ArticleLiterature Review

Natural Withanolides: An Overview

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Abstract

Withanolides are a group of naturally occurring C28 steroids built on an ergostane skeleton functionalized at carbons 1, 22 and 26, commonly known as the withanolide skeleton. Over the period of August 1996 to March 2010, 360 new naturally occurring withanolides were isolated and identified. This review provides a comprehensive summary of the structural classification and distribution of these new compounds. The diverse biological and pharmacological activities of natural withanolides are also discussed based on their structural features. A total of 211 references are cited in this review.

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... These secondary metabolites are unique to the Solanaceae family and are commonly found across 19 genera, including Physalis, Acnistus, Datura and Jaborosa (Guan et al., 2014;Misra et al., 2006;Wu et al., 2020b). Withanolides are structurally diverse steroids based on an ergostane skeleton and functionalised at carbons 1, 22 and 26 (Chen et al., 2011;Le Canh et al., 2021;Wu et al., 2018;Wu et al., 2020b). The oxidation of C-22 and C-26, or C-23 and C-26 results in the formation of δ or γ-lactone ring, whereas the oxidation of C-1 will form 1-one (Chen et al., 2011;Guan et al., 2014). ...
... Withanolides are structurally diverse steroids based on an ergostane skeleton and functionalised at carbons 1, 22 and 26 (Chen et al., 2011;Le Canh et al., 2021;Wu et al., 2018;Wu et al., 2020b). The oxidation of C-22 and C-26, or C-23 and C-26 results in the formation of δ or γ-lactone ring, whereas the oxidation of C-1 will form 1-one (Chen et al., 2011;Guan et al., 2014). Accordingly, Withanolides are classified into two types: with δ-lactone or δ-lactol ring (Type A) and with γ-lactone or γ-lactol ring (Type B) (see Fig. 1). ...
... Accordingly, Withanolides are classified into two types: with δ-lactone or δ-lactol ring (Type A) and with γ-lactone or γ-lactol ring (Type B) (see Fig. 1). The majority of P. minima Withanolides are Type A, which can be further classified based on the presence or absence of epoxides, chirality and position of epoxides, as shown in Fig. 2 (Chen et al., 2011). ...
Article
The Southeast Asian rainforests, notably in East Malaysia, are home to a diverse range of medicinal plant species with limitless therapeutic potential. Physalis minima (family Solanaceae) is a native East Malaysia plant which is closely linked to P. angulata, are recognized for their various pharmacology properties are abundance in Withanolides, a C28-steroidal lactones based on an ergostane skeleton. This review focuses on the bioactive compounds of this herb, as it is frequently used to treat inflammation, neurodegenerative disease and cancer among East Malaysian ethnic groups. In this review, a total of 103 Withanolides were reported, with 59 of them being newly characterized. Previous scientific data revealed that Withanolides were intriguing principal compounds for inflammatory, neuroinflammatory and cancer treatment due to unique steroidal structure and strong bioactivities. Despite their excellent pharmacological characteristics, only a few Withanolides have been extensively studied, and the majority of them, particularly the newly discovered Withanolides, remained unknown for their therapeutic properties. This indicates that P. minima compounds are worth to be investigate for its pharmacological effects.
... It is commonly used for a spectrum of health-promoting effects including youthful vigor, activation of the immune and neuronal systems, muscle strength, and endurance. Trusted for its adaptogenic, cardiotropic, and cardioprotective effects, it is often marked as a health and brain tonic and used as a home-remedy for stress, frailty, anxiety, insomnia, nervous exhaustion, loss of memory, and cognitive disorders [1][2][3][4][5]. In spite of its extensive use, there are limited studies on the extraction of bioactive components from different parts of the plant that describe their mechanism(s) of action for the recognized/trusted bioactivities of Ashwagandha. ...
... Ashwagandha is a prominent herb, generally used for overall health promotion including stress and anxiety management, youthful vitality, activation of the immune and nervous systems, and muscle strength and endurance. Some pre-clinical trials and clinical studies also supported the therapeutic use of Ashwagandha for brain-related disorders such as anxiety, cognitive and neurological disorders, and Parkinson's disease [2,47,49]. Wi-A, Wid-A, and Wid-N are considered as major bioactive compounds obtained from the root, stem, and leaves of Ashwagandha extracts. Wi-A isolated from roots has been shown to possess a variety of health benefits such as anti-inflammatory and anti-oxidative activities, an inhibition of OVA-induced lung injury and fibrosis, and a reduction in the infarct area and intimal hyperplasia [3,[11][12][13][14][15][16]. ...
... Wi-N has been well documented in in vitro and in vivo models for its anti-stress and anti-aging activities [32][33][34][35][36][37][38]. It has also been reported that Wi-N possesses multifunctional neuroprotective effects in alleviating cognitive dysfunction by the inhibition of acetylcholinesterase (AChE), the modification of Aβ processing, and protection against oxidative stress and anti-inflammatory effects [2][3][4]16,36,37]. The anti-stress effect of Ashwagandha extracts has also been evident by studies on the biological model of animals [39,40]. ...
Article
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Withania somnifera (Ashwagandha) is used in Indian traditional medicine, Ayurveda, and is believed to have a variety of health-promoting effects. The molecular mechanisms and pathways underlying these effects have not yet been sufficiently explored. In this study, we investigated the effect of Ashwagandha extracts and their major withanolides (withaferin A and withanone) on muscle cell differentiation using C2C12 myoblasts. We found that withaferin A and withanone and Ashwagandha extracts possessing different ratios of these active ingredients have different effects on the differentiation of C2C12. Withanone and withanone-rich extracts caused stronger differentiation of myoblasts to myotubes, deaggregation of heat- and metal-stress-induced aggregated proteins, and activation of hypoxia and autophagy pathways. Of note, the Parkinson’s disease model of Drosophila that possess a neuromuscular disorder showed improvement in their flight and climbing activity, suggesting the potential of Ashwagandha withanolides for the management of muscle repair and activity.
... WFA was the first compound of this group to be isolated from Withania somnifera (Winter cherry), a plant used in Ayurvedic medicine. The chemistry and biological activity of Withanolides has been reviewed comprehensively [101,102]. WFA and various other Withanolides were reported to possess anti-inflammatory as well as anti-cancer activity against several types of tumours. A plethora of possible mechanisms of action and targets related to cancer have been described ( [101,102] and literature cited there). ...
... WFA and various other Withanolides were reported to possess anti-inflammatory as well as anti-cancer activity against several types of tumours. A plethora of possible mechanisms of action and targets related to cancer have been described ( [101,102] and literature cited there). ...
... In conclusion, these findings reveal a very interesting new mechanism of action and extend various previous attempts [101,102] to explain the anti-cancer activity of WFA. These data are of particular interest with regard to previous reports on an anti-leukemic potential of WFA [104] or other withanolides. ...
Article
The transcription factor MYB is expressed predominantly in hematopoietic progenitor cells, where it plays an essential role in the development of most lineages of the hematopoietic system. In the myeloid lineage, MYB is known to cooperate with members of the CCAAT box/enhancer binding protein (C/EBP) family of transcription factors. MYB and C/EBPs interact with the co-activator p300 or its paralog CREB-binding protein (CBP), to form a transcriptional module involved in myeloid-specific gene expression. Recent work has demonstrated that MYB is involved in the development of human leukemia, especially in acute T-cell leukemia (T-ALL) and acute myeloid leukemia (AML). Chemical entities that inhibit the transcriptional activity of the MYB-C/EBPβ-p300 transcription module may therefore be of use as potential anti-tumour drugs. In searching for small molecule inhibitors, studies from our group over the last 10 years have identified natural products belonging to different structural classes, including various sesquiterpene lactones, a steroid lactone, quinone methide triterpenes and naphthoquinones that interfere with the activity of this transcriptional module in different ways. This review gives a comprehensive overview on the various classes of inhibitors and the inhibitory mechanisms by which they affect the MYB-C/EBPβ-p300 transcriptional module as a potential anti-tumor target. We also focus on the current knowledge on structure-activity relationships underlying these biological effects and on the potential of these compounds for further development.
... Some of the secondary metabolites in Physalis fruits and plants render them commercially valuable, and many such compounds have antibacterial, antiinflammatory, and anticancer activities that are useful in medical applications. The whole herb of Physalis is used in traditional medicine to treat fever, diabetes, pharyngitis, boils, coughs, and mastitis [20][21][22] . Fruits, including the fruiting calyces of a few Physalis species, often have curative and culinary uses 1,23 , and berries are used as both medicine and food. ...
... The pf02G034050 (GO: 0006694, p ≤ 0) and pf03G074230 (GO: 0016126, p ≤ 9e-06) genes, related to steroid biosynthetic processes, were found to be positively selected (Supplementary Table 28). Some steroid compounds isolated from Physalis plants contain chloride ions 39 that are thought to be formed by reaction with an epoxide group 21 . Consistent with this, the positively selected gene pf03G066370 (GO: 0006821, p = 0) was found to be a chloride transport-related gene (Supplementary Table 28). ...
... Steroids are present in all eukaryotes, and they modulate the fluidity and flexibility of cell membranes 41 . Some steroid compounds exhibit potential anticancer, anti-inflammatory, and apoptotic activities 20,21 . Thus, steroid-based drugs have a broad range of therapeutic applications; consequently, they represent the category of pharmaceuticals with the largest market share 71 . ...
Article
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The fruits of Physalis (Solanaceae) have a unique structure, a lantern-like fruiting calyx known as inflated calyx syndrome (ICS) or the Chinese lantern, and are rich in steroid-related compounds. However, the genetic variations underlying the origin of these characteristic traits and diversity in Physalis remain largely unknown. Here, we present a high-quality chromosome-level reference genome assembly of Physalis floridana (~1.40 Gb in size) with a contig N50 of ~4.87 Mb. Through evolutionary genomics and experimental approaches, we found that the loss of the SEP -like MADS-box gene MBP21 subclade is likely a key mutation that, together with the previously revealed mutation affecting floral MPF2 expression, might have contributed to the origination of ICS in Physaleae, suggesting that the origination of a morphological novelty may have resulted from an evolutionary scenario in which one mutation compensated for another deleterious mutation. Moreover, the significant expansion of squalene epoxidase genes is potentially associated with the natural variation of steroid-related compounds in Physalis fruits. The results reveal the importance of gene gains (duplication) and/or subsequent losses as genetic bases of the evolution of distinct fruit traits, and the data serve as a valuable resource for the evolutionary genetics and breeding of solanaceous crops.
... Withanolides are steroidal lactones, with the ergostane skeleton having diverse biological and pharmacological activities [1]. Withanolides specifically exist in the plant genera of the Solanaceae family including Withania, Physalis, Datura, Nicandra, Dunalia, Lyerium, Tubocapsicus and Jaborosa. ...
... Withanolides specifically exist in the plant genera of the Solanaceae family including Withania, Physalis, Datura, Nicandra, Dunalia, Lyerium, Tubocapsicus and Jaborosa. These have also been isolated from Lamiaceae, Taccaceae and Fabaceae families and some marine sources [1]. Among the withanolide constituents isolated to date, withaferin A (WA) has attained the interest of the pharmacologists, clinical pharmacists, and chemists owing to its wide-ranging therapeutic potential. ...
... WA obstructed the activity of TNF-α, phorbol-12-myristate-13-acetate (PMA), IL-1b and EPCR shedding induced by cecal ligation and punctures. It also inhibited TACE, PMA induced phosphorylation of p38, extracellular regulated kinase (ERK) 1 2 and JNK. [20]. ...
Article
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Withaferin A (WA) is a pivotal withanolide that has conquered a conspicuous place in research, owning to its multidimensional biological properties. It is an abundant constituent in Withania somnifera Dunal. (Ashwagandha, WS) that is one of the prehistoric pivotal remedies in Ayurveda. This article reviews the literature about the pharmacological profile of WA with special emphasis on its anticancer aspect. We reviewed research publications concerning WA through four databases and provided a descriptive analysis of literature without statistical or qualitative analysis. WA has been found as an effective remedy with multifaceted mechanisms and a broad spectrum of pharmacological profiles. It has anticancer, anti-inflammatory, antiherpetic, antifibrotic, antiplatelet, profibrinolytic, immunosuppressive, antipigmentation, antileishmanial, and healing potentials. Evidence for wide pharmacological actions of WA has been established by both in vivo and in vitro studies. Further, the scientific literature accentuates the role of WA harboring a variable therapeutic spectrum for integrative cancer chemoprevention and cure. WA is a modern drug from traditional medicine that is necessary to be advanced to clinical trials for advocating its utility as a commercial drug.
... Withanolides, a class of polyoxygenated steroidal lactones frequently encountered in plants of the family Solanaceae [1], are known to exhibit a variety of biological activities including cytotoxic, anti-feedant, insecticidal, trypanocidal, leishmanicidal, antimicrobial, anti-inflammatory, phytotoxic, cholinesterase inhibitory and immune-regulatory activities, and the effects on neurite outgrowth and synaptic reconstruction [2,3]. Despite these interesting and diverse biological activities, studies on withanolides have not proceeded beyond preliminary evaluation in cellular and biochemical assays, arguably due to their supply issues as is the case with many biologically active natural products (NPs), including Studies with W. somnifera and another Solanaceae species, Physalis crassifolia, also suggested that the plant growth rate, yields of biomass and major withanolides, and the ability to produce structurally-diversified withanolides were improved when cultivated using the aeroponic technique compared to soil cultivation under identical controlledenvironmental conditions. ...
... Despite these interesting and diverse biological activities, studies on withanolides have not proceeded beyond preliminary evaluation in cellular and biochemical assays, arguably due to their supply issues as is the case with many biologically active natural products (NPs), including Studies with W. somnifera and another Solanaceae species, Physalis crassifolia, also suggested that the plant growth rate, yields of biomass and major withanolides, and the ability to produce structurally-diversified withanolides were improved when cultivated using the aeroponic technique compared to soil cultivation under identical controlledenvironmental conditions. Thus, aeroponic cultivation of W. somnifera resulted in the production of two unusual withanolides, 3α-(uracil-1-yl)-2,3-dihydrowithaferin A and 3β-(adenin-9-yl)-2,3-dihydrowithaferin, in addition to withaferin A (1), 2,3-dihydrowithaferin A-3β-O-sulfate (2), and ten other known withanolides [17] (see Supplementary Data, Figure S2). Significantly, the aeroponic cultivation of P. crassifolia produced eleven new 17β-hydroxywithanolides [18] together with 15α-acetoxyphysachenolide D, 15αacetoxy-28-hydroxyphysachenolide D, 18-acetoxy-17-epi-withanolide K, and physachenolide D encountered in the wild-crafted/soil-grown plant [19] (see Supplementary Data, Figure S3). ...
... A small number of chlorinated withanolides have previously been encountered in plants of Solanaceae as minor metabolites and many of these occur as 5,6-chlorohydrins containing 5α-chloro-6β-hydroxy substituents [25,[44][45][46][47][48]. It has been suggested that the chlorine atom present in these 5,6-chlorohydrins may originate from NaCl present in the plant [2]. However, the occurrence of corresponding 5β,6β-epoxides as major matabolites in their source plants (as in P. costomatl) suggests that 5,6-chlorohydrins of withanolides may be possible artifacts formed from their corresponding 5β,6β-epoxides during the extraction of these plants and/or during the isolation of withanolides. ...
Article
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Withanolides constitute one of the most interesting classes of natural products due to their diversity of structures and biological activities. Our recent studies on withanolides obtained from plants of Solanaceae including Withania somnifera and a number of Physalis species grown under environmentally controlled aeroponic conditions suggested that this technique is a convenient, reproducible, and superior method for their production and structural diversification. Investigation of aeroponically grown Physalis coztomatl afforded 29 withanolides compared to a total of 13 obtained previously from the wild-crafted plant and included 12 new withanolides, physacoztolides I−M (9–13), 15α-acetoxy-28-hydroxyphysachenolide C (14), 28-oxophysachenolide C (15), and 28-hydroxyphysachenolide C (16), 5α-chloro-6β-hydroxy-5,6-dihydrophysachenolide D (17), 15α-acetoxy-5α-chloro-6β-hydroxy-5,6-dihydrophysachenolide D (18), 28-hydroxy-5α-chloro-6β-hydroxy-5,6-dihydrophysachenolide D (19), physachenolide A-5-methyl ether (20), and 17 known withanolides 3–5, 8, and 21–33. The structures of 9–20 were elucidated by the analysis of their spectroscopic data and the known withanolides 3–5, 8, and 21–33 were identified by comparison of their spectroscopic data with those reported. Evaluation against a panel of prostate cancer (LNCaP, VCaP, DU-145, and PC-3) and renal carcinoma (ACHN) cell lines, and normal human foreskin fibroblast (WI-38) cells revealed that 8, 13, 15, and 17–19 had potent and selective activity for prostate cancer cell lines. Facile conversion of the 5,6-chlorohydrin 17 to its 5,6-epoxide 8 in cell culture medium used for the bioassay suggested that the cytotoxic activities observed for 17–19 may be due to in situ formation of their corresponding 5β,6β-epoxides, 8, 27, and 28.
... Withanolides belong to a group of naturally occurring C-28 steroid lactones [6]. These compounds are generally highly oxygenated, and these functionalities have led to many structural modifications [7][8][9][10]. The current classification of withanolides constitutes 22 types based on their structural differences. ...
... The increased cytotoxicity of the di-and triacetate analogs of the compound WA could be due to increased lipophilicity, leading to enhanced cell permeability [79,115,116]. Compound 132 showed 3-5 times increased activity, with IC50 values of 0.175 and 0.205 μM against breast cancer and melanoma cells, respectively, compared to WA, with IC50 = 0.540 and 1.00 μM, while jaborosalactone V diacetate 133 was found to be equipotent to WA, suggesting that the C-4 hydroxyl group is not crucial for activity [8,78] ...
... The increased cyto-toxicity of the di-and triacetate analogs of the compound WA could be due to increased lipophilicity, leading to enhanced cell permeability [79,115,116]. Compound 132 showed 3-5 times increased activity, with IC 50 values of 0.175 and 0.205 µM against breast cancer and melanoma cells, respectively, compared to WA, with IC 50 = 0.540 and 1.00 µM, while jaborosalactone V diacetate 133 was found to be equipotent to WA, suggesting that the C-4 hydroxyl group is not crucial for activity [8,78] ...
Article
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Natural products are a major source of biologically active compounds that make promising lead molecules for developing efficacious drug-like molecules. Natural withanolides are found in many flora and fauna, including plants, algae, and corals, that traditionally have shown multiple health benefits and are known for their anti-cancer, anti-inflammatory, anti-bacterial, anti-leishmaniasis, and many other medicinal properties. Structures of these withanolides possess a few reactive sites that can be exploited to design and synthesize more potent and safe analogs. In this review, we discuss the literature evidence related to the medicinal implications, particularly anticancer properties of natural withanolides and their synthetic analogs, and provide perspectives on the translational potential of these promising compounds.
... The genus Withania is generally distinguished by the presence of withanolides, highly oxygenated C28 steroidal lactones which are identified from over 25 Solanaceae species, including Acnistus, Datura, Jaborosa, Nicandra and Mandragora [37][38][39]. Withanolides were also found in Taccaceae, Lamiaceae and Myrtaceae [40][41][42][43]. These findings are closely comparable to those found in previous works [32,33] reporting that catechin derivatives are likely to be the same major compounds found in tea. ...
... The genus Withania is generally distinguished by the presence of withanolides, highly oxygenated C28 steroidal lactones which are identified from over 25 Solanaceae species, including Acnistus, Datura, Jaborosa, Nicandra and Mandragora [37][38][39]. Withanolides were also found in Taccaceae, Lamiaceae and Myrtaceae [40][41][42][43]. ...
Article
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Withania aristata (Aiton) Pauquy, a medicinal plant endemic to North African Sahara, is widely employed in traditional herbal pharmacotherapy. In the present study, the chemical composition, antioxidant, antibacterial, and antifungal potencies of extract from the roots of Withania aristata (Aiton) Pauquy (RWA) against drug-resistant microbes were investigated. Briefly, RWA was obtained by maceration with hydro-ethanol and its compounds were identified by use of high-performance liquid chromatography (HPLC). The antioxidant activity of RWA was determined by use of ferric-reducing antioxidant power (FRAP), 1,1-diphenyl-2-picrylhydrazyl (DPPH), and total antioxidant capacity (TAC). The evaluation of the antimicrobial potential of RWA was performed against drug-resistant pathogenic microbial strains of clinical importance by use of the disc diffusion agar and microdilution assays. Seven compounds were identified in RWA according to HPLC analysis, including cichoric acid, caffeic acid, apigenin, epicatechin, luteolin, quercetin, and p-catechic acid. RWA had excellent antioxidant potency with calculated values of 14.0 ± 0.8 µg/mL (DPPH), 0.37 ± 0.08 mg/mL (FRAP), 760 ± 10 mg AAE/g (TAC), and 81.4% (β-carotene). RWA demonstrated good antibacterial potential against both Gram-negative and Gram-positive bacteria, with inhibition zone diameters ranging from 15.24 ± 1.31 to 19.51 ± 0.74 mm, while all antibiotics used as drug references were infective, except for Oxacillin against S. aureus. Results of the minimum inhibitory concentration (MIC) assay against bacteria showed that RWA had MIC values ranging from 2.13 to 4.83 mg/mL compared to drug references, which had values ranging from 0.031 ± 0.003 to 0.064 ± 0.009 mg/mL. Similarly, respectable antifungal potency was recorded against the fungal strains with inhibition zone diameters ranging from 25.65 ± 1.14 to 29.00 ± 1.51 mm compared to Fluconazole, used as a drug reference, which had values ranging from 31.69 ± 1.92 to 37.74 ± 1.34 mg/mL. Results of MIC assays against fungi showed that RWA had MIC values ranging from 2.84 ± 0.61 to 5.71 ± 0.54 mg/mL compared to drug references, which had values ranging from 2.52 ± 0.03 to 3.21 ± 0.04 mg/mL. According to these outcomes, RWA is considered a promising source of chemical compounds with potent biological properties that can be beneficial as natural antioxidants and formulate a valuable weapon in the fight against a broad spectrum of pathogenic microbes.
... Some withanolides, such as Physachenolide D, act as potential activators of quinone reductase or selective inhibitors of the COX-2 enzyme, exhibiting cytotoxic or cell differentiation inducing activities. The proposed mechanism of action, based on the results of bioassay evaluation in withanolides, relies on the α, β-unsaturated ketone unit in ring A and group 5β, 6β-epoxy in ring B [389]. ...
... 17β-hydroxywithanolides is as a new class of potent anti-androgenic molecules capable of inhibiting PSA expression and displaying selectivity for LNCaP and PC-3 cell lines. Preliminary structure-activity relationships identified physacenolide D as a 17β-hydroxywitanolide with promising antitumor activity in xenograft mice implanted with LNCaP and PC-3 cells [389,391]. Luteolin displays multiple biological activities, such as anti-inflammatory and anti-allergy with both antioxidant and pro-oxidant properties [392]. Moreover, luteolin is as a flavonoid compound that possesses anticancer activity against various types of human malignancies such as lung, breast, prostate, and colon tumors [392]. ...
... Based on the chromatographic fractionations and untargeted metabolomics analyzes conducted with bioactive subfractions, it was possible to annotate two withanolide glycosides, specifically (22R)-1-Oxo-3beta-(beta-Dglucopyranosyloxy)-14,20,22,27-tetrahydroxyergosta-5,24diene-26-oic acid delta-lactone and withanoside XI. This class of compounds belong to the group of withaesteroids that have a C28 ergostane skeleton in which C-26 and C-22 or C-26 and C-23 are oxidized to form a δ or ϒ-lactones (Chen et al. 2011). Withanolides have a great diversity of structures involving the nucleus and the side chain, including the formation of additional rings (Chen et al. 2011). ...
... This class of compounds belong to the group of withaesteroids that have a C28 ergostane skeleton in which C-26 and C-22 or C-26 and C-23 are oxidized to form a δ or ϒ-lactones (Chen et al. 2011). Withanolides have a great diversity of structures involving the nucleus and the side chain, including the formation of additional rings (Chen et al. 2011). The first isolated withanolide, withaferin A, was obtained from Withania somnifera (L.) Dunal (Solanaceae), and is well known for presenting cytotoxic activity to cancer cells (Zhang et al. 2012). ...
Article
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The fall armyworm, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae), is a major pest of maize crops and others row crops on the American continent, and this pest has spread to Africa and Asia. Such lepidopteran pest presents resistant populations to synthetic insecticides and to Bacillus thuringiensis (Bt) toxins and, consequently, new (bio) insecticides with distinct modes of action are required. In order to search for derivatives from Solanaceae as a potential source of bioactive compounds, a screening of 38 ethanolic extracts were prepared from 25 Solanaceae species. Using dietary exposure assessment, the ethanolic extracts from leaves of Acnistus arborescens (L.) Schltdl. and Datura stramonium L. were the most promising derivatives. A bioguided fractionation was performed with both plant species. The A. arborescens dichloromethane fraction was the most active, causing sublethal (growth inhibition) and lethal toxicity. Thus, this fraction was submitted to another fractionation procedure resulting in three subfractions (dichloromethane, ethyl acetate and methanol) that were tested against S. frugiperda caterpillars. All subfractions lead to significant sublethal effects, however, without significant mortality. The chemical diversity in the subfractions of A. arborescens was assessed through untargeted approaches, such as molecular networking and the in silico annotation tool NAP, by which two withanolides glycosides were annotated: (22R)-1-Oxo-3beta-(beta-D-glucopyranosyloxy)-14,20,22,27-tetrahydroxyergosta-5,24-diene-26-oic acid delta-lactone and withanoside XI. Therefore, derivatives of Solanaceae present promising compounds that may be useful in the framework of S. frugiperda integrated pest management. In addition, metabolomics is an innovative alternative and powerful approach to facilitate the putative identification of compounds in studies of natural products.
... Some withanolides, such as Physachenolide D, act as potential activators of quinone reductase or selective inhibitors of the COX-2 enzyme, exhibiting cytotoxic or cell differentiation inducing activities. The proposed mechanism of action, based on the results of bioassay evaluation in withanolides, relies on the α, β-unsaturated ketone unit in ring A and group 5β, 6β-epoxy in ring B [389]. ...
... 17β-hydroxywithanolides is as a new class of potent anti-androgenic molecules capable of inhibiting PSA expression and displaying selectivity for LNCaP and PC-3 cell lines. Preliminary structure-activity relationships identified physacenolide D as a 17β-hydroxywitanolide with promising antitumor activity in xenograft mice implanted with LNCaP and PC-3 cells [389,391]. Luteolin displays multiple biological activities, such as anti-inflammatory and anti-allergy with both antioxidant and pro-oxidant properties [392]. Moreover, luteolin is as a flavonoid compound that possesses anticancer activity against various types of human malignancies such as lung, breast, prostate, and colon tumors [392]. ...
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... Physalis peruviana L. belongs to the family Solanaceae, containing at least 120 species [11]. Many Physalis species are used for traditional medicinal applications in Asia and South America [12] since they contain the bioactive compound class withanolides. Withanolides include more than 300 natural C-28 steroidal lactones [12], and some exhibit anticancer functions [13][14][15][16][17][18][19][20]. ...
... Many Physalis species are used for traditional medicinal applications in Asia and South America [12] since they contain the bioactive compound class withanolides. Withanolides include more than 300 natural C-28 steroidal lactones [12], and some exhibit anticancer functions [13][14][15][16][17][18][19][20]. For example, withaferin A [17,19], 4β-hydroxywithanolide [18,19], and withanone [13] have demonstrated anti-breast-cancer effects. ...
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Breast cancer expresses clinically heterogeneous characteristics and requires multipurpose drug development for curing the different tumor subtypes. Many withanolides have been isolated from Physalis species showing anticancer effects, but the anticancer function of physapruin A (PHA) has rarely been investigated. In this study, the anticancer properties of PHA in breast cancer cells were examined by concentration and time-course experiments. In terms of cellular ATP content, PHA inhibited the proliferation of three kinds of breast cancer cells: MCF7 (estrogen receptor (ER)+, progesterone receptor (PR)+/−, human epidermal growth factor receptor 2 (HER2)−), SKBR3 (ER−/PR−/HER2+), and MDA-MB-231 (triple-negative). Moreover, PHA induced G2/M arrest in MCF7 and MDA-MB-231 cells. In terms of flow cytometry, PHA induced the generation of reactive oxygen species (ROS), the generation of mitochondrial superoxide, mitochondrial membrane potential depletion, and γH2AX-detected DNA damage in breast cancer MCF7 and MDA-MB-231 cells, which were suppressed by the ROS inhibitor N-acetylcysteine (NAC). In terms of flow cytometry and Western blotting, PHA induced apoptotic expression (annexin V, and intrinsic and extrinsic apoptotic signaling), which was suppressed by NAC and an apoptosis inhibitor (Z-VAD-FMK), in breast cancer cells. Therefore, PHA is a potential anti-breast-cancer natural product that modulates the oxidative-stress response, cell-cycle disturbance, apoptosis, and γH2AX-detected DNA damage.
... Ergostane-type steroids are characteristic not only of fungi but also of plants [19][20][21] and sponges [22]. These steroids are not a focus of the present paper. ...
... Elsebai et al. isolated nitrogenous metabolites of phenalenone, conio-azasterol (18), and S-dehydroazasirosterol (19), from the marine endophytic fungus Coniothyrium cereal [120]. Another nitrogenous hybrid of 9-dehydroergosterol fused through the morpholine ring with alternariol, pestauvicomorpholine A (20), was isolated from the fermentation product of the fungus Pestalotiopsis uvicola [121]. No cytotoxicity was detected for any of the tested compounds 16-20. ...
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Mushrooms are known not only for their taste but also for beneficial effects on health attributed to plethora of constituents. All mushrooms belong to the kingdom of fungi, which also includes yeasts and molds. Each year, hundreds of new metabolites of the main fungal sterol, ergosterol, are isolated from fungal sources. As a rule, further testing is carried out for their biological effects, and many of the isolated compounds exhibit one or another activity. This study aims to review recent literature (mainly over the past 10 years, selected older works are discussed for consistency purposes) on the structures and bioactivities of fungal metabolites of ergosterol. The review is not exhaustive in its coverage of structures found in fungi. Rather, it focuses solely on discussing compounds that have shown some biological activity with potential pharmacological utility.
... Similarly, phytosteroids like with anolides revealed their antiinflammatory activity by targeting COX-2 (O'Banion, Winn, & Young, 1992;Ristimäki, Narko, & Hla, 1996). In addition to antiinflammatory activity, phytosteroids facilitated cancer chemoprevention through selective COX-2 enzymes (Chen, He, & Qiu, 2011). ...
Article
Natural products and their derivatives are known to be useful for treating numerous diseases since ancient times. Because of their high therapeutic potentials, the use of different medicinal plants is possible to treat varied inflammation-mediated chronic diseases. Among natural products, phytosteroids have emerged as promising compounds mostly because they have diverse pharmacological activities. Currently, available medications exert numerous systemic toxicities, including hypertension, immune suppression, osteoporosis, and metabolic abnormalities. Thus, further research on phytosteroids to subside these complications is of significant importance. In this study, the information on phytosteroids, their types, and actions against inflammation , and allergic complications was collected by a systematic survey of literature on several scientific search engines. The literature review suggested that phytosteroids exhibit antiinflammatory action via different modes through transrepression or selective COX-2 enzymes. Also, in silico ADMET analysis was carried out on available phytosteroids to uncover their pharmacokinetic properties. Our analysis has shown that eight compounds: withaferin A, stigmasterol, β-sitosterol, guggulsterone, diosgenin, sarsasapogenin, physalin A, and dioscin, Àisolated from medicinal plants show similar pharmacokinetic properties as compared to dexamethasone, commercially available glucocorticoid. These phytosteroids could be useful for the treatment of inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel diseases, multiple sclerosis, asthma, and cardiovascular diseases. Thus, systematic research is Abbreviations: (PI3K)
... Withanolides are mainly found in the Solanaceae family, specifically represented by the genera of Datura, Physalis, Withania (Huang et al., 2020). Synthesis of withanolides built on an ergostane skeleton, in which C-26 and C-23, or C-26 and C-22 are oxidized to form a δ or γ lactone rings via triterpenoid pathway (Gao et al., 2018;Chen et al., 2011). First withaferin A was isolated from the valuable Indian medicinal plant Withania somnifera (Lavie et al., 1965). ...
Article
Physalis minima L. is commonly known as wild Gooseberry. Traditionally this plant has been used in different ethnopharmacological and modern medicinal practices. No systematic evaluation is done from an underutilized alternative resource of withaferin A content from P. minima. Withaferin A is a steroidal lactone withanolide mainly found in the plant Withania somnifera and other few members of family Solanaceae. The present investigation evaluated withaferin A content from 30 chemotypes collected from different geographical regions in India. Among 30 different chemotypes, an elite clone (17.13 ± 0.31 mg/g dry weight (DW) withaferin A) was selected for in vitro shoot multiplication. Well-organized micropropagation has been studied using five different cytokinins in Murashige and Skoog (MS) medium. Among them, aromatic cytokinin “meta-Topolin” (mT) at 1.0 mg/l triggered the highest number (83.26 ± 1.02) of multiple shoots and shoot length (4.87 ± 0.69) after 28 days of explant implantation. Maximum root induction was showed in ½ MS medium with 0.5 mg/l indole-3-butyric acid (IBA) to trigger 75.65 ± 1.03 roots and root length 4.56 ±0.25 cm after 14 days of culture. In vitro well-rooted plantlets were excised for hardening and show; 99.02% survival rate. Genetic stability of micropropagated plants were performed with cytological and molecular marker-based selection. Simultaneously, phytochemical stability was performed with HPLC (High performance liquid chromatography) analysis. In our experiment no significant difference showed between the mother plant and micropropagated plants. Thus, our protocol can be used for large-scale commercial cultivation of elite chemotype of this medicinal plant.
... Major active compounds among the W. somnifera phytochemicals are over 20 alkaloids including anaferin, cuscohygrine, anahygrin and steroidal lactones such as withanolides, withaferin, withanamides, withanosides (Fig. 2), withanolide glycosides, liganamides and steroidal saponins (10-13). Withanolides are a family of structurally complex steroidal lactones which act as potential drugs and aid in various biological and physiological activities (14). They are characterized by an ergostane skeleton whose C-22 and C-26 are oxidized to form δ lactones with 2-ene-1-one in ring A of the steroid (15). ...
Article
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Cancer is a leading cause of mortality worldwide, the conventional chemotherapeutic drugs have been known for their toxicity and numerous side effects. A new approach to treat cancer involves phytochemical drugs. In the present review, anti-cancer activity of a class of steroidal lactones called withanolides obtained from Withania somnifera (L.) Dunal is discussed. The commonly studied bioactive compounds namely withaferin-A, withanoside IV, withanoside VI and withanolide-A among others obtained from methanolic and chloroform extract of the leaves and various alcoholic, aqueous and chloroform extract of roots have shown inhibition to various human cancer cell lines including skin, breast, colon, prostate, liver, ovary, cervical and lung. Prominent mechanisms of action include induction of apoptosis by NOS upregulation, ROS production and NBS2 or COX-2 inhibition; cytotoxicity by humoral and cell mediated immune response, activation of p53 and pRB and inhibition of various viral oncoproteins; cell cycle arrest by Cdc2 facilitated mitotic catastrophe, cyclin-D1 down-regulation and inhibition of transcription factors. Cancers are also controlled by inhibition of angiogenesis and metastasis of the tumor cells. In addition to anti-tumorogenic properties, W. somnifera also holds properties that make it a potential adjuvant in integrated cancer therapeutics and in enhancing the effectiveness of ongoing radiation therapy.
... Natural products are an important source of anti-cancer drugs, including well-known and effective chemotherapeutic agents such as paclitaxel, vincristine, adriamycin and vinblastine (Newman and Cragg, 2020). Withanolides are a group of naturally occurring steroidal lactones isolated from some members of the Solanaceae plant family (Chen, et al., 2011). This class of natural products has shown promising anti-cancer properties against lung, breast, prostate, pancreatic, ovarian, renal and melanoma cancer cells (Chang, et and withanolide E (Xu, et al., 2017). ...
Preprint
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Melanoma is an aggressive skin cancer that metastasizes to other organs. While immune checkpoint blockade with anti-PD-1 has transformed the treatment of advanced melanoma, many melanoma patients fail to respond to anti-PD-1 therapy or develop acquired resistance. Thus, effective treatment of melanoma still represents an unmet clinical need. Our prior studies support the anti-cancer activity of the 17beta-hydroxywithanolide class of natural products, including physachenolide C (PCC). As single agents, PCC and its semi-synthetic analog demonstrated direct cytotoxicity in a panel of murine melanoma cell lines, which share common driver mutations with human melanoma; the IC50 values ranged from 0.18 - 1.7 micromolar. PCC treatment induced apoptosis of tumor cells both in vitro and in vivo. In vivo treatment with PCC alone caused the complete regression of established melanoma tumors in all mice, with a durable response in 33% of mice after discontinuation of treatment. T cell-mediated immunity did not contribute to the therapeutic efficacy of PCC or prevent tumor recurrence in YUMM2.1 melanoma model. In addition to apoptosis, PCC treatment induced G0-G1 cell cycle arrest of melanoma cells, which upon removal of PCC, re-entered the cell cycle. PCC-induced cycle cell arrest likely contributed to the in vivo tumor recurrence in a portion of mice after discontinuation of treatment. Thus, 17beta-hydroxywithanolides have the potential to improve the therapeutic outcome for patients with advanced melanoma.
... Several lactones have been isolated and characterized from various Datura spp. These phytochemicals are classified as C 28 steroids based on an ergostane skeleton and are highly abundant in various genera of the family Solanaceae (Chen et al., 2011;Guo et al., 2018). Datura lactones possess a rare epoxide moiety in the lactone ring structure which makes them unique as compared to the withanolide group of compounds. ...
Article
Background: Datura stramonium L. is widely used across the world for its therapeutic potential to treat inflammatory disorders. The current work was designed to isolate and identify steroidal lactones from D. stramonium leaves and evaluate their anti-inflammatory and analgesic properties. Methods: Several compounds were isolated from D. stramonium leaves and characterized by nuclear magnetic resonance and high-resonance electron spray ionization mass spectrometry techniques. Further, anti-inflammatory properties of these compounds were evaluated by in vitro assays, such as release of NO and pro-inflammatory cytokines by lipopolysaccharide (LPS)-activated J774A.1 macrophages. Using in vivo models, anti-inflammatory and analgesic effects were examined by mouse tail-flick, carrageenan-induced inflammation in rat paw model, vascular permeability in rats, and acetic acid-induced writhing in mice. The docking studies were performed for assessing the binding efficiency of the test compounds with cyclooxygenase-1 (COX-1) and COX-2, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), inducible nitric oxide synthases (iNOS) and nuclear factor-κB (NF-κB). Results: Three lactones were isolated and confirmed as daturalactone (D1), 12-deoxywithastramonolide (D23), and daturilin (D27). Further, the isolated compounds showed nitric oxide inhibition and pro-inflammatory cytokines released by LPS-activated J774A.1 macrophages. The in vivo results suggest that D1, D23 and D27 (20 mg/kg) were able to reduce the pain and inflammation in various animal models. The docking analysis showed that these three compounds actively bind with COX-1, COX-2, LOX-1, NF-κB, and iNOS, validating the anti-inflammatory effects of the lactones. Conclusion: These findings demonstrate substantial anti-inflammatory and analgesic properties of D. stramonium-derived lactones and their potential as anti-inflammatory agents to treat chronic inflammatory ailments.
... Withanolides are steroidal lactones that possess significant immunomodulatory, antimicrobial, antioxidant, and anti-inflammatory properties [29]. Withametelin (WMT) is a potent withanolide derivative obtained from the leaves of Datura innoxa that exhibit diverse pharmacological properties, including anti-inflammatory, antioxidant, antidepressant, and anticancer [30][31][32]. ...
Article
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Vincristine (VCR) is a widely used chemotherapy drug that induced peripheral painful neuropathy. Yet, it still lacks an ideal therapeutic strategy. The transient receptor potential (TRP) channels, purinergic receptor (P2Y), and mitogen-activated protein kinase (MAPK) signaling play a crucial role in the pathogenesis of neuropathic pain. Withametelin (WMT), a potential Phytosteroid isolated from datura innoxa, exhibits remarkable neuroprotective properties. The present investigation was designed to explore the effect of withametelin on VCR-induced neuropathic pain and its underlying molecular mechanism. Initially, the neuroprotective potential of WMT was confirmed against hydrogen peroxide (H2O2)-induced PC12 cells. To develop potential candidates for neuro-pathic pain treatment, a VCR-induced neuropathic pain model was established. Vincristine (75 μg/kg) was administered intraperitoneally (i.p.) for 10 consecutive days (day 1-10) for the induction of neuropathic pain. Gabapentin (GBP) (60 mg/kg, i.p.) and withametelin (0.1 and 1 mg/kg i.p.) treatments were given after the completion of VCR injection on the 11th day up to 21 days. The results revealed that WMT significantly reduced VCR-induced pain hypersensitivity, including mechanical allodynia, cold allodynia, and thermal hyperalgesia. It reversed the VCR-induced histo-pathological changes in the brain, spinal cord, and sciatic nerve. It inhibited VCR-induced changes in the biochemical composition of the myelin sheath of the sciatic nerve. It markedly downregulated the expression levels of TRPV1 (transient receptor potential vanilloid 1); TRPM8 (Transient receptor potential melastatin 8); and P2Y nociceptors and MAPKs signaling, including ERK (Extracellular Signal-Regulated Kinase), JNK (c-Jun N-terminal kinase), and p-38 in the spinal cord. It suppressed apoptosis by regulating Bax (Bcl2-associated X-protein), Bcl-2 (B-cell-lymphoma-2), and Caspase-3 expression. It considerably attenuated inflammatory cytokines, oxidative stress, and genotoxicity. This study suggests that WMT treatment suppressed vincristine-induced neuropathic pain by targeting the TRPV1/TRPM8/P2Y nociceptors and MAPK signaling.
... The methanol, dichloromethane, and 300 ethyl acetate extracts, semi-pure fractions, and compounds 1-3 exhibited potent 301 cytotoxicity against the other cancer cell lines, viz., Hep2, HT29, RD, Vero, and 302 MDCK by inducing apoptosis (Abdeljebbar et al. 2009;Bakrim et al. 2018 W. coagulans (Fig. 41.7). These compounds inhibited nitric oxide production in Chen et al. (2011). Under this section, only some selected bioactive withanolides 381 identified by bioassay guided isolation will be discussed. ...
Chapter
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Plants belonging to Withania genus are well-known medicinal plants and are commonly used as herbal medicine in the Ayurvedic health system. These plants belong to the family Solanaceae and comprise of 23 known species distributed in North Africa, the Middle East, Asia, the Mediterranean, and the Canary Islands. However, only six species, namely, Withania somnifera (L.) Dunal, Withania coagulans (Stocks) Dunal, Withania adpressa Coss, Withania aristata (Aiton) Pauquy, Withania frutescens (L.) Pauquy, and Withania obtusifolia Täckh, are extensively investigated with regard to their pharmacological properties and bioactive constituents. Therefore, in this chapter, the traditional uses of the six Withania species and the pharmacological validations of the plants and plant-derived constituents are discussed. Applications of the bioactive constituents in drug discovery are explained by discussing the semisynthetic modifications and structure-activity relationships.
... A great deal of attention has been paid to withanolides, a class of steroid compounds, due to their multiple bioactivities, such as immunosuppressive, anti-inflammation, antimicrobial, and antitumor properties [13][14][15]. Extensive studies have been carried out on the anticancer activity of the above-mentioned compounds. Especially, previous studies have shown that some withanolides can inhibit JAK/STAT3 signaling to exhibit the antitumor effect [16,17]. ...
Article
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Introduction Previously, we have reported a withanolide-type steroid, named tubocapsenolide A (TA), which shows potent anti-proliferative activity in several cancer cell lines. However, its inhibitory effect on the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway and therapeutic potential on osteosarcoma have not been reported. Objectives In the present study, we aimed to investigate the effect and molecular mechanism of TA in osteosarcoma. Methods The biological functions of TA in U2OS cells were investigated using colony formation, 5-ethynyl-20-deoxyuridine (EDU) staining, and cell cycle/apoptosis assays. The interaction between TA and Src homology 2 phosphatase 2 (SHP-2) was detected by enzyme activity and validated by target-identification methods such as drug affinity responsive target stability (DARTS), cellular thermal shift assay (CETSA), and biolayer interferometry (BLI). The in vivo anti-tumor efficacy of TA was analyzed in the xenograft tumor model. Western blotting analysis was performed to detect the protein expression levels. Results TA exhibited antitumor activity against osteosarcoma both in vitro and in vivo by regulating the JAK/STAT3 signaling pathway. Mechanically, TA interacted with SHP-2 directly and activated its phosphatase activity. Importantly, protein tyrosine phosphatase (PTP) inhibitor, SHP-2 inhibitor, and SHP-2 siRNA could reverse the inhibitory effect of TA on the JAK/STAT3 signaling pathway and restored the TA-induced cell death. Conclusion TA activated the phosphatase activity of SHP-2, which resulted in the inhibition of the JAK/STAT3 pathway and contributed to the antitumor efficacy of TA. Collectively, these findings suggested that TA could serve as a novel therapeutic agent for the treatment of osteosarcoma.
... These include remediation of neurodegenerative pathologies, cancer, malaria, gastrointestinal, thyroid and renal dysfunctions. WS has been used to enhance memory and cognition, augment stress coping abilities and reproductive health and as a strong immunity booster to combat pathogenic infections (Chen et al., 2011;Kulkarni and Dhir, 2008;Singh and Kumar, 2011;Singh et al., , 2015Winters, 2006). The major bioactive phytochemicals isolated and purified from various parts of WS herb are steroidal lactones (withanolides including withanolides A to Y, dehydrowithanolide R, withasomniferin A, withasomidienone, withasomniferols A to C, withaferin A, and withanone) and alkaloids (withanine, somniferine, somnine, somniferinine, withananine, psuedowithanine, tropine, cuscohygrine, isopelletierine, anaferine, anahydrine, ashwagandhine, cuscohygrine, tropine and pseudotropine and sitoindoside) (Mishra et al., 2000;Singh et al., 2015). ...
Article
Brain and neuronal circuits constitute the most complex organ networks in human body. They not only control and coordinate functions of all other organs, but also represent one of the most-affected systems with stress, lifestyle and age. With global increase in aging populations, these neuropathologies have emerged as major concern for maintaining quality of life. Recent era has witnessed a surge in nutritional remediation of brain dysfunctions primarily by “nutraceuticals” that refer to functional foods and supplements with pharmacological potential. Specific dietary patterns with a balanced intake of carbohydrates, fatty acids, vitamins and micronutrients have also been ascertained to promote brain health. Dietary herbs and their phytochemicals with wide range of biological and pharmacological activities and minimal adverse effects have gained remarkable attention as neuro-nutraceuticals. Neuro-nutraceutical potentials of herbs are often expressed as effects on cognitive response, circadian rhythm, neuromodulatory, antioxidant and anti-inflammatory activities that are mediated by effects on gene expression, epigenetics, protein synthesis along with their turnover and metabolic pathways. Epidemiological and experimental evidence have implicated enormous applications of herbal supplementation in neurodegenerative and psychiatric disorders. The present review highlights the identification, experimental evidence and applications of some herbs including Bacopa monniera, Withania somnifera, Curcuma longa, Helicteres angustifolia, Undaria pinnatifida, Haematococcus pluvialis, and Vitis vinifera, as neuro-nutraceuticals.
... Major active compounds among the W. somnifera phytochemicals are over 20 alkaloids including anaferin, cuscohygrine, anahygrin and steroidal lactones such as withanolides, withaferin, withanamides, withanosides (Fig. 2), withanolide glycosides, liganamides and steroidal saponins (10-13). Withanolides are a family of structurally complex steroidal lactones which act as potential drugs and aid in various biological and physiological activities (14). They are characterized by an ergostane skeleton whose C-22 and C-26 are oxidized to form δ lactones with 2-ene-1-one in ring A of the steroid (15). ...
Article
Full-text available
Cancer is a leading cause of mortality worldwide, the conventional chemotherapeutic drugs have been known for their toxicity and numerous side effects. A new approach to treat cancer involves phytochemical drugs. In the present review, anti-cancer activity of a class of steroidal lactones called withanolides obtained from Withania somnifera (L.) Dunal is discussed. The commonly studied bioactive compounds namely withaferin-A, withanoside IV, withanoside VI and withanolide-A among others obtained from methanolic and chloroform extract of the leaves and various alcoholic, aqueous and chloroform extract of roots have shown inhibition to various human cancer cell lines including skin, breast, colon, prostate, liver, ovary, cervical and lung. Prominent mechanisms of action include induction of apoptosis by NOS upregulation, ROS production and NBS2 or COX-2 inhibition; cytotoxicity by humoral and cell mediated immune response, activation of p53 and pRB and inhibition of various viral oncoproteins; cell cycle arrest by Cdc2 facilitated mitotic catastrophe, cyclin-D1 down-regulation and inhibition of transcription factors. Cancers are also controlled by inhibition of angiogenesis and metastasis of the tumor cells. In addition to anti-tumorogenic properties, W. somnifera also holds properties that make it a potential adjuvant in integrated cancer therapeutics and in enhancing the effectiveness of ongoing radiation therapy.
... W. coagulans fruits are used in cheese production due to their ability to coagulate the milk. The numerous medicinal properties of W. coagulans are mainly due to the compounds of withanolides that are naturally synthesized by the plant (Haq et al., 2013;Chen et al., 2011). Due to the accumulation of the medicinal compound withanolide A in the aboveground parts of W. coagulans in comparison with the root of W. somnifera (L.) Dunal, indicates the economical and easy harvesting of withanolides (Rathore et al., 2016). ...
Article
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p>In order to develop a protocol for the effective micropropagation of the important medicinal plant Withania coagulans (Stocks) Dunal, the effects of different concentrations and combinations of growth regulators on the nodal explants in two independent experiments were investigated. For shooting, a MS medium fortified with different concentrations and combinations of IBA (0.01, 0.1 and 0.5 mg l-1), BA (0.5, 1 and 2 mg l-1), Kin (0.5 and 1 mg l-1), PG (0.5 mg l-1) and GA (0.5 mg l-1) was used and the highest shooting response, shoot number and shoot length were obtained in the MS + IBA (0.01 mg l-1) + BA (0.5 mg l-1) + PG (0.5 mg l-1) + GA (0.5 mg l-1) treatment. In the second experiment, the effect of MS supplemented with different combinations and concentrations of IBA (0.1, 0.5, 1 and 2 mg l-1), NAA (0.1 and 1 mg l-1) and PG (1 mg l-1) on rooting of the nodal explants was investigated, which showed that the highest rooting response (%) was observed in the MS fortified with NAA (0.1 mg l-1), NAA (1 mg l-1), NAA (0.1 mg l-1) + PG (1 mg l-1), and NAA (1 mg l-1) + PG (1 mg l-1) treatments, as well as the highest number of roots at NAA (0.1 mg l-1) and the highest root length at IBA (1 mg l-1). Our findings highlight a complete micropropagation method for W. coagulans from the nodal explant that can make a significant contribution to the development of W. coagulans material for medical applications.</p
... According to a review in 2009, the phytoconstituents of WS isolated and reported from aerial parts, roots and berries include more than 12 alkaloids, 40 withanolides and several sitoindosides (Mirjalili et al. 2009a). Chen et al. (2011) provided a comprehensive summary of the 360 naturally occurring withanolides isolated and identified during 1996-2010 from plants of the Nightshade family. Withaferin A was discovered in 1965 from WS and since then up to 2014 exhaustive research has resulted in the discovery of 167 natural products including 127 C 28 -ergostane steroids (withanolides), ...
... To date, several reviews concerning research progress of withanolides have been published in the last decades, which mainly focus on their classification, structural features, biological activity, and biosynthesis (Zhang and Tong, 2016;Chen et al., 2011;Misico et al., 2011;Huang et al., 2020;. Even though some of the physalins are included in those reviews, physalins have not been reviewed separately in any literature with systematical review. ...
Article
Physalins, including physalins and neophysalins, are a class of highly oxygenated ergostane-type steroids. They are commonly known by the name of 16,24-cyclo-13,14-seco steroids, in which the disconnection of C-13 and C-14 produces an eight or nine-membered ring and the carbocyclization of C-16 and C-24 generates a new six-membered ring. Meanwhile, the oxidation of C-18 methyl to carboxyl group forms a 18,20-lactone, and the oxidation of C-14 and C-17 gets a heterocyclic oxygen acrossing rings C and D. Additionly, physalins frequently form an oxygen bridge to connect C-14 to C-27. Physalins are a kind of characteristic constituents from the species of the genus Physalis (Solanaceae), which are reported with a wide array of pharmacological activities, including anticancer, anti-inflammatory, immunoregulatory, antimicrobial, trypanocidal and leishmanicidal, antinociceptive, antidiabetic and some other activities. Herein,the research progress of physalins from the genus Physalis during the decade from 1970 to 2021 on phytochemistry, pharmacology, pharmacokinetics and application in China are systematically presented and discussed for the first time.
... The fruit of Physalis peruviana L. contains a wide diversity of biochemical compounds. withanolides and their derivatives are the most emblematic metabolites of Physalis species, and they have been shown to exert a wide range of pharmacological activities in vitro, such as immunomodulatory, angiogenesis inhibitor, anticholinesterase, antioxidant, antibacterial, and antitumoral activities [9]. This family of compounds with a steroid backbone has attracted the attention of pharmacologists, as withanolides and derivatives are mostly concentrated in aerial parts of plants, such as the leaves. ...
Article
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Purpose: Golden berry (Physalis peruviana L.) is an exotic fruit exported from Colombia to different countries around the world. A review of the literature tends to demonstrate a hypoglycaemic effect with an improvement in insulin sensitivity after oral ingestion of fruit extracts in animal models. However, little is known about their potential effects in humans, and very little is known about the mechanisms involved. This study aimed at identifying discriminant metabolites after acute and chronic intake of golden berry. Method: An untargeted metabolomics strategy using high-performance chemical isotope-labelling LC-MS was applied. The blood samples of eighteen healthy adults were analysed at baseline, at 6 h after the intake of 250 g of golden berry (acute intervention), and after 19 days of daily consumption of 150 g (medium-term intervention). Results: Forty-nine and 36 discriminant metabolites were identified with high confidence, respectively, after the acute and medium-term interventions. Taking into account up- and downregulated metabolites, three biological networks mainly involving insulin, epidermal growth factor receptor (EGFR), and the phosphatidylinositol 3-kinase pathway (PI3K/Akt/mTOR) were identified. Conclusions: The biological intracellular networks identified are highly interconnected with the insulin signalling pathway, showing that berry intake may be associated with insulin signalling, which could reduce some risk factors related to metabolic syndrome. Primary registry of WHO.
... Natural products are an important source of anti-cancer drugs, including well-known and effective chemotherapeutic agents such as paclitaxel, vincristine, adriamycin, and vinblastine [12]. Withanolides are a group of naturally occurring steroidal lactones isolated from some members of the Solanaceae plant family [3]. This class of natural products has shown promising anti-cancer properties against lung, breast, prostate, pancreatic, ovarian, renal, and melanoma cancer cells [2,8,10,19,23,27,28,30]. Structural optimization of withanolides has yielded superior drug candidates. ...
Article
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Melanoma is an aggressive skin cancer that metastasizes to other organs. While immune checkpoint blockade with anti-PD-1 has transformed the treatment of advanced melanoma, many melanoma patients fail to respond to anti-PD-1 therapy or develop acquired resistance. Thus, effective treatment of melanoma still represents an unmet clinical need. Our prior studies support the anti-cancer activity of the 17β-hydroxywithanolide class of natural products, including physachenolide C (PCC). As single agents, PCC and its semi-synthetic analog demonstrated direct cytotoxicity in a panel of murine melanoma cell lines, which share common driver mutations with human melanoma; the IC50 values ranged from 0.19–1.8 µM. PCC treatment induced apoptosis of tumor cells both in vitro and in vivo. In vivo treatment with PCC alone caused the complete regression of established melanoma tumors in all mice, with a durable response in 33% of mice after discontinuation of treatment. T cell-mediated immunity did not contribute to the therapeutic efficacy of PCC or prevent tumor recurrence in YUMM2.1 melanoma model. In addition to apoptosis, PCC treatment induced G0-G1 cell cycle arrest of melanoma cells, which upon removal of PCC, re-entered the cell cycle. PCC-induced cycle cell arrest likely contributed to the in vivo tumor recurrence in a portion of mice after discontinuation of treatment. Thus, 17β-hydroxywithanolides have the potential to improve the therapeutic outcome for patients with advanced melanoma.
... About its fragmentation pattern, it was observed the loss of one acetoxy group at 437.2690 [M À 60 þ H] þ , and sequential neutral losses of two water molecules, which led to the formation of the product ions at m/z 419.2587 and 401.2481. The removal of the lactone moiety can be identified at 265.1592 [M À AcO À H 2 O À CO À Lac þ H] þ , resulting from the cleavage of the C-20 and C-22 bond, suggesting the presence of a a,b-unsaturated dimethyl d-lactone, typical of type A withanolides (Chen et al. 2011 .7) and one of them hydroxylated (d C 69.5), and eight non protonated carbons representing three ketone carbonyls (d C 203.6, 167.3, and 171.5), three olefinic carbons (d C 139.2, 149.2, and 122.2), and two quaternary carbons (d C 49.5 and 45.7). ...
Article
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Bioassay-guided fractionation of dichloromethane extract from Athenaea velutina leaves led to the isolation of three withanolides, all being reported for the first time in this species. They were identified as withacnistin (1), withacnistin acetate (2) and a new withanolide, designated as withalutin (3). The structures were established by spectral data analysis, including MS, 1D and 2D NMR. In addition, in silico ADMET studies were employed to understand the pharmacokinetic properties of these withanolides. The withanolides isolated from A. velutina reduced cancer cell viability with IC50 values ranging from 1.52 to 5.39 µM. In silico prediction revealed that withanolides have good gastrointestinal absorption or oral bioavailability properties; and are not likely to be mutagenic or hepatotoxic. These findings revealed that A. velutina is an important source of cytotoxic withanolides.
... 5,6 Phytochemical investigations have reported withanolides 7 as the most frequently occurring constituents in Physalis species, 8 which include physalins, C 28 highly oxygenated C/D seco-steroids, that occur in Physalis and closely related genera belonging to the Solanaceae. 9 In addition, labdane diterpenoids, flavonoids, sucrose esters, and ceramides 4 have been reported from this genus. Previous phytochemical studies on Physalis nicandroides reported the characterization of sucrose esters, 10 labdane diterpenoids, 11,12 and withanolides. ...
Article
The aim of the present study is to report the isolation, structural elucidation, and antiviral evaluation of four new withanolide-type steroids, named nicansteroidins A-D (1-4), together with nine related known compounds (5-13) isolated from the aerial parts of Physalis nicandroides. Their structures were established based on an extensive spectroscopic analysis, including 1D and 2D NMR techniques. Outstandingly, nicansteroidins A and B possess an unusual side chain with an exocyclic double bond on the δ-lactone system, whereas nicansteroidins C and D have an uncommon cycloperoxide functionality in ring A as distinct structural motifs. Their biological evaluation as inhibitors of human immunodeficiency virus type 1 replication revealed that two compounds from this series, 7 and 13, displayed strong inhibition of HIV-1 replication with IC50 values lower than 2 μM. Moreover, cellular mechanism experiments showed that the main target of these compounds in the HIV replication cycle is viral transcription. This study is the first report of withanolide-type steroids as HIV inhibitors and provides insight into their potential as candidates for further preclinical studies.
... The withanolides are polyoxygenated C-28 ergostane-type steroids and polyhydroxy C-28 steroidal lactones with nine carbons side chain, generally attached to C-17 and a general characteristic of C-1, C-22, and C-26 oxidation (Maurya, 2010). Appropriate oxidation of δ-lactone or δ-lactol at C-22, C-26, and γ-lactone relating C-23 and C-26, divided withanolides into two types (Alali et al., 2014;Chen et al., 2011;Glotter, 1991). Withanolides are mostly restricted in leaves with a concentration range around 0.001 to 0.5% (Mirjalili et al., 2009). ...
Article
Background : Ayurveda is a highly recognized, well-documented, and well-accepted traditional medicine system. This system utilizes many natural products in various forms for therapeutic purposes. Thousands of plants mentioned in the Ayurvedic system are useful in disease mitigation and health preservation. One potential plant of the Ayurvedic system is “Ashwagandha” [Withania somnifera (L.) Dunal], commonly regarded as Indian Ginseng. It possesses various therapeutic activities, such as neuroprotective, hypoglycemic, hepatoprotective, antiarthritic, and anticancer effects. Purpose : Here we present a comprehensive insight on the anticancer effects of W. somnifera and mechanistic attributes of its bioactive phytocompounds. This review also provides an updated information on the clinical studies pertaining to cancer, safety evaluation and opportunities for chemical modifications of withanolides, a group of specialized phytochemicals of W. somnifera. Methods : The present study was performed in accordance with the guidelines of the Preferred Reporting Items for Systemic Reviews and Meta-Analysis. Various scientific databases, such as PubMed, Science Direct, Scopus, Google Scholar, were explored for related studies published up to May 2021. Results : An updated review on the anticancer potential and mechanisms of action of the major bioactive components of W. somnifera, including withanolides, withaferin A and withanone, is presented. Comprehensive information on clinical attributes of W. somnifera and its active components are presented with the structure-activity relationship (SAR) and toxicity evaluation. Conclusion : The outcome of the work clearly indicates that W. somnifera has a significant potential for cancer therapy. The SAR revealed that various withanolides in general and withaferin A in particular have binding energies against various proteins and tremendous potential to serve as the lead for new chemical entities. Nevertheless, additional studies, particularly well-designed clinical trials are required before therapeutic application of withanolides for cancer treatment.
... Physalins (steroidal constituents) are the most active representatives of secondary metabolites of the genus [101]. Most withanolide compounds are produced by Solanaceae plants, in particular 19 genera of Solanaceae, including Acnistus, Datura, Deprea, Dunalis, Discopodium, Exodeconus, Hyoscyamus, Iochroma, Jaborosa, Larnax, Lycium, Nicandra, Physalis, Salpichroa, Trechonaetes, Tubocapsicum, Vassobia, Withania, and Witheringia [102,103]. Nowadays, several withanolides have been isolated and characterized from different parts of P. peruviana, including dihydrowithaferins, physachenolides, physacoztolides, perulactones, withaperuvins, alkekenginins, withaferins, hydroxy-withanolides, physagulins, withaperuvins, physalolactones, withalongolide, physapubescins, withaphysanolides, viscosalactones, and phyperunolides [5,8]. Almost 351 withanolides have been identified and isolated from the Physalis genus, mainly from P. peruviana and P. angulata [104]. ...
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Background: Plant-derived medicines are widespread and continue to increase in traditional and modern medicine, especially in developing countries. Physalis peruviana L. is among the most used plants in conventional medication worldwide. This review aimed to highlight the ethnotherapeutic uses and phytochemical status of identified compounds in P. peruviana. Methods: Data were collected from Google Scholar, PubMed/Medline, SciFinder, Science Direct, Scopus, the Wiley Online Library, Web of Science, and any other helpful search engine using Physalis peruviana as the primary keyword. Results: Some countries, worldwide, use P. peruviana in their traditional medicine system to manage diverse ailments, mainly diseases and gastrointestinal tract disorders (25.33%). Leaf was the mostly used part (49.28%), prepared by decoction (31.58%) and overall administrated orally (53.57%) as the main route of admission. Around 502 phytoconstituents were identified in different plant parts, especially fruit (38.19%) ethanol/ethyl acetate extract. In most cases (36.17%), the solvent of the extract was not specified. Several phytochemical classes were found in the plant, especially terpenes (26.09%) and phenolic compounds (14.94%). Esters were also abundant (11.55%). In the terpenes category, carotenoids were the most abundant (11.15% followed by monoterpenes (8.76%) and diterpenes (3.18%). However, flavonoids (5.17%) followed by cinnamic acid derivatives (3.99%), monophenolic compounds (1.79%), and phenolic acids (1.33 M) are the most reported phenolic compounds. Hexadecanoic acid (palmitic acid) was the most cited (five times). Conclusion: P. peruviana plays an essential role in managing diseases in some countries and is rich in chemical compounds, which need to be isolated and investigated pharmacologically before clinical trials.
... 2013;Hepper, 1991). This genus is known to synthesize diverse structure of withanolides which showed pronounced biological activities including AChE inhibitory potential (Chen et al., 2011). The Moroccan flora includes three Withania species among them W. adpressa Coss. ...
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Natural substances have long served as sources of therapeutic drugs against various pharmacological targets. Neurodegenerative diseases especially Alzheimer’s disease (AD) affects the central nervous system causing progressive degeneration of neurons. Withanolides, isolated from Withania species, have shown acetylcholinesterase inhibition activity and their neuroprotective effects may be beneficial in the treatment of cholinergic system associated diseases, such as Alzheimer’s disease. This study was undertaken to highlight the neuroprotective effects of withaferin A (WA) isolated from W. adpressa leaves using a scopolamine-induced memory impairment model in mice. The in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition potential of WA were assessed. The learning and memory enhancing activities of WA at different doses (1, 3 and 5 mg/kg) were investigated using specific behavioral tests: Novel object recognition (NOR) and Barnes maze (BM). Biochemical analysis such as acetylcholinesterase was finally evaluated. WA substantially inhibited AChE and BuChE enzymes with IC50 values of 45.5 ± 0.14 and 68.2 ± 0.27 µg/mL, respectively and ameliorated the amnesic effect generated by scopolamine. Noteworthy, rotarod results revealed no significant differences between WA and control groups Also, learning, and spatial memory performance in NOR and BM tests were improved compared to the control groups. Furthermore, the activity of acetylcholinesterase in the brain was significantly inhibited (p < 0.05) by WA at the three tested doses. WA also possessed certain affinity in both enzymes with low binding energy compared to the reference drug donepezil in a molecular docking study. This study displays that WA could be used for enhancing learning and memory impairment and appears to be a promising candidate for Alzheimer’s disease treatment.
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Seven undescribed withanolides (1-7) and six artificial withanolides (8-13), along with 20 known compounds (14-33) were isolated from the aerial parts of Tubocapsicum anomalum. Their structures were confirmed by comprehensive spectroscopic analyses. The absolute configuration of compound 1 was defined by single-crystal X-ray crystallography. All isolates were evaluated for their antiproliferative effects against five human tumor cell lines (Hep3B, MDA-MB-231, SW480, HCT116 and A549), among which compound 24 (tubocapsanolide A) exhibited the highest activities against the MDA-MB-231 cells with an IC50 value of 1.89 ± 1.03 μM. Further studies showed that 24 exhibited significant damage to mitochondria in MDA-MB-231 cells, including excess reactive oxygen species, decreased mitochondrial membrane potential, and apoptosis initiation. In addition, compound 24 also inhibited cell migration. These findings show that tubocapsanolide A may be a promising molecule for triple-negative breast cancer treatment and merit further evaluation.
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Background The Himalayan region has been reported as rich accumulation of natural wealth, particularly of aromatic and medicinal plants. Indian Ajuga species (Ajuga brachystemon, Ajuga integrifolia, Ajuga macrosperma and Ajuga parviflora) belonging to Lamiaceae family have been reported from different parts of Uttarakhand. Phytochemical studies revealed presence of various bioactive compounds including neo-clerodane diterpenoids, steroids, phytoecdysteroids, sphingolipids, triterpenoids, flavonoids, fatty acids, iridoids, triglycerides, withanolides, phenylethanoid glycosides and quinols. Modern pharmacological activities of Ajuga species including anti-inflammatory, anti plasmodial activity, anti-platelet activity, antioxidant activity, analgesic assay, anti diabetic activity, antifungal activity, insecticidal activity and cytotoxity have been published by various researchers. Objective The present study is aimed to explore chemical composition, pharmacological and biological activities of Ajuga species as worked out by researchers and scientific community. Due to excessive use of Ajuga species it needs to be conserved and requires important measures for its conservation. Methods The analysis of essential oils and plant extract has been reported through solvent extraction, steam distillation method, GC-MS analysis and HPLC. Results Literature survey revealed reports of Ajuga L. to be used against various ailments such as stomach-ache, dermatitis, malaria, snake-bite, ear-ache, arthritis, bleeding, wounds, asthma, pneumonia, respiratory problems, fever, dysentery, and joint pain. Conclusion The detailed description would be helpful in future studies. Recent biotechnological approaches have been reported useful to conserve A. bracteosa due to over exploitation for research purpose whereas A. brachystemon and A. macrosperma have been reported rarely in the wild.
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Physalins are a structurally complex family of 13,14-secosteroids isolated from the genus Physalis. We disclose a two-step construction of the CDE ring moiety of the physalins from a steroidal compound bearing 14-OH, 18-COOMe, and 17, 20-α-epoxide based on our biosynthetic proposal. C13-C14 bond cleavage by an alkoxy radical at C-14 and spontaneous epoxide ring opening gave a compound having a cyclononene and γ-lactone. Diastereoselective dihydroxylation of the resulting alkene with OsO4 provided the CDE ring moiety of physalin.
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Novel withangulatin A (WA) derivatives were synthesized and evaluated for antiproliferative activity against four human cancer cell lines (U2OS, MDA-MB-231, HepG2, and A549). Among these derivatives, 10 exhibited the most potent antiproliferative activity, with an IC50 value of 74.0 nM against the human breast cancer cell line MDA-MB-231 and potency that was 70-fold that of WA (IC50 = 5.22 µM). Moreover, 10 caused G2-phase cell cycle arrest in a concentration-dependent manner and induced the apoptosis of MDA-MB-231 cells by increasing intracellular reactive oxygen species (ROS). Compound 10 showed a high selectivity index (SI = 267.03) for breast cancer MDA-MB-231 cells. These results suggest that 10 is a promising anticancer agent.
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Isocitrate dehydrogenase (IDH) is one key rate-limiting enzyme in the tricarboxylic acid cycle, which is related to various cancers. Tomatillo (Physalis ixocarpa), a special tomato, is widely consumed as nutritious vegetable in Mexico, USA, etc. As a rich source for withanolides, the fruits of P. ixocarpa were investigated, leading to the isolation of 11 type-A withanolides including 4 new ones (1 is an artificial withanolide). All these withanolides were evaluated for their inhibition on mutant IDH1 enzyme activity. Among them, physalin F (11) exhibited potent enzyme inhibitory activity and binding affinity with mutant IDH1. It inhibits the proliferation of HT1080 cells by selectively inhibiting the activity of mutant IDH1. Since Ixocarpalactone A, another major type-B withanolide in this plant, could act on another energy metabolism target PHGDH, the presence of different types of withanolides in tomatillo and their synergistic effect could make it a potential antitumor functional food or drug.
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The medicinal properties of Ashwagandha (Withania somnifera) are attributed to triterpenoid steroidal lactones, withanolides, which are proposed to be derived from phytosterol pathway, through the action of cytochrome P450 (CYP450) enzymes. Here, we report the characterization of three transcriptome-mined CYP450 genes (WsCYP749B1, WsCYP76 and WsCYP71B10), which exhibited induced expression in response to methyl jasmonate treatment indicating their role in secondary metabolism. All three WsCYP450s had the highest expression in leaf compared to other tissues. In planta characterization of WsCYP450s through virus induced gene silencing (VIGS) and transient overexpression approaches and subsequent metabolite analysis indicated differential modulation in the accumulation of certain withanolides in W. somnifera leaves. While WsCYP749B1-vigs significantly enhanced withaferin A (~ 450%) and reduced withanolide A (~ 50%), its overexpression drastically led to enhanced withanolide A (> 250%) and withanolide B (> 200%) levels and reduced 12-deoxywithastramonolide (~ 60%). Whereas WsCYP76-vigs led to reduced withanolide A (~ 60%) and its overexpression increased withanolide A (~ 150%) and reduced 12-deoxywithastramonolide (~ 60%). Silencing and overexpression of WsCYP71B10 resulted in significant reduction of withanolide B (~ 50%) and withanolide A (~ 60%), respectively. Further, while VIGS of WsCYP450s negatively affected the expression of pathogenesis-related (PR) genes and compromised tolerance to bacteria P. syringae DC3000, their overexpression in W. somnifera and transgenic tobacco led to improved tolerance to the bacteria. Overall, these results showed that the identified WsCYP450s have a role in one or several steps of withanolides biosynthetic pathway and are involved in conferring tolerance to biotic stress.
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Globally, Alzheimer’s disease (AD) is one of the most prevalent age-related neurodegenerative disorders associated with cognitive decline and memory deficits due to beta-amyloid deposition (Aβ) and tau protein hyperphosphorylation. To date, approximately 47 million people worldwide have AD. This figure will rise to an estimated 75.6 million by 2030 and 135.5 million by 2050. According to the literature, the efficacy of conventional medications for AD is statistically substantial, but clinical relevance is restricted to disease slowing rather than reversal. Withaferin A (WA) is a steroidal lactone glycowithanolides, a secondary metabolite with comprehensive biological effects. Biosynthetically, it is derived from Withania somnifera (Ashwagandha) and Acnistus breviflorus (Gallinero) through the mevalonate and non-mevalonate pathways. Mounting evidence shows that WA possesses inhibitory activities against developing a pathological marker of Alzheimer’s diseases. Several cellular and animal models’ particulates to AD have been conducted to assess the underlying protective effect of WA. In AD, the neuroprotective potential of WA is mediated by reduction of beta-amyloid plaque aggregation, tau protein accumulation, regulation of heat shock proteins, and inhibition of oxidative and inflammatory constituents. Despite the various preclinical studies on WA’s therapeutic potentiality, less is known regarding its definite efficacy in humans for AD. Accordingly, the present study focuses on the biosynthesis of WA, the epidemiology and pathophysiology of AD, and finally the therapeutic potential of WA for the treatment and prevention of AD, highlighting the research and augmentation of new therapeutic approaches. Further clinical trials are necessary for evaluating the safety profile and confirming WA’s neuroprotective potency against AD.
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Ethnopharmacological relevance Physalis divaricata D. Don. is an erect weed of family Solanaceae. The root extract of this plant is used by the indigenous communities of Sub-Himalayan region of Uttarakhand, India for the treatment of liver disorders. Aim of the study To evaluate hepatoprotective potential of P. divaricata in paracetamol (PCM) induced hepatotoxicity in rats. Material and methods The dried roots of P. divaricata were subjected to extraction using different solvents. The chloroform extract, methanol extract and bioactive aqueous fraction of methanol extract were evaluated for hepatoprotective effect. After initial in vitro screening, all extracts were screened for hepatoprotective potential in PCM (3 g/kg p.o) induced hepatotoxicity. Following PCM administration, extracts were administered orally for 7 days in increasing dose concentrations. All the animals were euthanized on eighth day, serum and liver tissues were collected and subjected to various biochemical and histopathological analysis. Aqueous fraction of methanol extract was further analyzed using LC- MS analysis. Results Methanol extract and its bioactive aqueous fraction exhibited significant and better in vitro antioxidant and antiproliferative activity as compared to chloroform extract. PCM treatment caused hepatotoxicity as assessed by altered levels of various hepatic biomarkers (increase in the levels of ALT, AST, ALP, albumin, triglycerides, cholesterol, TBARS, and AOPPs as well as decrease in GSH and TrxR levels) along with histopathological changes (portal to portal bridging, necrosis, and inflammation). Methanolic extract (200, 400 and 800 mg/kg) and its aqueous fraction treatment (25, 50 and 100 mg/kg) significantly restored elevated hepatic biomarkers, oxidative stress, and protected normal hepato-architecture. LC-MS analysis of aqueous fraction showed presence of rutin and kaempferol. In silico analysis further showed the capability of rutin to make complex with TNF-α and block its interaction with the target site. Conclusion Aqueous fraction showed maximum hepatoprotective potential as conceived through in vitro and in vivo studies. Presence of rutin may explain hepatoprotective potential of P. divaricata.
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Withanolide derivatives have anticancer, anti-inflammatory, and other functions and are components of Indian traditional Ayurvedic medicine. Here, we found that 2,3-dihydro-3β-methoxy withaferin-A (3βmWi-A), a derivative of withaferin-A (Wi-A) belonging to a class of withanolides that are abundant in Ashwagandha (Withania somnifera), lengthened the period of the circadian clock. This compound dose-dependently elongated circadian rhythms in Sarcoma 180 cancer cells and in normal fibroblasts including NIH3T3 and spontaneously immortalized mouse embryonic fibroblasts (MEF). Furthermore, 3βmWi-A dose-dependently upregulated the mRNA expression and promoter activities of Bmal1 after dexamethasone stimulation and of the nuclear orphan receptors, Rora and Nr1d1, that comprise the stabilization loop for Bmal1 oscillatory expression. We showed that 3βmWi-A functions as an inverse agonist for RORa with an IC50 of 11.3 μM and that 3βmWi-A directly, but weakly, interacts with RORa (estimated dissociation constant [Kd], 5.9 μM). We propose that 3βmWi-A is a novel modulator of circadian rhythms.
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Ethnopharmacological relevance: Physalis angulata L. is commonly used in many countries as popular medicine for the treatment of a variety of diseases such as malaria, hepatitis, dermatitis and rheumatism. But the anti-inflammatory active constituents of this medicinal plant and their molecular mechanism are still not elucidated clearly. Aim of the study: The aim of the study is to isolate and identify a series of compounds from the ethanolic extract of Physalis angulata L., and to investigate the anti-inflammatory activities in vitro and molecular mechanism of physagulin A, physagulin C, and physagulin H. Materials and methods: In order to further understand the anti-inflammatory mechanism of the three compounds, their potential anti-inflammatory activities were investigated in vitro in LPS-activated RAW 264.7 macrophage cells by Griess assay, ELISA, Western blot and immunofluorescence methods in the present study. Results: Physagulin A, physagulin C, and physagulin H could not only inhibit the release of NO, PGE2, IL-6 and TNF-α, but also could down-regulate the expression of iNOS and COX-2 proteins. Furthermore, physagulin A, physagulin C, and physagulin H could remarkably block the degradation of IκB-α and the nuclear translocation of NF-κB/p65 in LPS-activated RAW 264.7 cells. However, none of them could inhibit the phosphorylation of MAPKs family proteins ERK, JNK and p38. Thus, the anti-inflammatory actions of physagulin A, physagulin C, and physagulin H were mainly due to the significant inhibition of NF-κB signal pathway rather than MAPKs signaling pathway. Conclusions: All the results clearly showed that physagulin A, physagulin C and physagulin H demonstrated anti-inflammatory activity and can be used as novel NF-κB inhibitors. They are potential to be developed as an alternative or complementary agents for inflammatory diseases.
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Physalis peruviana L. is among plant species possessing evident nutritional, nutraceutical, and commercial interests. This review highlights the complexity of the chemical composition supporting the multiple pharmacotherapeutic indications and dietary values of this plant through evidence-based studies from Google Scholar, PubMed/Medline, SciFinder, Science Direct, Scopus, the Wiley online library, and Web of Science. The literature mentions at least 40 compounds isolated from different parts; others are still under investigation. High yields in carotenoids, amino acids, minerals, vitamin C, vitamin E, and essential fatty acids have healthy nutritional benefits. Various phytoconstituents, particularly withanolides, exhibit anti-carcinogenic, anti-inflammatory and antidiabetic potentials, as well as cardiovascular and liver protective effects. Prospective studies reveal that the leaves would also provide various beneficial bioactive chemicals worth being isolated. However, clinical evidence-based studies are seldom. Therefore, adequate pharmaceutical formulations and more in-depth controlled clinical trials are needed to fill the gap.
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Physachenolide C (1) is a 17β-hydroxywithanolide natural product with a unique anticancer potential, as it exhibits potent and selective in vitro antiproliferative activity against prostate cancer (PC) cells and promotes TRAIL-induced apoptosis of renal carcinoma (RC) and poly I:C-induced apoptosis of melanoma cells. To explore the effect of ring A/B modifications of physachenolide C (1) on these biological activities, 23 of its natural and semisynthetic analogues were evaluated. Analogues 4-23 were prepared by chemical transformations of a readily accessible compound, physachenolide D (2). Compound 1 and its analogues 2-23 were evaluated for their antiproliferative activity against PC (LNCaP and 22Rv1), RC (ACHN), and melanoma (M14 and SK-MEL-28) cell lines and normal human foreskin fibroblast (HFF) cells. Most of the active analogues had selective and potent activity in reducing cell number for PC cell lines, some showing selectivity for androgen-independent and enzalutamide-resistant 22Rv1 cells compared to androgen-dependent LNCaP cells. Analogues with IC50s below 5.0 μM against ACHN cells, when tested in the presence of TRAIL, showed a significantly increased ability to reduce cell number, and those analogues active against the M14 and SK-MEL-28 cell lines exhibited enhanced activity when combined with poly I:C. These data provide additional structure-activity relationship information for 17β-hydroxywithanolides and suggest that selective activities of some analogues may be exploited to develop natural products-based tumor-specific agents for cancer chemotherapy.
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Covering: March 2010 to December 2020. Previous review: Nat. Prod. Rep., 2011, 28, 705This review summarizes the latest progress and perspectives on the structural classification, biological activities and mechanisms, metabolism and pharmacokinetic investigations, biosynthesis, chemical synthesis and structural modifications, as well as future research directions of the promising natural withanolides. The literature from March 2010 to December 2020 is reviewed, and 287 references are cited.
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Increasing evidence have reported that NLRP3 inflammasome has a crucial role in various kinds of immunological diseases including colitis. However, there have only a few drug candidates directly targeting inflammasomes for the therapy of colitis. Here, we first reported that Tubocapsanolide A (TA), a natural small molecule, as a novel inhibitor of NLRP3 inflammasome for the treatment of colitis. TA inhibited the activation of NLRP3 inflammasome and suppressed the secretion of IL-1β and IL-18 in macrophages. Moreover, the ASC oligomerization was inhibited by TA. The assembly of the NLRP3 inflammasome was also restrained by TA, while had little effects on potassium and chloride efflux. Biolayer interferometry analysis showed that TA could directly bind to NLRP3. Importantly, LC-MS/MS analysis further demonstrated that TA covalently bound to the cysteine 514 residue (Cys514) of NLRP3. In vivo experiments showed that TA remarkably ameliorated DSS-induced experimental colitis in mice. However, the protection of TA against DSS-induced experimental colitis was abrogated in NLRP3-deficient (Nlrp3-/-) mice. Taken together, this study indicates TA as a novel inhibitor of NLRP3, which identifies Cys514 as a novel regulatory site of NLRP3 and suggests TA as a promising candidate compound for the treatment of colitis.
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Two new spiranoid withanolides, (20R,22R,23R)-12 beta,17 beta ,22-trihydroxy-1-oxo-12,23-cycloergosta-2,24-dien-26,23-olide (3) and (23R)-5 alpha,6 beta,12 beta,21-tetrahydroxy-1,22-dioxo-12,23-cycloergosta-2,17,24-trien-26,23-olide(4)were isolated from plants of Jaborosa odonelliana and Jaborosa runcinata, respectively. Compounds 3 and 4 were characterized by a combination of spectroscopic methods (ID and 2D NMR, MS) and molecular modelling.
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One new withanolide (1) has been isolated from the methanolic extract of Ajuga parviflora. Its structure was established as 3β, 14β, 17β, 20, 28-pentahydroxy-l-oxo-(20R, 22R) witha-5,24-dienolide (1) on the basis of spectroscopic data including two-dimensional NMR techniques. Another withanolide coagulin-J and pyrrolizidine alkaloid lagularinine have also been reported for the first time from A.parviflora.
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The chloroform extract of the fresh berries of Withania somnifera has been investigated to af-ford stigmasterol, its glucoside, withanone, 27-hydroxy withanolide A along with two new with-anolides, namely, iso-withanone (1) and 6α, 7α-epoxy-1α, 3β , 5α-trihydroxy-witha-24-enolide (2). Compound 1 possesses an uncommon 17α-oriented side chain whereas compound 2 has 1α, 3β -dihydroxy group which is a molecule of biogenetic significance for withasteroids.
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Three new withanolides, coagulins M, N, and O were isolated from the whole plant of Withania coagulans. Their structures were established as (14R,17R,20ζ,22R)-5α,6β,27-trihydroxy-14,20-epoxy-1-oxo-witha-24-enolide (1), (14R,17S,20ζ,22R)-15α,17-dihydroxy-14,20-epoxy-3β-(O-β-D- glucopyranosyl)-1-oxo-witha-5,24-dienolide (2) and (14R,20ζ,22R)-14,20- dihydroxy-3β-(O-Dβ-D-glucopyranosyl)-1-oxo-witha-5,24-dienolide (3) respectively, by extensive spectroscopic studies.
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The cholinergic hypothesis of Alzheimer's disease originally postulated a connection between some of the cognitive impaiments of this disorder, particularly memory, and a disturbance in cerebral cholinergic neurotransmission. A decade of neurochemical, anatomical, pathological and psychopharmacological research has since reinforced and refined the hypothesis. Current evidence suggests a critical role for cortical cholinergic projections, originating in the basal forebrain, in the memory component (possibly via activation of encoding mechanisms) of both Alzheimer and Parkinson types of dementia. In more advanced stages of Alzheimer's disease, the involvement of other transmitters extends the search for potential long-term therapy beyound the cholinergic system. Nevertheless, the cholinergic hypothesis still merits investigation today with a view to obtaining more precise information on the role of the human cerebral cholinergic system memory and, with the advent of novel approaches to cholinergic therapy, to improving the management of at least mildly demented patients.
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The non-basic fraction of the benzene and ethyl acetate extracts of the roots of Withania somnifera furnish six withanolides, of which three are new, in addition to β-sitosterol, its 3-O-β-D(+)-glucoside and linear benzo[6:7]chroman. The structures of new withanolides, withasomniferols A to C have been established respectively as 5α, 20αF(R), 27-trihydroxy-6α,7α-epoxy-1-oxowitha-2,24-dienolide 5, 5α,20α F(R)-dihydroxy-6α,7α-expoxy-1-oxowitha-2-enolide 6 and 5α,14α,20α F(R)-trihydroxy-1-oxowitha-2,7,24-trienolide 7 by a study of their physical and spectral (UV, IR, 1H and 13C NMR and Mass) characteristics.
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From the leaves of Withania somnifera ( Solanaceac ), collected from Tamil Nadu, a new withanolide, 3αmethoxy-2,3-dihydro-27-deoxywithaferin A (1) in addition to the known derivatives withaferin A (4), 2,3-dihydrowithaferin A (5) 3β-methoxy-2,3-dihydrowithaferin A (2) and 27-deoxywithaferin A (3) have been isolated, and their structures elucidated on the basis of physical, chemical and spectral methods.
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A new withanolide has been isolated from the aerial parts of Datura tatula as a minor constituent and its structure established as 5β, 6β-epoxy-21-hydroxy-1-oxo-witha-2,24-dienolide 2 on the basis of 1H NMR and mass spectral data and conversion to withatatulin 3, a known withanolide.
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Two new antifungal withanolides, (1) and (2) have been isolated from the defatted methanolic extract of Ajuga parviflora. Their structures were established as 3β,17β,20-trihydroxy-1-oxo-(20R, 22R)-witha-5,14,24-trienolide (1), 28-hydroxy-14,20-epoxy-1-oxo-(22R)-witha-2,5,24-trienolide (2) on the basis of spectroscopic data including two dimensional NMR tech­niques. The pyrrolizidine alkaloids senecionine (3) and integerrimine (4) are also reported for the first time from A. parviflora
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Minor new withanolides, daturametelins C, D, E, F and G-Ac, have been isolated from the methanolic extract of the fresh aerial parts of Datura metel L. (Solanaceae) and their structures have been determined mainly by spectroscopic means. Daturametelins E anf F are the first withanolides having a 1-one-3β-O-sulfate structure in ring A.
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In the course of studying differentiation-inducers from plants, their isolation was performed from the methanolic extract of Arctium Fructus (the fruits of Arctium lappa L., Compositae), and then their phagocytic activity on differentiated mouse myeloid leukemia cells (MI) was monitored. Thirteen compounds, including five new ones, were isolated as differentiation-inducers toward MI cells. These consisted of two lignans, eight sesquilignans and three dilignans. Arctigenin (2) was the most effective compound of all those isolated, and it induced differentiation of MI cells at a concentration 0.5 μM. Sesquilignans were less effective than lignans and dilignans showed even weaker activity. These lignoids were inactive towards a human acute promyelocytic leukemia cell line (HL-60).
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Phytotoxic effects of Iochroma australe extract and 4,7,20-oxowithanolides were examined in Petri dish bioassays at 10, 100, and 1000 ppm. The extract and the major constituent (17S,20R,22R)-4,7,20α-trihydroxy-1oxowitha-2,5,24-trienolide (2) reduced growth of the radicle of the weeds Sorghum halepense (Monoct.) and Chenopodium album (Dicot.). Neither the extract nor withanolides had significant effect on germination or radicle length of the commercial crop species Lactuca sativa. From our experimental data we conclude that the withanolides tested here are natural products with selective herbicidal activity against weed species.
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Withametelin, a novel hexacyclic withanolide of leaves has been characterized as 1 on the basis of spectroscopic studies.
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The structures of two new C28 steroidal lactone glycosides have been established; Spectroscopic and X-ray diffraction analyses of tubocapsigenin A diacetate, one of sapogenol derivative of these glycosides, have presented a new class of steroidal lactone structure.
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The B-secowithanolide (+)-jaborol (1) was obtained from Chilean Jaborosa maciellanica (Solanaceae). It is probably the result of in vivo oxidative cleavage of the C-9(10) bond of a more classical withanolide precursor.
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Withajardins A, B, C and D are withanolides with a new skeleton isolated from the leaves of Deprea orinocensis. Their structure and the absolute configuration of withajardin C were established by spectral analysis, including 2D-NMR and X-ray diffraction. The 13C NMR assignments of withajardins and acnistins were compared and biogenetic pathways to these compounds were formulated.
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From leaves of Jaborosa leucotricha a new withanolide (20S,22R)-1,6β,27-trihydroxy-19-norwitha- 1,3,5(10),24-tetraenolide has been isolated and fully characterized. The structure of this compound gives further insight into the metabolism of withanolides.
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From whole Jaborosa odonelliana plants, a new withanolide (20R,22R,23S-12β,17β,22-trihydroxy-l-oxo-12,23-cycloergosta-2,5,24-trien-26,23-olide has been isolated and characterized by spectroscopic, chemical and X-ray diffraction studies.
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The structure of a new naturally occurring steroidal lactone of the withanolide group isolated from Withania somnifera chemotype III has been elucidated as (20R,22R)-14α,2OαF-dihydroxy-1-oxowitha-2,5,16,24-tetraenolid. This compound is considered to be an intermediate in the biosynthesis of withanolide E, and is at the origin of the unusual α-oriented side-chain in this compound. The comparative composition of withanolides in different sub-chemotypes of III is provided.
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Eight new steroidal lactones of the withanolide series have been isolated from the leaves of Withania somnifera(Solanaceae) growing in North-Western India. This population of W. somnifera differs from those investigated so far and constitutes a new chemotype. The new compounds (IV)—(XI) have been investigated by chemical degradation and interconversion reactions, as well as by analysis of their spectral properties. The following structures have been assigned: 5α,17α-dihydroxy-1-oxo-6α,7α-epoxy-22R-witha-2,24-dienolide (IV); 5α,17α-dihydroxy-1-oxo-22R-witha-2,6,24-trienolide (V); 5α,27-dihydroxy-1-oxo-6α,7α-epoxy-22R-witha-2,24-dienolide (VIa); 4β,17α-dihydroxy-1-oxo-5β,6β-epoxy-22R-witha-2,24-dienolide (VIIa); 17α,27-dihydroxy-1-oxo-22R-witha-2,5,24-trienolide (VIIIa); 7α,27-dihydroxy-1-oxo-22R-witha-2,5,24-trienolide (VIIIa); 7α,27-dihydroxyl-1-oxo-22R-witha-2,5,24-trienolide (IXa); 1α,3β,5α-trihydroxy-6α,7α-epoxy-22R-with-24-enolide (Xa); 4β-hydroxy-5β,6β-epoxy-1-oxo-22R-witha-2,14,24-trienolide (XIa).
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Nicandra physaloides(Solanaceae) contains four new methyl steroid, relatives (1)–(4), all containing an aromatic ring D; the constituion of the first is demonstrated by crystallographic analysis using direct methods.
Article
In the course of screening for cell differentiation inducers from botanical sources, the methanol extract of Withania somnifera L. (DUN.) showed activity. From the aerial parts of the plant, sixteen withanolides, including three new compounds, 14, 15 and 16, were isolated and their structures elucidated to be (20S,22R)-4β,5β,6α,27-tetrahydroxy-1-oxo- witha-2,24-dienolide, (20R,22R,24S,25R)-4β,20β-dihydroxy-5β,6β-epoxy-3β- methoxy-1-oxowithanolide and 3-O-[β-D-glucopyranosyl(1→6)-β-D- glucopyranosyl]-(20S,22R)-1α,3β-dihydroxywitha-5,24-dienolide, respectively, from the spectral data. Of these withanolides, 1, 2, 3 and 4 showed potent cell differentiation inducing activity against M1 cells. The most potent compound, 3, showed more potent activity than dexamethasone, the positive control. These active compounds have the same partial structure of the AB ring part, having a 4β-hydroxy-5β,6β-epoxy-2-en-1-one moiety.
Article
Six new spiranoid withanolides, (20R,22,R,23S)-5alpha-chloro-6beta,12beta,17beta,22-tetrahydroxy-1-oxo-12,23-cycloergosta-2,24-dien-26,23-olide (2), (20R,22,R,23S)-5beta,6beta-epoxy-12beta,17beta,22-trihydroxy-1-oxo-12,23-cycloergosta-2,24-dien-26,23-olide (3), (20R,22R,23S)-5beta,6beta-epoxy-4beta,12beta,17beta,22-tetrahydroxy-1-oxo-12,23-cycloergosta-2,24-dien-26,23-olide (4),(20R,22R,23S)-5alpha,6beta,12beta,17beta,22-pentahydroxy-1-oxo-12,23-cycloergosta-2,24-dien-26,23-olide (5),(20R,22R,23S)-6beta,12beta,17beta,22-tetrahydroxy-5alpha-methoxy-1-oxo-12,23-cycloergosta-2,24-dien-26,23-olide (6), and (20R,22R,23S)-6beta,12beta,17beta,22-tetrahydroxy-2alpha,5alpha-epidioxy-1-oxo-12,23-cycloergosta-3,24-dien-26,23-olide (7), were isolated from the leaves of Jaborosa odonelliana. Compounds 2 - 7 were characterized by a combination of spectroscopic methods (1D and 2D NMR, MS) and molecular modeling.
Article
In addition to the known compounds withanolide A (4), withanone (5), and NIC-3 (6), three 16-hydroxylated withanolides were isolated from Exodeconus maritimus. The new withanolides were identified as 6α,7α-epoxy-5α,16β-dihydroxy-1-oxowitha-2,17(20),24-trienolide (exodeconolide A, 1), 6α,7α-epoxy-5α,16α-dihydroxy-1-oxowitha-2,17(20),24-trienolide (exodeconolide B, 2), and 6α,7α-epoxy-5α,16α,17α-trihydroxy-1-oxowitha-2, 24-dienolide (exodeconolide C, 3), by a combination of spectroscopic (1D and 2D NMR, MS) and chemical methods with the aid of molecular modeling.
Article
The phytochemical investigation of Iochroma coccineum (Solanaceae) afforded three withanolides: withaferine A [1], withacnistine [2], and a new compound, the (17R,20S,22R)-4-beta-hydroxy-1-oxo-5-beta,6-beta-epoxy-16-alpha-acetoxywitha-2,24-dienolide, which we called isochromolide [3]. The structure of 3 was deduced on the basis of nmr and mass spectral comparison with 1 and 2 and definitively established by X-ray crystallography.
Article
Three new withanolides, coagulins P, Q and R, were isolated from the whole plant of Withania coagulans. Their structures were determined as 20,27-dihydroxy-3β-(O-β-D-glucopyranosyl)-1-oxo-(20S,22R)-witha-5,14,24-trienolide, 1α,20-dihydroxy-3β-(O-β-D-glucopyranosyl)-(20S,22R)-witha-5,24-dienolide and 3β,17β-dihydroxy-14,20-epoxy-1-oxo-(22R)-witha-5,24-dienolide by a combination of 1D- and 2D-NMR and mass spectroscopic studies.