivity of the two potential reaction sites based on MO computations are given and implications for the biological activity of this type of sesquiterpene lactones are discussed.
In previous reports we attributed the cytoprotective activity of several sesquiterpene lactones to the presence of a nonhindered electrophilic acceptor in their structure. We suggested that the mechanism of protection would be, at least in part, mediated through a reaction between the electrophilic acceptor and the sulfhydryl-containing groups of the mucosa. We report here the gastric cytoprotective effect of simple molecules containing an alpha, beta-unsaturated carbonyl group. In the present paper, we undertake the study of molecular accessibility and molecular shape, in addition to conformational, electronic, and steric factors. Our results helped to establish two important facts connecting chemical structure with cytoprotective effect. Firstly, an adequate molecular accessibility appears to be necessary to produce the biological response, and secondly, the alpha,beta-unsaturated carbonyl system has to be included in a cyclic structure or, at least, in the proximity of a cyclic system.