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Natural Withanolides: An Overview
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.
... 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. ...
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.
... 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. ...
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.
... According to research, Datura stramonium significantly slowed the mitotic process in cancer cells [8]. Withanolides [9] from Datura innoxia had unique anticancer properties [8]. The methanolic extract of Datura metel showed promise as an anticancer agent when tested on the MCF-7 cell line, as reported by many scientific reports. ...
... It was found that a part of the leaves of the Datura alba plant that is high in alkaloids have anticancer and antimitotic capabilities. Cytotoxic activity of withametelins I, J, K, L, M, N, O, P, 12-β-hydroxy-1,10-secowithametelin B and 1,10-s-withametelin B has been investigated from methanolic extracts of D. metel, by using MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay [9][10][11][12]. Cytotoxic activity against A549 (lung), BGC-823 (gastric), and K562 (leukemia) cancer cell lines has been exhibited by the Withametelins I, K, L, and N. IC50 values were observed ranging from 0.05 to 3.5 µM. ...
Cancer is one of the life-threatening diseases and the second leading cause of death in the world. The estrogen receptor can be considered as one of the significant drug targets for cancer. A large number of clinically used anticancer drugs were identified from phytochemicals. Multiple literatures suggested that extracts of Datura sp. significantly inhibit estrogen receptors associated with human cancer. In the present study, all reported natural products present in Datura sp. were subjected to molecular docking against estrogen receptors. The top hits were shortlisted based on binding orientation and docking score and subjected to molecular dynamics simulation to explore the conformational stability followed by binding energy calculation. The ligand [(1S,5R)-8-Methyl-8-Azabicyclo [3.2.1] Octan-3-yl] (2R)-3-Hydroxy-2-Phenylpropanoate depicts highly acceptable MD simulations outcomes and drug-likeness profile. Knowledge-based de novo design and similar ligand screening were executed using the structural information. The designed ligand DL-50 exhibited satisfactory binding, drug-likeness profile, and well-accepted ADMET profile followed by easy synthetic accessibility which further requires experimental validation.
Graphical abstract
... Physalis plants, traditional medicinal herbs used in Asia and South America [11], contain withanolides, the C-28 steroidal lactones [11], and show anticancer effects [12][13][14][15][16][17]. Physapruin A (PHA), a withanolide isolated from P. peruviana, was first reported in 1933 [18] and showed antiproliferation effects for human prostate, renal [19], oral [20], and breast [21] cancer cells recently. ...
... Physalis plants, traditional medicinal herbs used in Asia and South America [11], contain withanolides, the C-28 steroidal lactones [11], and show anticancer effects [12][13][14][15][16][17]. Physapruin A (PHA), a withanolide isolated from P. peruviana, was first reported in 1933 [18] and showed antiproliferation effects for human prostate, renal [19], oral [20], and breast [21] cancer cells recently. ...
Physalis plants are commonly used traditional medicinal herbs, and most of their extracts containing withanolides show anticancer effects. Physapruin A (PHA), a withanolide isolated from P. peruviana, shows antiproliferative effects on breast cancer cells involving oxidative stress, apoptosis, and autophagy. However, the other oxidative stress-associated response, such as endoplasmic reticulum (ER) stress, and its participation in regulating apoptosis in PHA-treated breast cancer cells remain unclear. This study aims to explore the function of oxidative stress and ER stress in modulating the proliferation and apoptosis of breast cancer cells treated with PHA. PHA induced a more significant ER expansion and aggresome formation of breast cancer cells (MCF7 and MDA-MB-231). The mRNA and protein levels of ER stress-responsive genes (IRE1α and BIP) were upregulated by PHA in breast cancer cells. The co-treatment of PHA with the ER stress-inducer (thapsigargin, TG), i.e., TG/PHA, demonstrated synergistic antiproliferation, reactive oxygen species generation, subG1 accumulation, and apoptosis (annexin V and caspases 3/8 activation) as examined by ATP assay, flow cytometry, and western blotting. These ER stress responses, their associated antiproliferation, and apoptosis changes were partly alleviated by the N-acetylcysteine, an oxidative stress inhibitor. Taken together, PHA exhibits ER stress-inducing function to promote antiproliferation and apoptosis of breast cancer cells involving oxidative stress.
... 1 H NMR data of the compound ( 24. According to the above-mentioned data and by comparison with previously reported data of related compounds [37][38][39]. Compound 3 is identified as 3α, 14 β-dihydroxy withaphysalin N. ...
... As a result, screening medicinal plant extracts, as well as isolating and identifying their bioactive compounds are critical in the development of effective medications [43]. Based on the literature, P. peruviana L. is rich in withanolides [38,44], so it was interesting to investigate in depth. Withanolides are natural steroidal lactones metabolized mainly by plants belonging to the family Solanaceae mainly the genus Physalis. ...
Background
Cadmium is an environmentally toxic metal that has deleterious effects on both animals and humans due to its accumulation in different body tissues. Physalis peruviana L. fruit and calyx contain many active constituents which are used traditionally for their different biological activities. Based on the traditional uses of P. peruviana L. calyx, we aimed to evaluate the nephroprotective effect of their 80% aqueous methanol extract (AME) and n-butanol fraction (Bu.F.) against cadmium chloride-induced nephrotoxicity in rats and to correlate this activity with phytoconstituents isolated using molecular docking studies.
Methods
The n-butanol fraction of P. peruviana L. calyx was fractionated using various chromatographic techniques and the isolated compounds were identified based on their chemical and spectroscopic data. The nephroprotective activity was assessed using cadmium chloride-induced nephrotoxicity in the rat model, by measuring some important parameters such as body weight, kidney weight, serum urea, and creatinine levels, oxidative stress markers, inflammatory markers, and histopathological examinations of kidney tissue. Molecular docking studies of the isolated compounds were performed.
Results
Three withanolides named 4 β-hydroxywithanolide E (1), Physalin B (2) and 3 α , 14 β -dihydroxywithaphysalin N (3) were isolated and identified from the n -butanol fraction of P. peruviana L calyx extract. The extract and its butanol fraction significantly improved the serum kidney function markers and tissue oxidative status including malondialdehyde (MDA), reduced glutathione (GSH) and catalase (CAT). Additionally, the extracts significantly decreased the levels of tumor necrosis factor-alpha (TNF-α) and nuclear factor kappaB (NF-κβ). Moreover, the histological changes were ameliorated by the extracts. The molecular docking study showed that the isolated compounds displayed a remarkable inhibitory activity against IκB kinase.
Conclusion
The AME and its butanol fraction of P. peruviana L calyx showed potential nephroprotective activity against cadmium chloride-induced nephrotoxicity which is correlated at least in part to its considerable withanolides content.
... Physalis peruviana L., also known as goldenberry, is an edible plant species belonging to the family Solanaceae, containing about 120 species [6], commonly applied in traditional medicines in Asia and South America [7]. Over 300 natural steroidal lactones belong to withanolides [7]. ...
... Physalis peruviana L., also known as goldenberry, is an edible plant species belonging to the family Solanaceae, containing about 120 species [6], commonly applied in traditional medicines in Asia and South America [7]. Over 300 natural steroidal lactones belong to withanolides [7]. At least 40 withanolides were reported from P. peruviana [8]. ...
The selective antiproliferation to oral cancer cells of Physalis peruviana-derived physapruin A (PHA) is rarely reported. Either drug-induced apoptosis and DNA damage or DNA repair suppression may effectively inhibit cancer cell proliferation. This study examined the selective antiproliferation ability of PHA and explored detailed mechanisms of apoptosis, DNA damage, and repair. During an ATP assay, PHA provided high cytotoxicity to two oral cancer cell lines (CAL 27 and Ca9-22) but no cytotoxicity to two non-malignant oral cells (HGF-1 and SG). This selective antiproliferation of PHA was associated with the selective generation of reactive oxygen species (ROS) in oral cancer cells rather than in non-malignant oral cells, as detected by flow cytometry. Moreover, PHA induced other oxidative stresses in oral cancer cells, such as mitochondrial superoxide generation and mitochondrial membrane potential depletion. PHA also demonstrated selective apoptosis in oral cancer cells rather than non-malignant cells in annexin V/7-aminoactinmycin D and caspase 3/7 activity assays. In flow cytometry and immunofluorescence assays, PHA induced γH2AX expressions and increased the γH2AX foci number of DNA damages in oral cancer cells. In contrast, the mRNA expressions for DNA repair signaling, including homologous recombination (HR) and non-homologous end joining (NHEJ)-associated genes, were inhibited by PHA in oral cancer cells. Moreover, the PHA-induced changes were alleviated by the oxidative stress inhibitor N-acetylcysteine. Therefore, PHA generates selective antiproliferation, oxidative stress, and apoptosis associated with DNA damage induction and DNA repair suppression in oral cancer cells.
... Cape gooseberry (Physalis peruviana L.), also commonly known as goldenberry, is a member of the Solanaceae family which is native to the Andes and has been introduced in different countries since its domestication [1]. Antispasmodic, diuretic, antiseptic, sedative and analgesic properties, in addition to throat trouble relief and the elimination of intestinal parasites and amoeba, are among the properties attributed to P. peruviana fruits and husks [2,3], and they are used empirically in traditional medicine to treat cancer and The derivatives from withanolides D and E (Figure 2), important backbones for withanolides [32][33][34] found in the husks and fruits of P. peruviana from Costa Rica, include 34 previously described compounds, as shown in Table S1 (Supplementary Materials). The derivatives from withanolides D and E (Figure 2), important backbones for withanolides [32][33][34] found in the husks and fruits of P. peruviana from Costa Rica, include 34 previously described compounds, as shown in Table S1 (Supplementary Materials). ...
... Antispasmodic, diuretic, antiseptic, sedative and analgesic properties, in addition to throat trouble relief and the elimination of intestinal parasites and amoeba, are among the properties attributed to P. peruviana fruits and husks [2,3], and they are used empirically in traditional medicine to treat cancer and The derivatives from withanolides D and E (Figure 2), important backbones for withanolides [32][33][34] found in the husks and fruits of P. peruviana from Costa Rica, include 34 previously described compounds, as shown in Table S1 (Supplementary Materials). The derivatives from withanolides D and E (Figure 2), important backbones for withanolides [32][33][34] found in the husks and fruits of P. peruviana from Costa Rica, include 34 previously described compounds, as shown in Table S1 (Supplementary Materials). Other observed fragments corresponded with the loss of acetyl, methoxy or glycoside moieties if present in the compound [26]. ...
There is increasing interest in research of secondary metabolites from Physalis peruviana (Cape gooseberry) because of their potential bioactivities. In this study, the profile of compounds found in fruits and husks from Costa Rica was determined through ultra-performance liquid chromatography coupled with high-resolution mass spectrometry using a quadrupole time-of-flight analyzer (UPLC-ESI-QTOF MS) on extracts (n = 10) obtained through pressurized liquid extraction (PLE) conditions. In total, 66 different compounds were identified, comprising 34 withanolides, 23 sucrose ester derivatives and 9 flavonoids. UPLC-DAD analysis was performed to determine the β-carotene in fruits and to quantify the flavonoids in all 10 samples, with the results showing higher contents in samples from the Dota region (58.6–60.1 μg/g of dry material versus 1.6–2.8 mg/g of dry material). The Folin–Ciocalteau total polyphenolic content (FC) and antioxidant activity using the DPPH method showed better results for the husk extracts, with the ones from the Dota region holding the best values (4.3–5.1 mg GAE/g of dry material versus IC50 = 1.6–2.3 mg of dry material/mL). In addition, a significant negative correlation was found between the RU, FC and DPPH values (r = −0.902, p < 0.05), aligning with previous reports on the role of polyphenols in antioxidant activity. Principal correlation analysis (PCoA) and hierarchical clustering (HC) analysis were performed on HRMS results, and they indicated that the D1 and D2 fruit samples from the Dota region were clustered with husks related to a higher presence of the analyzed metabolites. In turn, principal component analysis (PCA) performed on the flavonoid content and antioxidant activity yielded results indicating that the D1 and D2 husks and fruit samples from the Dota region stood out significantly, showing the highest antioxidant activity. In summation, our findings suggest that P. peruviana husks and fruits from Costa Rica constitute a substrate of interest for further studies on their potential health benefits.
... 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]. ...
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.
... Withanolides, the natural steroids mainly distributed in Solanaceae, are a group of ergostane compounds with 28 carbons, in which C-23/C-26, or C-22/C-26 properly oxidized resulting in the formation of a δ-or γ-lactone ring [2]. To date, withanolides have been reported to possess potent antiproliferative activity [3,4]. ...
... In summary, four novel withanolide-type compounds (1)(2)(3)(4), together with three known analogues (5-7), were obtained from P. peruviana L.. Compounds 2-3 possess a 13,14-seco-withaphysalin skeleton, while others were two withaphysalin-type withanolides (1, 7) and three normal withanolides (4)(5)(6). The cytotoxic activities of these isolated compounds were evaluated against MCF-7. ...
Background:
Many drugs for anti-tumour have been developed, nevertheless, seeking new anticancer drug is the focus of ongoing investigation. Withanolides have been reported to possess potent antiproliferative activity. Literature findings revealed that a diversity of withanolides were obtained from Physalis peruviana, however, the antitumor activity of these bioactive compounds is still unclear.
Methods:
The EtOAc fraction of P. peruviana were decolorized on Middle Chromatogram Isolated (MCI) Gel column, repeatedly subjected to column chromatography (CC) over sephadex LH-20, preparative High Performance Liquid Chromatography (HPLC) and silica gel to afford compounds. Their chemical structures of the new isolates were elucidated through analyzing spectroscopic and HRESIMS data. All these obtained metabolites were appraised for their potential antiproliferative activity against the human breast cancer cell line MCF-7 by MTT assay, and in vitro antibacterial activity of the isolated compounds (1-7) were evaluated against E. coli, B. cereus and S. aureus. Results: Four new withanolides, including one withaphysalin-type withanolide (peruranolide A, 1), two 13,14-seco-withaphysalins (peruranolides B-C, 2-3), as well as one normal withanolide (peruranolide D, 4), were purified and separated from P. peruviana L.. Compound 5 was discovered to exhibit potent cytotoxic effect with an IC50 value of 3.51 μM. In vitro antibacterial activities, compounds 1-7 had no obvious inhibitory activity against E. coli, but had moderate inhibitory activities against B. cereus and S. aureus.
Conclusions:
Our findings might offer valuable clues for the utilization of withanolides as lead compounds for antineoplastic or antibacterial drug development.
... 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. ...
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.
... Therefore, the high concentration of saponins in plants could provide greater health benefits when taken. Furthermore, plant-derived steroids possess several health benefits, such as antitumor, immunomodulatory, anti-inflammatory, antileishmanial, and antimicrobial activities (Chen et al., 2011). More still, Kamal et al. (2014) chronicled biological significance of plant-derived steroids extensively. ...
Telfairia occidentalis leaves are known to possess many therapeutic potentials such as antidiabetic, anti-inflammatory, anticholesterolemic etc. To maximize their use in phytomedicine, the conditions used in preparation methods are crucial. Therefore, this study estimated the effect of extraction temperature on the phytochemicals, minerals, and antioxidant properties of T. occidentalis leaves. The powdered samples of T. occidentalis leaves were extracted using water at 1000C and 250C, respectively, followed by the phytochemical, mineral and antioxidant analyses of the plant extracts. The concentration of most constituent metabolites in the cold extract of T. occidentalis leaves was significantly (p < 0.05) higher than that of the hot extract. The highest mineral concentrations in hot and cold extracts of T. occidentalis leaves were sodium (2.22 mg/L) and potassium (2.77 mg/L), respectively. In the antioxidant study, the EC50 values (131.20 ± 1.70 μg/ml and 105.08 ± 0.54 μg/ml) of the hot extract of T. occidentalis leaves were significantly (p < 0.05) lower than those of the cold extract (228.17 ± 23.03 μg/ml and 151.47 ± 14.68 μg/ml). The study reveals that the extracts hold varying biological importance. The cold aqueous extract can be an excellent nutritional adjuvant for the supply of essential nutrients, whereas the hot aqueous extract can act as an important agent in ameliorating pathological conditions thrive on excessive free radical generation. Therefore, the different extraction procedures can be utilized based on the desired biological outcome.
... In addition, the Acnistus breviflorus plant has been found to produce steroids such as compound 116 and compound 117, which possess cytostatic activity. Similarly, cytotoxic withanolide (117, structure seen in Figure 24) has been isolated from Withania frutescens, another plant from the Solanaceae family [159]. ...
This review delves into the investigation of the biological activity and structural diversity of steroids and related isoprenoid lipids. The study encompasses various natural compounds, such as steroids with aromatic ring(s), steroid phosphate esters derived from marine invertebrates, and steroids incorporating halogen atoms (I, Br, or Cl). These compounds are either produced by fungi or fungal endophytes or found in extracts of plants, algae, or marine invertebrates. To assess the biological activity of these natural compounds, an extensive examination of referenced literature sources was conducted. The evaluation encompassed in vivo and in vitro studies, as well as the utilization of the QSAR method. Numerous compounds exhibited notable properties such as strong anti-inflammatory, anti-neoplastic, anti-proliferative, anti-hypercholesterolemic, anti-Parkinsonian, diuretic, anti-eczematic, anti-psoriatic, and various other activities. Throughout the review, 3D graphs illustrating the activity of individual steroids are presented alongside images of selected terrestrial or marine organisms. Additionally, the review provides explanations for specific types of biological activity associated with these compounds. The data presented in this review hold scientific interest for academic science as well as practical implications in the fields of pharmacology and practical medicine. The analysis of the biological activity and structural diversity of steroids and related isoprenoid lipids provides valuable insights that can contribute to advancements in both theoretical understanding and applied research.
... Withanolides, a kind of highly-oxidized C28 ergosterol steroids, mainly exist in plants of Solanaceae family and have been attracting a rising interest because of their biological characteristics, especially anti-cancer activity [31]. Previous studies have reported that the anti-tumor effect of withanolides depends on both α, β-unsaturated ketone in ring A and 5β, 6β-epoxy group in ring B [32,33]. ...
Anomanolide C (AC), a natural withanolide isolated from Tubocapsicum anomalum, has been reported to have exhibits remarkable anti-tumour activities in several types of human cancers, particularly triple-negative breast cancer (TNBC). However, its intricate mechanisms still remain need to be clarified. Here, we evaluated whether AC could inhibit cell proliferation and the role of AC in ferroptosis induction and autophagy activation. Subsequently, the anti-migration potential of AC was found via autophagy-dependent ferroptosis. Additionally, we found that AC reduced the expression of GPX4 by ubiquitination and inhibited TNBC proliferation and metastasis in vitro and in vivo. Moreover, we demonstrated that AC induced autophagy-dependent ferroptosis, and led to Fe2+ accumulation via ubiquitinating GPX4. Moreover, AC was shown to induce autophagy-dependent ferroptosis as well as to inhibit TNBC proliferation and migration via GPX4 ubiquitination. Together, these results demonstrated that AC inhibited the progression and metastasis of TNBC by inducing autophagy-dependent ferroptosis via ubiquitinating GPX4, which might shed light on exploiting AC as a new drug candidate for the future TNBC therapy.
... Withanolides are a group of naturally occurring polyoxygenated steroidal lactones arranged on a C 28 ergostane skeleton and the structural variation of withanolides is due to the number and nature of oxygenated substituents and the rings' degree of unsaturation [19,20]. Withanolides possess the major biological activities of the plant and plant's extract and different mechanisms have been reported for these pharmacological activities. ...
Ashwagandha (Withania somnifera) is a very popular medicinal herb originated mainly in India and found in the Middle East and parts of Africa. Ashwagandha has gained recognition as the most revered plant in Ayurvedic medicine. Studies indicated that it is used as anxiolytic, anti-inflammatory, antioxidant, adaptogen, memory enhancer, and possess an effect on neurodegenerative diseases. Additionally, it was revealed that the plant exerts antibacterial, antiviral, antitumor, aphrodisiac, and cardiovascular protection activities. Due to the biological and nutritional importance of nutraceuticals, particularly ashwagandha, and as part of the ongoing research of the natural products and its bioactive phytochemicals, this review aims to summarize the recent analytical techniques that have been reported for the determination of different chemical constituents of Withania somnifera quantitatively and qualitatively, and to highlight new challenges.
... It is a medicinal plant endemic to Ethiopia, locally called ameraro, used for the treatment of schistosomiasis, leprosy, and stomach-ache [2]. Plants in the family Solanaceae are rich sources of withanolides [3], a group of compounds with oxygenated ergostane type steroidal structure with an α-lactone ring in the side chain and a 2-en-1-one system in ring A. These compounds exhibit a range of bioactivities, including immunomodulatory, antibacterial, antiinflammatory, and cytotoxic activities [4]. A literature survey on phytochemical studies of D. penninervium has shown that different withanolides have been isolated earlier from different parts of the plant [5 -7]. ...
Discopodium penninervium is a medicinal plant endemic to Ethiopia. Its twigs extract led to the isolation of three new withanolides, discopodinolides A - C, and four known analogues. The structures of the compounds were elucidated using NMR, HRMS data analyses, and literature data. The relative configurations were defined by single-crystal X-ray crystallography and NOESY correlations. The antibacterial efficacy of the isolated compounds was evaluated against four commonly dispersed environmental strains of Escherichia coli, Bacillus subtilis, Bacillus pumilus, and Bacillus megaterium. Discopodinolides B and C exhibited moderate antibacterial activities against the pathogenic strains of E. coli, B. subtilis, and B. megaterium.
... As part of the discovery strategies to search for new bioactive compounds from plant biodiversity, phytochemical and pharmacological studies have shown a series of promising metabolites with potential antitumor effects in in vitro tests (6). Pharmacological studies involving the class of withanolides metabolites, which are natural steroidal lactone triterpenoids, have suggested potential anticancer properties in human cancer cells in vitro, as well as tumor angiogenesis and metastasis suppression effects (7)(8)(9) via production of ROS, interference on cell cycle or cytoskeleton destabilization (10,11). However, the molecular mechanism by which withanolides inhibit the proliferation of human cancer cells is still largely unknown. ...
Background/aim:
Aurelianolide A and B were identified and isolated from Aureliana fasciculata var. fasciculata leaves. Withanolides are naturally occurring C-28 steroidal lactone triterpenoids with cytotoxic and anticancer properties, among other relevant pharmacological activities. Herein we have described, for the first time, the cytotoxic effects of aurelianolides on human cancer cells.
Materials and methods:
Aurelianolide A and B were tested on human leukemia cell lines: THP-1, MOLT-4, Jurkat, K562 and K562-Lucena 1.
Results:
For aurelianolide A, MOLT-4 had the lower IC50 (1.17 μM) and for aurelianolide B, Jurkat was the most susceptible cell line (IC50 2.25 μM). On the other hand, the multidrug resistant (MDR) cell line K562-Lucena 1 showed higher IC50 for both aurelianolides. Using 293T, a non-tumor embryonic kidney cell line, we observed an excellent selectivity index for both aurelianolides, from 2.24 (aurelianolide B in K562-Lucena 1) to 45.5 (aurelianolide A in MOLT-4). Aurelianolide A and B activated caspase 3/7 with consequent induction of apoptosis on Jurkat and K562-Lucena 1 cell lines. We have not observed induction of necrosis.
Conclusion:
Aurelianolides A and B have important cytotoxic effects on human leukemia cell lines by the activation of the caspase pathway.
... The differences in the chemical structure of withanolides have received noteworthy attention for their diverse biological effects in vitro and in vivo against cancer, inflammation, stress, microbes, and neurodegenerative conditions. Approximately 900 withanolides have been found in the last 50 years, with 24 different structural variations [64,65]. Several withanolides, including chantriolide A, physalins A, B, C, and O, viscosalactone B, withanolides D, E, and F, and withaferin A-diacetate, a diacetyl derivative of withaferin A, show anticancer properties against a variety of cancer cells [66][67][68]. ...
Cancer represents the second most deadly disease and one of the most important public health concerns worldwide. Surgery, chemotherapy, radiation therapy, and immune therapy are the major types of treatment strategies that have been implemented in cancer treatment. Unfortunately, these treatment options suffer from major limitations, such as drug-resistance and adverse effects, which may eventually result in disease recurrence. Many phytochemicals have been investigated for their antitumor efficacy in preclinical models and clinical studies to discover newer therapeutic agents with fewer adverse effects. Withaferin A, a natural bioactive molecule isolated from the Indian medicinal plant Withania somnifera (L.) Dunal, has been reported to impart anticancer activities against various cancer cell lines and preclinical cancer models by modulating the expression and activity of different oncogenic proteins. In this article, we have comprehensively discussed the biosynthesis of withaferin A as well as its antineoplastic activities and mode-of-action in in vitro and in vivo settings. We have also reviewed the effect of withaferin A on the expression of miRNAs, its combinational effect with other cytotoxic agents, withaferin A-based formulations, safety and toxicity profiles, and its clinical potential.
... Several withanolides have been obtained and characterized over the past five decades. This type of steroid has attracted significant attention from numerous researchers, not only because of its complex structural features but because of its multiple bioactivities and potential in drug research and development (Ichikawa et al. 2006, Misra et al. 2008, Chen et al. 2011, Dar et al. 2015, Ahmad and Dar 2017. More than 12 alkaloids, 40 withanolides, and quite a few sitoindosides have been reported from this plant species (Mishra et al. 2000, Mirjalili et al. 2009a). ...
The journey of drug discovery from plant natural products is practiced from the development of first medicine, morphine and still continuing in the modern era. The plant Withania somnifera (Ashwagandha), known as Indian Ginseng is one of the most reputed medicinal plants of Ayurveda, principally due to the presence of steroidal lactone, collectively known as withanolides. The withanolides are C-28 steroidal lactone triterpenoids having ergostane structure backbone. In this structure, six membered lactone ring was formed after the oxidation of C-22 and C-26 carbon atoms. Among various withanolides, withaferin A, withanolide A and withanone are the most abundant. The withanolides has been well studied for its antiserotogenic, addaptogenic, neuroprotective and anticancer activity in addition to widely known for their antioxidant, anti-inflammatory, immunomodulating, anti-stress and rejuvenating properties. The industrial demand of dried plant material with respect to withanolide drugs preparation from this species is increasing gradually which fail to meet the current ashwagandha global market by our conventional cultivation method due to a range of issues such as low seed viability and poor germination, biotic and abiotic environmental factors, soil ecological factors fail to maintain uniform withanolide synthesis, accumulate and moreover, these methods are time consuming and laborious. Under such circumstances, biotechnological advances must be adopted to increase the yield for the continuous supply of bioactive compounds. In vitro cell, tissue and organ culture could offer an alternative to field-grown plants for seasonal independent production of cellular biomass in a large scale which will deliver an adequate number of raw materials of uniform quality for pharmaceutical purposes. Other biotechnological methods are also involved such as the application of various elicitors, feeding of precursor molecules, genetic transformation particularly hairy root culture, genetic engineering specifically metabolic engineering and exploitation of bioreactor technology for quality production in huge quantity.
... Plants from of the species Physalis displays a broad wide variety of biological works but instead pharmacological effects, viz., anti-in lammatory, immuno-modulatory, antitumor, antioxidant and hypoglycemic activities [4]. Pharmacological studies with plants from genus Physalis [5] indicate the presence of natural withanolides besides other secondary metabolites [6]. ...
A Plants have been exploited for the bene it of humankind to cure diseases/ ailments since prehistoric times. Plant medicinal importance is due to secondary metabolites endowed with speci ic biochemical/ metabolic/ physiological action on the human/ animal system. A wide variety of functional activities has been attributed to the secondary metabolites or plant-based natural products (PBNPs) that cure common illnesses to cure chronic disorders and their associated long-term complications. PBNPs are bioactive compounds that serve as promising lead molecules for drug development and design. Plants from the family Solanaceae are well-known as common vegetables. Phytochemical analysis of P. minima ethanolic leaf extracts (PMELE) acknowledged an existence of alkaloids, glycosides (anthraquinone, cardiac), carbohydrates, phytosterols, lavonoids, amino acids, tannins, but instead saponins. Additional, GCMS analysis con irmed the involvement of bioactive compounds viz, cyclobutanol; D-Alanine; 2-Heptanol, 6-Amino-2-Methylnh2; 1-Pentanol, 4-Aminonh2; Benzeneethanamine, 3-Fluoro-β.,5-Dihydroxy-N-Methylf; L-Alanine, N-(N-Acetyl-glycyl)-, Butyl Ester respectively. From the study, it is evident that P. minimise is a reservoir of phytochemicals which has been acknowledged by its therapeutic potential through ethnomedicinal uses.
... Withanolides are C28 steroids that occur naturally. Their structure is based on an ergostane skeleton in which C-26 and C-22, or C-26 and C-23, are oxidized to form either delta lactone (Type A) or gamma lactone (Type B), respectively [18]. The axonal outgrowth of normal cortical neurons after WA treatment has been reported [12]. ...
Objective: Circadian rhythms are present almost in all living organisms and synchronized with the zeitgebers (time givers), especially lightdark (LD) cycles. The jetlag and rotating shift work schedules lead to desynchronization of the circadian clock with zeitgebers which may cause various health problems. Studies have shown that withanolide-A (WA) is a potent nootropic and neuroprotective agent found in Withania somnifera. Thus, the objective was to study the effect of WA on the circadian locomotor activity rhythm following the phase inversion of 12:12 h LD cycle in mice and its impact on the spatial memory in mice.Methods: Adult male mice were housed in the chronocubicle and recorded circadian locomotor activity rhythm by using ClockLab setup. The experimental mice were administered with WA (10 μmol/kg/day) for 13 consecutive days at about ZT15 and then evoked an acute phase inversion of 12:12 h light-dark cycle. Further, the Barnes maze test was performed to check the effect of WA on spatial memory following the phase inversion.Results: The results showed that WA-treated group took significantly fewer transient cycles (4.66+0.66) for re-entrainment than the control (9.5+0.43) and vehicle-treated (8.33+1.28) mice following the phase inversion. Similarly, WA-treated mice traveled less distance to reach the target zone in the Barnes maze compared to vehicle and control groups.Conclusion: These results suggest that the WA may act as chronobiotic and neuroprotective agent since it decreased the transient cycles for re-entrainment and retaining spatial memory following the phase inversion.
... Withametelin and daturaolone (Baig et al., 2021) were isolated in our previous studies. Withametelins is a subclass of withanolides mainly found in Datura genus (Chen et al., 2011;Muhammad et al., 2021). Withametelin possess antifungal (Singh et al., 2001) cytotoxicity against lung (Rao et al., 2016), liver, prostate and mammary cell lines . ...
Safe preclinical dose determination is predictive of human toxicity and can have a profound impact on the overall progress of the compound in early drug discovery process. In this respect, current study sought to investigate for the first time the acute and subacute oral toxicity of two pharmacologically active natural compounds i.e., withametelin and daturaolone in Sprague Dawley rats following OECD guideline 420 and 407, respectively. As per acute toxicity studies, withametelin and daturaolone were characterized as Globally Harmonized System (GHS) category 4 and 5 compounds, respectively. Sub-acute daily dose of withametelin was 5, 2.5, and 1.25 mg/kg but, for daturaolone, it was 10, 5, and 2.5 mg/kg. High dose (5 and 2.5 mg/kg) withametelin groups showed dose dependent changes in the general, hematological, biochemical and histopathological parameters in both sexes, the most prominent being hyperthyroidism while no toxicity was observed at lower doses (1.25 and 0.75 mg/kg), No Observable Adverse Effect Level (NOAEL) being 1.25 mg/kg. Daturaolone was comparatively safer and showed dose dependent significant changes in hepatic enzyme (Alanine Transaminase), bilirubin, creatinine, and glucose levels while histological changes in testes were also observed. Lower doses (5, 2.5, and 1.25 mg/kg) of daturaolone showed no significant toxic effects and 5 mg/kg was declared as its NOAEL. Depending upon our findings, starting effective oral dose levels of 1.25 mg/kg/day for withametelin and 5 mg/kg/day for daturaolone are proposed for repeated dose (up to 28 days) preclinical pharmacological evaluation models. Long term studies with more behavioral, biochemical, histopathological and hormonal parameters are proposed to strengthen the findings. (2022), Toxicity evaluation induced by single and 28-days repeated exposure of withametelin and daturaolone in Sprague Dawley rats. Front. Pharmacol. 13:999078.
... Ashwagandha root extract contains the major active phytoconstituents like withanolides, withanamides, alkaloids, sitoindosides, reducing sugars, starch, peroxidases, glycosides, withanicil, benzyl alcohol, dilcitol, 2-phenyl ethanol, 3,4,5-trihydroxy cinnamic acid, phenyl acetic acid, benzoic acid, etc [7][8][9]. Withanolides have various pharmacological activities in the body include immunomodulating, anti-inflammatory, neuroprotective, memory loss, hepatoprotective, antioxidant, hypoglycaemic, gastrointestinal issues, constipation, antiarthritic, antimicrobial, anticancer, insomnia, skin conditions, Alzheimer's, Huntington's, and Parkinson's disorders, etc. [3][4][5][6][10][11][12]. Therefore, ashwagandha root extract used in many nutraceutical and pharmaceutical formulations as a supplement for the prevention and treatment of various human disorders. ...
Ashwagandha (Withania somnifera) extract is a popular health supplement, used in many nutraceutical and pharmaceutical formulations for good health benefits along with the prevention and treatment of various human diseases. The purpose of this study was to evaluate the impact of The Trivedi Effect®-Consciousness Energy Healing Treatment on the characteristic properties of the phyto-compounds present in the ashwagandha root extract using LC-MS, GC-MS, and NMR spectroscopy. Ashwagandha root extract was divided into two parts, one part of the sample was termed as untreated/control sample, while the other part of the sample received The Trivedi Effect®-Biofield Energy Healing Treatment remotely by a renowned Biofield Energy Healer, Mr. Mahendra Kumar Trivedi and termed as Biofield Energy Treated sample. The LC-ESI-MS data revealed that the chromatographic peak area% of the phytoconstituents present in the treated sample was significantly altered in the range of 31.13% to 20.61% compared to the control sample. Similarly, the average peak area of the treated sample was significantly improved by 20.61% compared to the control sample. A total of 14 withanolides such as viscosa lactone B, dihydrowithanolide D, withanolide A, withanolide B, etc. were proposed with m/z 489, 473, 471, and 455 at the retention times (Rt ) of 13.2, 14.5, 14.8, and 18.2 minutes, respectively. At Rt 13.2 minutes (m/z: 489), the peak area% and mass peak intensity of the phytocompound in the treated ashwagandha were significantly increased by 2.57% and 14.83%, respectively compared with the control sample. Similarly, at Rt 14.5 minutes (m/z: 473), peak area% was increased by 3.76%, but the mass peak intensity was significantly decreased by 26.48% in the treated sample compared with the control sample. At Rt 14.8 minutes (m/z: 471), peak area % was same, but the mass peak intensity was increased by 2.74% in the treated ashwagandha compared with the control sample. Subsequently, at Rt 18.2 minutes (m/z: 455), peak area% was increased 1.01%, whereas the peak intensity was significantly decreased by 10.90% in case of the treated sample compared to the control sample. These findings intensify to assume that The Trivedi Effect®-Consciousness Energy Healing Treatment might be responsible for the overall improvement of relative concentrations and altered relative abundance of the phytoconstituents in the ashwagandha root extract compared to the control sample. This Biofield Energy Treated ashwagandha root extract would be helpful to design better nutraceutical/pharmaceutical formulations against inflammatory diseases, immunological disorders, sexual disorders, arthritis, stress, cancer, diabetes, aging, and other chronic infections.
... The undesirable side effects of synthetic AGIs on patients thus motivated scientists to find alternative plant-based treatments for treating and managing DM. In fact, certain natural compounds have been found effective as a-amylase and a-glucosidase inhibitors, particularly Withanolides, a family of steroidal lactones (Chen et al., 2011;Oboh et al., 2016). These pharmaceutically active compounds were discovered in a medicinal plant called Withania somnifera, commonly known as 'Ashwagandha' or 'Indian ginseng'. ...
Diabetes mellitus (DM) is a global chronic disease characterized by hyperglycemia and insulin resistance. The unsavory severe gastrointestinal side-effects of synthetic drugs to regulate hyperglycemia have warranted the search for alternative treatments to inhibit the carbohydrate digestive enzymes (e.g. α-amylase and α-glucosidase). Certain phytochemicals recently captured the scientific community's attention as carbohydrate digestive enzyme inhibitors due to their low toxicity and high efficacy, specifically the Withanolides-loaded extract of Withania somnifera. That said, the present study evaluated in silico the efficacy of Withanolide A in targeting both α-amylase and α-glucosidase in comparison to the synthetic drug Acarbose. Protein-ligand interactions, binding affinity, and stability were characterized using pharmacological profiling, high-end molecular docking, and molecular-dynamic simulation. Withanolide A inhibited the activity of α-glucosidase and α-amylase better, exhibiting good pharmacokinetic properties, absorption, and metabolism. Also, Withanolide A was minimally toxic, with higher bioavailability. Interestingly, Withanolide A bonded well to the active site of α-amylase and α-glucosidase, yielding the lowest binding free energy of −82.144 ± 10.671 kcal/mol and −102.1043 ± 11.231 kcal/mol compared to the Acarbose-enzyme complexes (−63.220 ± 13.283 kcal/mol and −82.148 ± 10.671 kcal/mol). Hence, the findings supported the therapeutic potential of Withanolide A as α-amylase and α-glucosidase inhibitor for DM treatment.
... Physalis peruviana L. is an edible Solanaceae plant [5] and functions as a traditional medicine in Asia and South America [6]. P. peruviana is rich in withanolides [7] and shows anticancer effects [8][9][10][11]. ...
Physalis peruviana-derived physapruin A (PHA) is a potent compound that selectively generates reactive oxygen species (ROS) and induces cancer cell death. Autophagy, a cellular self-clearance pathway, can be induced by ROS and plays a dual role in cancer cell death. However, the role of autophagy in PHA-treated cancer cells is not understood. Our study initially showed that autophagy inhibitors such as bafilomycin A1 enhanced the cytotoxic effects of PHA in breast cancer cell lines, including MCF7 and MDA-MB-231. PHA treatment decreased the p62 protein level and increased LC3-II flux. PHA increased the fluorescence intensity of DAPGreen and DALGreen, which are used to reflect the formation of autophagosome/autolysosome and autolysosome, respectively. ROS scavenger N-acetylcysteine (NAC) decreased PHA-elevated autophagy activity, implying that PHA-induced ROS may be required for autophagy induction in breast cancer cells. Moreover, the autophagy inhibitor increased ROS levels and enhanced PHA-elevated ROS levels, while NAC scavenges the produced ROS resulting from PHA and autophagy inhibitor. In addition, the autophagy inhibitor elevated the PHA-induced proportion of annexin V/7-aminoactinmycin D and cleavage of caspase-3/8/9 and poly (ADP-ribose) polymerase. In contrast, NAC and apoptosis inhibitor Z-VAD-FMK blocked the proportion of annexin V/7-aminoactinmycin D and the activation of caspases. Taken together, PHA induced ROS to promote autophagy, which might play an antioxidant and anti-apoptotic role in breast cancer cells.
... 3 The most typical secondary metabolites in this genus are withanolides, which are a class of naturally occurring C 28 steroidal lactones with an ergostane skeleton, in which C-26 and C-22 or C-23 are commonly oxidized to form a δ or γ-lactone ring. 4 The withanolides are divided into at least 22 subtypes according to their different modified skeletons. One subtype called withaphysalins is characterized by the oxidation of C-18 to an aldehyde or acid, which then cyclizes with OH-20 to afford a hemiacetal, an acetal, or a lactone. ...
... 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). ...
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.
Two new withanolides, (17R,20S,22R)-4β-acetoxy-5β,6β-epoxy-27-hydroxy-1-oxo-witha-2,24-dienolide (5) and (17R,20S,22R)-5β,6β-epoxy-27-hydroxy-1,4-dioxo-witha-24-enolide (9), and seven known withanolides with normal structure (3-9) were isolated from aerial parts of Cuatresia colombiana. Several semisynthetic derivatives were prepared from the natural metabolites withaferin A and jaborosalactone 38. The compounds were fully characterized by a combination of spectroscopic methods (1D and 2D NMR and MS). The compounds isolated from C. colombiana, sixteen withanolides previously isolated from different Solanaceae species with different skeletons and semisynthetic derivatives, were evaluated for their antibacterial activity against a selected panel of Gram-positive and Gram-negative bacteria. According to the bioactivity against S. aureus and E. faecalis, the compounds evaluated were divided into three groups: compounds with high activity (MIC 0.063 mM), compounds with moderate activity (0.5 mM > MIC > 0.125 mM) and non-active compounds (MIC ≥ 1 mM); in addition, some structure-activity relationship keys could be inferred.
The investigation of the chemical constituents of Datura ceratocaula and D. discolor allowed to isolate three new withanolides, datucerolide A (1) from the first species, and datudiscolides A (8) and B (9) from the second. In addition, seven known withanolides and five ubiquitous compounds were isolated from these plants, along with 27-O-β-d-glucopyranosyl dinnoxolide A (5), which was obtained as the tetraacetyl derivative 4. All the structures were elucidated by analyses of their spectroscopic and spectrometric data and that of dinnoxolide A (6) was confirmed by X-ray diffraction analysis. The structure 4 was assigned earlier to daturametelin G-Ac and that of 5 to datinolide B, therefore, it will be discussed whether these assignments are correct. On the other hand, the structure of datudiscolide A (8) was previously assigned to the aglycone of dinoxin B (14), however, a revision of its reported NMR data showed inconsistencies with the proposed structure. The inhibitory activity of withanolides 2, 3, 6-8, 12, and 13 against acetylcholinesterase enzyme (AChE) was evaluated. Compounds 6, 7, 12, and 13 exhibited the best activity with IC50 values ranging from 2.8 to 21.5 μM.
Mycobacterium tuberculosis (Mtb) is one of the major causes of death worldwide and there is a pressing need for the development of novel drug leads. The Imidazole Glycerol Phosphate Dehydratase (IGPD) of Mtb is one of the key enzymes in the histidine biosynthesis pathway and has been recognized as the potentially underexploited drug target for anti-tuberculosis treatment. In the present study, 6063 structurally diverse plant secondary metabolites (PSM) were screened for their efficiency in inhibiting the catalytic activity of IGPD through molecular docking. The top 150 PSMs with the lowest binding energy represent the chemical classes, including Tannins (34%), Flavonoid Glycosides (14%), Terpene Glycosides (10%), Steroid Lactones (9.3%), Flavonoids (6.6%), Steroidal Glycosides (4.6%), etc. Bismahanine, Ashwagandhanolide, and Daurisoline form stable IGPD-inhibitor complexes with binding free energies of -291.3 ± 16.5, -279.0 ± 25.0, and -279.8 ± 17.6 KJ/mol, respectively, as determined by molecular dynamics simulations. These PSM demonstrated strong H-bond interactions with the amino acid residues Ile279, Arg281, and Lys276 in the catalytic region of IGPD, as revealed by structural snapshots. On the basis of our findings, these three PSM could be considered as possible leads against IGPD and should be explored in vitro and in vivo.Communicated by Ramaswamy H. Sarma.
The present volume is the third in a trilogy that documents naturally occurring organohalogen compounds, bringing the total number—from fewer than 25 in 1968—to approximately 8000 compounds to date. Nearly all of these natural products contain chlorine or bromine, with a few containing iodine and, fewer still, fluorine. Produced by ubiquitous marine (algae, sponges, corals, bryozoa, nudibranchs, fungi, bacteria) and terrestrial organisms (plants, fungi, bacteria, insects, higher animals) and universal abiotic processes (volcanos, forest fires, geothermal events), organohalogens pervade the global ecosystem. Newly identified extraterrestrial sources are also documented. In addition to chemical structures, biological activity, biohalogenation, biodegradation, natural function, and future outlook are presented.KeywordsChlorineBromineIodineFluorineOrganohalogenHeterocyclesPhenolsTerpenesPeptidesAlkaloidsMarineTerrestrialExtraterrestrialBacteriaFungiBiological activityBiohalogenationBiodegradationNatural function
Chemical investigation of the deep-sea-derived fungus Hypocrea sp. ZEN14 afforded a new 3α-hydroxy steroidal lactone, hyposterolactone A (1) and 25 known secondary metabolites (2-26). The structure of the new compound was established by detailed spectroscopic analysis, electronic circular dichroism (ECD) calculation as well as a J-based configuration analysis. Compound 10 showed potent cytotoxicity against Huh7 and Jurkat cells with IC50 values of 1.4 μM and 6.7 μM, respectively.
The withanolides are naturally occurring steroidal lactones found mainly in plants of the Solanaceae family. The subtribe Withaninae includes species like Withania sominifera, which are a source of many bioactive withanolides. In this work, we selected and evaluate the ADMET-related properties of 91 withanolides found in species of the subtribe Withaninae computationally, to predict the relationship between their structures and their pharmacokinetic profiles. We also evaluated the interaction of these withanolides with known targets of Alzheimer’s disease (AD) through molecular docking and molecular dynamics. Withanolides presented favorable pharmacokinetic properties, like high gastrointestinal absorption, lipophilicity (logP ≤ 5), good distribution and excretion parameters, and a favorable toxicity profile. The specie Withania aristata stood out as an interesting source of the promising withanolides classified as 5-ene with 16-ene or 17-ene. These withanolides presented a favourable pharmacokinetic profile and were also highlighted as the best candidates for inhibition of AD-related targets. Our results also suggest that withanolides are likely to act as cholinesterase inhibitors by interacting with the catalytic pocket in an energy favorable and stable way.
Communicated by Ramaswamy H. Sarma
A novel coronavirus strain (COVID-19) caused severe illness and mortality worldwide from 31 December 2019 to 21 March 2023. As of this writing, 761,071,826 million cases have been diagnosed worldwide, with 6,879,677 million deaths accorded by WHO organization and has spread to 228 countries. The number of deaths is closely connected to the growth of innate immune cells in the lungs, mainly macrophages, which generate inflammatory cytokines (especially IL-6 and IL-1β) that induce “cytokine storm syndrome” (CSS), multi-organ failure, and death. We focus on promising natural products and their biologically active chemical constituents as potential phytopharmaceuticals that target virus-induced pro-inflammatory cytokines. Successful therapy for this condition is currently rare, and the introduction of an effective vaccine might take months. Blocking viral entrance and replication and regulating humoral and cellular immunity in the uninfected population are the most often employed treatment approaches for viral infections. Unfortunately, no presently FDA-approved medicine can prevent or reduce SARS-CoV-2 access and reproduction. Until now, the most important element in disease severity has been the host’s immune response activation or suppression. Several medicines have been adapted for COVID-19 patients, including arbidol, favipiravir, ribavirin, lopinavir, ritonavir, hydroxychloroquine, chloroquine, dexamethasone, and anti-inflammatory pharmaceutical drugs, such as tocilizumab, glucocorticoids, anakinra (IL-1β cytokine inhibition), and siltuximab (IL-6 cytokine inhibition). However, these synthetic medications and therapies have several side effects, including heart failure, permanent retinal damage in the case of hydroxyl-chloroquine, and liver destruction in the case of remdesivir. This review summarizes four strategies for fighting cytokine storms and immunomodulatory deficiency induced by COVID-19 using natural product therapy as a potential therapeutic measure to control cytokine storms.
Six new withanolides, angulasteroidins A-F (1-6), along with twelve known analogues (7-18) were isolated from the whole plants of Physalis angulata. Their structures were elucidated by analysis of 1D and 2D NMR, ECD spectra and HRESIMS data. Compounds 2-4, 7-9, and 15 exhibited significantly inhibitory activity on the production of nitric oxide in the LPS-activated RAW 264.7 mouse macrophage cell line with IC50 values ranging from 0.23 to 9.06 μM.Six new withanolides, angulasteroidins A-F (1-6), along with twelve known analogues (7-18) were isolated from the whole plants of Physalis angulata . Their structures were elucidated by analysis of 1D and 2D NMR, ECD and IR spectra, HRESIMS data, and ECD calculation. Compounds 1 and 6 were rare 1-10 seco withanolides. Compounds 2-4, 7-9, and 15 exhibited significant inhibitory activity on the production of nitric oxide in the LPS-activated RAW 264.7 mouse macrophage cell line with IC50 values ranging from 0.23 to 9.06 μM.
Alzheimer’s Disease is a prominent neurodegenerative disorder affecting the age group 60 and above. Cholinergic hypothesis, amyloid β cascade, oxidative stress is some of the known etiologies of marked importance to name a few. We have undertaken a computational analysis where fifteen phytochemicals were selected. These natural molecules were studied and analysed against acetylcholinesterase, butyrlcholinesterase, BACE and amyloid β monomer and protofibril. The binding affinities of Genistein, Huperzine A, kaempferol, Methyl quercetin, Paclitaxel and Withinolide A against AChE and BuChE enzymes were found to be -7.7 to -8.6 Kcal/mol, respectively. Various phytochemicals like Genistein, kaempferol, Piceatannol, Ginkgolide B, Methyl quercetin and Withinolide A were found to bind the BACE-1 enzyme with the binding affinities of -6.7 to -7.9 Kcal/mol. All the phytochemicals experienced efficient binding towards Aβ monomer and Aβ protofibril. Withinolide A was found to bind all the PDB’s efficiently with binding affinity of -8.4, -8.9, -7.7, -6.6 and -6.8 Kcal/mol against AChE enzyme, BuChE enzyme, BACE-1 enzyme, Aβ monomer and Aβ protofibril, respectively as a result it can be carried forward for the further preclinical and clinical studies.
Leishmaniasis is a group of infectious diseases caused by Leishmania protozoa. The ineffectiveness, high toxicity, and/or parasite resistance of the currently available antileishmanial drugs has created an urgent need for safe and effective leishmaniasis treatment. Currently, the molecular-docking technique is used to predict the proper conformations of small-molecule ligands and the strength of the contact between a protein and a ligand, and the majority of research for the development of new drugs is centered on this type of prediction. Leishmania N-myristoyltransferase (NMT) has been shown to be a reliable therapeutic target for investigating new anti-leishmanial molecules through this kind of virtual screening. Natural products provide an incredible source of affordable chemical scaffolds that serve in the development of effective drugs. Withania somnifera leaves, roots, and fruits have been shown to contain withanolide and other phytomolecules that are efficient anti-protozoal agents against Malaria, Trypanosoma, and Leishmania spp. Through a review of previously reported compounds from W. somnifera-afforded 35 alkaloid, phenolic, and steroid compounds and 132 withanolides/derivatives, typical of the Withania genus. These compounds were subjected to molecular docking screening and molecular dynamics against L. major NMT. Calycopteretin-3-rutinoside and withanoside IX showed the highest affinity and binding stability to L. major NMT, implying that these compounds could be used as antileishmanial drugs and/or as a scaffold for the design of related parasite NMT inhibitors with markedly enhanced binding affinity.
For the first time, an effort was made to study potential effects of leaf and stem explants of three genotypes of Withania somnifera (L.) Dunal (i.e., G1, G2, and G3) for hairy root induction via applying four strains of Agrobacterium rhizogenes (i.e., LBA 9402, A4, and ATTC 15834) and A. tumefaciens (i.e., C58C1). Furthermore, to improve withaferin A production, the superior treatment was subjected to elicitation with β-cyclodextrin (β-CD) and methyl jasmonate (MeJA) (alone or in combination) after 48 h exposure time. Among 24 treatments resulted from multiplying three main factors, the superiority of “G3/ATCC/LEAF” treatment was verified in terms of “ induction rate ” and “ number of induced roots ” alongside “ growth curve ”, and utilized subsequently for elicitation assay. The highest amounts of withaferin A were quantified for both hairy root sample groups of “0.5 mM β-CD + 100 µM MeJA” (9.57 mg/g DW) and “5.0 mM β-CD + 100 µM MeJA” (17.45 mg/g DW), with the fold change values of 6.84-fold and 12.46-fold compared to control, respectively. Similarly, either individual or simultaneous applications of both elicitors, apart from some fluctuations, could overall boost transcript magnitudes of the four selected genes of HMGR , SQS , SMT-1 , and SDS/CYP710A involved in withanolides biosynthetic pathway as compared with control. The results, altogether, demonstrated the superiority of leaf explant and Agropine-type strain of ATCC 15834 for hairy root induction, followed by synergistic effect of exogenous application of both MeJA and β-CD on the in vitro production of withaferin A, and possibly other types of withanolides in the hairy root culture of W. somnifera .
A pulldown using a biotinylated natural product of interest in the 17β-hydroxywithanolide (17-BHW) class, physachenolide C (PCC), identified the bromodomain and extra-terminal domain (BET) family of proteins (BRD2, BRD3, and BRD4), readers of acetyl-lysine modifications and regulators of gene transcription, as potential cellular targets. BROMOscan bromodomain profiling and biochemical assays support PCC as a BET inhibitor with increased selectivity for bromodomain (BD)-1 of BRD3 and BRD4, and X-ray crystallography and NMR studies uncovered specific contacts that underlie the potency and selectivity of PCC toward BRD3-BD1 over BRD3-BD2. PCC also displays characteristics of a molecular glue, facilitating proteasome-mediated degradation of BRD3 and BRD4. Finally, PCC is more potent than other withanolide analogues and gold-standard pan-BET inhibitor (+)-JQ1 in cytotoxicity assays across five prostate cancer (PC) cell lines regardless of androgen receptor (AR)-signaling status.
Physapruin A (PHA), a Physalis peruviana-derived withanolide, exhibits antiproliferation activity against oral and breast cancer cells. However, its potential antitumor effects in combined treatments remain unclear. This investigation focused on evaluating the impact of the combined treatment of ultraviolet-C with PHA (UVC/PHA) on the proliferation of oral cancer cells. The UVC-caused antiproliferation was enhanced by combination with PHA in oral cancer (Ca9-22 and CAL 27) but not normal cells (SG), as evidenced by ATP detection, compared with UVC or PHA alone. UVC/PHA showed a greater extent of subG1 increase, G2/M arrest, annexin-V-assessed apoptosis, caspase 3/7 activation, and reactive oxygen species (ROS) in the UVC or PHA treatment of oral cancer compared to normal cells. Moreover, the mitochondrial functions, such as mitochondrial superoxide bursts and mitochondrial membrane potential destruction, of oral cancer cells were also enhanced by UVC/PHA compared to UVC or PHA alone. These oxidative stresses triggered γH2AX and 8-hydroxyl-2’-deoxyguanosine-assessed DNA damage to a greater extent under UVC/PHA treatment than under UVC or PHA treatment alone. The ROS inhibitor N-acetylcysteine reversed all these UVC/PHA-promoted changes. In conclusion, UVC/PHA is a promising strategy for decreasing the proliferation of oral cancer cells but shows no inhibitory effect on normal cells.
The genus Datura has been used as an important traditional medicine in China, as well as in other countries worldwide. This review summarizes the latest progress and perspective of the genus Datura, from the aspects of botany, traditional uses, phytochemistry, pharmacology, and toxicology. Up to May 2022, literatures were collected from online scientific databases, including Google Scholar, PubMed, SciFinder, CNKI, ACS, and Web of Science, and information was also obtained from “Flora Republicae Populairs Sinicae”, Chinese Pharmacopoeia, Chinese herbal classic books, and Ph.D. and M. Sc. dissertations. Studies on chemical constituents, pharmacological activities, and toxicity are mainly focused on D. metel, D. stramonium, and D. inoxia. Furthermore, 496 compounds have been discovered from the genus Datura, including withanolides, alkaloids, flavonoids, terpenoids, phenylpropanoids, steroids, amino acids, aromatics, and aliphatics. Among them, withanolides and alkaloids are two main active constituents. Pharmacological activities of extracts and compounds have been studied from the aspects of antitumor, antiinflammation, antioxidant, antimicrobial, antispasmodic, anticoagulant, analgesic, hypoglycemic and xanthine oxidase inhibitory activities, as well as the effects on central nervous system and immune system. Modern pharmacological studies have provided more clues to elucidate the traditional usages. The toxicity of the genus Datura is noteworthy, especially the potential toxicity on organs. This review would provide a comprehensive and constructive overview for new drug development and utilization of the genus Datura.
Lysine specific demethylase 1 (LSD1), which is overexpressed in several human cancers and acts as a demethylase of histone 3, lysine 4 and lysine 9, has become an attractive therapeutic target for cancer therapy. Based on our previous systematic studies, withanolides are important secondary metabolites mostly from the Solanaceae family of plants, which are crucial agents for cancer treatment. Here, withanolides were characterized as LSD1 inhibitors, especially withaferin A, with an IC50 value of 3.04 μM. In vitro bioactivity assays and virtual molecular docking indicated that withaferin A could inhibit MDA-MB-231 cell migration by inhibiting intracellular LSD1 activity. These findings provide a new withanolide-based natural molecular skeleton for LSD1 inhibitors with potential antitumor activity.
Withajardins, uncommon modified withanolide-type steroids, have been isolated exclusively from plants of the Solanaceae family so far. Two undescribed withajardins and the known tuboanosigenin were isolated from the hexane/EtOAc 1:1 extract from Athenaea velutina leaves. Their structures were established by an extensive analysis of 1D and 2D-NMR and HRMS data. The absolute configuration was determined by X-ray diffraction (withajardin L and tuboanosigenin) and circular dichroism (CD) analyses (withajardin M). The anti-inflammatory activity of compounds was evaluated through the inhibition of the lipopolysaccharide (LPS)-induced nitric oxide (NO), TNF-α, and IL-6 release in RAW264.7 cells. The cell viability effects to RAW 264.7 cells showed IC50 values of 74.4–354.4 μM. The compounds attenuated LPS-induced release of NO and decreased pro-inflammatory cytokines TNF-α and IL-6 in RAW264.7 cells.
Two new withaphysalin-type withanolides (18-O-ethylwithaphysalin R and 5-O-ethylphysaminimin C, 1 and 2), along with twelve known withanolides (3-14), were purified and identified from Physalis peruviana L. The chemical structures of these new isolates were elucidated through analyzing spectroscopic and HRESIMS data. All the obtained metabolites were appraised for their potential antiproliferative activity against the human breast cancer cell line MCF-7. Compound 7 was discovered to exhibit potent activity with an IC50 value of 3.51 µM and compounds 2, 6 and 14 showed weak cytotoxic effect.
Eight undescribed and two known withanolides were obtained from the aerial parts of Physalis minima. The structures of these compounds were defined by spectroscopic methods including 1D and 2D NMR, HRESIMS, and electronic circular dichroism (ECD) data analysis. Physminin E was elucidated to be a rare 13,14-seco-withanolide. Inhibitory effects of these compounds on nitric oxide (NO) production were evaluated by using LPS-activated RAW264.7 macrophages, and physminin C was shown to be the most active with an IC50 value of 3.5 μM. The further mechanistic analysis of NO inhibition was performed by molecular docking and Western blotting.
Withania somnifera is a miracle medicinal crop used traditionally in Ayurveda and Siddha for treating various diseases in South Asia. The root is the principal productive part of the Ashwagandha plant employed widely in the Indian system of medicine. The root is having potential medicinal properties and contains several alkaloids. One of the major alkaloids, Withanoloides, helps improving reproductive system in men and women, antistress, antioxidant, antiaging, diuretic, hypothyroid, immunomodulatory, antidementia, antihyperglycemic, anti-hypercholesterolemic, and cardiovascular activity. Leaves contain Withaferin A and B used for the treatment of thyroid and insomnia problems. It is drought tolerant cultivated mainly in Andhra Pradesh, Telangana, Karnataka, Rajasthan, Madhya Pradesh, and other states of India. Simple cultivation practices and higher root price attracting the farmer to grow Withania somnifera crop in large scale. The main challenges posed by farmers are interference of middlemen, lack of organized market, fluctuation in root price, demand-supply of roots, climatic variation, lower root yield, lack of availability of improved varieties, high fiber content in some location, lack of knowledge about improved post-harvest technology and problem occurrence with long term storage of roots.
Fungi are multifaceted microbes and are one of the largest groups among living organisms and have established themselves as an important source of the diverse bioactive metabolites. These metabolites are of different attributes such as antibacterial, antifungal, immunosuppressant, cholesterol-lowering, anticancer, anti-inflammatory, antidiabetic, etc. This group of microbes has been explored for producing bioactive metabolites for their pharmaceutical applications after the discovery of penicillin. Interestingly, some fungal metabolites or their derivatives have been brought to the market in the form of drugs under different categories such as penicillin G, cephalosporin C, fusidic acid, retapamulin, valnemulin, tiamulin (antibacterial), griseofulvin, micafungin, anidulafungin, caspofungin (antifungal), lovastatin (anti-hypercholesterolemic), and cyclosporine A (immunosuppressant). In earlier work in India, the bioactive metabolites were isolated from soil fungi by Hindustan Antibiotics Ltd. at Pune and Rishikesh and Hoechst Pharmaceuticals, Mumbai. Later, the emphasis was shifted to marine and endophytic fungi as interest shown by prime institutes like Hoechst Pharmaceuticals, Mumbai; Piramal Enterprises Ltd., Mumbai; Indian Institute of Integrated Medicine, Jammu; Banaras Hindu University, Varanasi; University of Jammu, Jammu; and University of Agricultural Sciences, Bangalore, to name few. This chapter highlights the bioactive metabolites from fungi isolated from various sources (soil, plants, marine, etc.) with some examples.KeywordsSoil fungiEndophytic fungiBioactive metabolitesAntibacterialAntifungalAnticancer
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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).
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.
Withametelin, a novel hexacyclic withanolide of leaves has been characterized as 1 on the basis of spectroscopic studies.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
Two new withanolides isolated from the whole plant material of Physalis peruviana (Solanaceae) have been characterized as (20R,22R)-5α,6β,14α,20,27-pentahydroxy-1-oxowith-24-enolide, and (20S,22R)-5β,6β-epoxy-4β,14β,15α-trihydroxy-1-oxowith-2,24-dienolide in addition to the known withanolides, withaphysanolide and viscosalactone B on the basis of spectroscopic techniques and chemical transformations.
Withafastuosin F, a new pentahydroxy withanolide and several other known withanolides have been isolated from the flowers of Datura fastuosa. The structure of the new compound has been elucidated as 5α,6β,12β,21,27-pentahydroxy-1-oxo-witha-2,24-dienolide from comprehensive spectral analysis.
Two withanolides, 28-hydroxywithanolide E and 4β-hydroxywithanolide E, the former being new, have been isolated from the calyces of Physalis peruviana. The structure of the new compound was determined primarily on the basis of extensive 1D and 2D NMR spectral analysis, notably 13C PENDANT, COSY 45, HMBC and HMQC.
A new withanolide belonging to the withajardins series was isolated from Deprea orinocensis and identified by 2D NMR spectroscopic data. The compound has an unusual pattern of substitution in the A-ring.
From leaves of Jaborosa leucotricha a new withanolide 17α,19-dihydroxy-5β,6β-epoxy-1-oxo-22R-witha-24-enolide has been isolated characterized by spectroscopic methods (1H and 13CNMR, MS); 19-hydroxywithanolides have not been previously reported.
From leaves of Jaborosa bergii five new withanolides were isolated and studied by spectroscopic (1H and 13C NMR, MS) and chemical methods. The new products were characterized as the epoxylactol and epoxylactone derivatives of 27-deoxy-2,3-dihydrojaborosalactone A having hydroxyl groups at C-14β and C-17β (jaborosalactol M and jaborosalactone M), the corresponding 2,3-dehydro derivatives, and the related 2,3-4,5-didehydro-6β-hydroxyepoxylactol (jaborosalactol N). The 14β,17β-dihydroxywithanolides have not been previously reported.