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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.
... Steroids skeleton containing a carbonyl group at position 1 are found in nature in the amount of over 200 compounds, mainly in plants [28,29]. The carbonyl group at position 1 of steroids plays a crucial role in determining the chemical and biological properties of these compounds. ...
... For example, withanolides and related steroids which has a carbonyl group at position 1, are acnistins, physalins, sativolides, spiranoid-δ-lactones, subtriflora-δ-lactones, trechonolides, withametelins, withajardins, withaphysalins, ring-D aromatic withanolides, and norbornane-type withanolides, which have been found in extracts of plants belonging to the families Datura, Dunalia, Hyoscyamus, Iochroma, Jaborosa, Larnax, Lycium, Solanum, Withania, and Witheringia [28][29][30][31]. As an example, we present steroids with different structures containing a carbonyl group in position 1 isolated from plants. ...
... Contignasterol (389), a highly oxygenated steroid with an unusual 14β-configuration, was obtained from the Papua New Guinea sponge Petrosia contignata [347]. Additionally, two unique pentacyclic steroids (390 and 391) with a cis C/D ring junction were 29 isolated from Xestospongia bergquistia and have been noted as powerful inhibitors of histamine release [348]. ...
This article presents a comprehensive overview of recent discoveries and advancements in the field of steroid chemistry, highlighting the isolation and characterization of various steroidal compounds from natural sources. The paper discusses a wide range of steroids, including pregnane steroids, steroidal alkaloids, ketosteroids, and novel triterpenoids, derived from marine organisms, fungi, and plants. Significant findings include the isolation of bioactive compounds such as the cytotoxic erectsterates from microorganisms, soft corals, the unusual tetracyclic steroid penicillitone from a fungal culture, and innovative steroidal derivatives with potential anti-inflammatory and anticancer activities. The synthesis of steroids from microorganisms as a tool for pharmaceutical development is also explored, showcasing the role of microbial biotransformation in generating steroidal drugs. Additionally, the paper emphasizes the ecological and medicinal relevance of these compounds, which are often used in traditional medicine and have potential therapeutic applications in treating diseases like cancer and microbial infections. This article serves as a vital resource for researchers interested in the chemical diversity of steroids and their applications in drug discovery and development.
... Physalis minima Linn (Solanaceae) is a pantropical perennial herb known for the presence of withanolides (Chen et al. 2011;Lem et al. 2022). Traditionally, the plant is consumed for the treatment of hypertension, earache, dizziness, prevention of cardiovascular diseases, and cancer prevention and treatment (Ahmad and Holdsworth 2003;Tammu et al. 2012). ...
... Most studies on P. minima have focused on the phytochemistry of the leaf and stem extracts, the discovery of novel withanolides, and their bioactivities in anti-inflammation and neuroprotection (Chen et al. 2011;Lem et al. 2022). Aside from the well-known C 28 -steroidal lactones (withanolides), the few recent studies available on the widely consumed fruits of P. minima have indicated that it may possess other bioactive compounds of medical interest (Joseph and Ravi 2022). ...
... In addition, the detection of seven steroids and two pentacyclic triterpenoids in this study indicates that the fruit of P. minima may possess some withanolides. According to earlier studies, as reported by Chen et al. (2011), Lem et al. (2022), and Hu et al. (2022), at least 130 different withanolides have been identified from P. minima, with about half of them being novel reports. This indicates that the fruits of P. minima may contain an array of withanolides and the majority of them possess anti-inflammation and cancer-inhibiting properties. ...
The pantropical Physalis minima are traditionally used for the prevention and treatment of various illnesses, diseases, and cancers. While most earlier studies on the species have focused on the phytochemistry of the leaf and stem extracts, recent studies have indicated that its fruit may contain bioactive compounds of medical interest. In this study, we investigated the cytotoxicity of extracts from the fruit of P. minima against colorectal cancer cell lines and revealed its phytochemical profile via high-resolution tandem mass spectrometry analysis. Following a 24-h treatment with the fruit extract, cytoplasm shrinkage and nucleus condensation were observed in the colorectal cancer cell lines HCT116 and HT29, indicating the induction of programmed cell death. Phytochemically, 71 putative metabolites were identified. Some of these metabolites have been reported to inhibit cancers to varying degrees, further supporting the correlation of the putative metabolites with the cytotoxicity against colorectal cancer cells demonstrated in this study.
... Moreover, more than 90 % of reported withanolides are oxidized at C-1 to form a 1-one. Except for the quaternary C-10, oxygen functional groups have been found in all carbons of the withanolide skeleton, resulting in an enormous structural diversity of known withanolides [27,28]. Despite this rich chemical variability, the compound class is not very widespread in the plant kingdom. ...
... The majority of them have been found in up to now 23 genera of the Solanaceae family, 10 of which are native to South America. These include the genus Jaborosa, where withanolides have been isolated from numerous species [27][28][29]. ...
... The structures of the isolated withanolides reported herein that constitute new natural products strongly differ from that of the previously isolated ones. Compounds 1-3 resemble trechonolide-type withanolides in parts of their skeleton [28,30]; however, they are the first examples of withanolides with a carboxylic function at C-21. The fact that we found different major withanolides in J. bergii than in previous studies is surprising. ...
Acetylcholinesterase (AChE) inhibitors are still an important option for managing symptoms of mild to moderate Alzheimerʼs disease. In this study, we aimed to evaluate the potential in vitro AChE inhibitory activity of two Argentinian endemic Solanaceae species, Jaborosa bergii and J. runcinata. UHPLC-DAD-HRMS metabolite profiling revealed the presence of withanolides in the active CH2Cl2 subextracts. Their fractionation led to the isolation and identification of two known spiranoid withanolides from J. runcinata and three new withanolides with a skeleton similar to that of trechonolide-type withanolides from J. bergii. The known compounds showed moderate AChE inhibitory activity, while the new ones were inactive.
... Structure-activity relationship (SAR) studies have revealed that the cytotoxic activities of these compounds are associated with the presence of a β-unsaturated ketone (ring A), a 5β, 6β-epoxide ring (ring B), along with a nine-carbon side chain substituted at C-17, featuring an α, β-unsaturated-δ-lactone. The structural classification of natural withanolides and their biological activities, particularly their cytotoxic effects, have been extensively studied [4][5][6][7][8]. ...
... I.M.C. Rodrigues & Stehmann, a species of the Solanaceae family [9], also known in the past as Aureliana fasciculata var. and their biological activities, particularly their cytotoxic effects, have been extensively studied [4][5][6][7][8]. ...
Athenaea fasciculata belongs to the Solanaceae family and is a promising source of cytotoxic withanolides known as aurelianolides A and B. In the last years, the pharmacological studies of these aurelianolides on different leukemia cell lines have stimulated new studies on their potential as alternative candidates for new lead anticancer drugs. However, the obtention of these two pure compounds by traditional preparative is a costly and long time-consuming process, which is performed in several steps. This study aimed to propose a straightforward approach for isolating aurelianolides A and B using high-speed countercurrent chromatography (HSCCC). In this study, among 10 different solvent systems, the system composed of n-hexane/ethyl acetate/methanol/water 3:6:2:1 (v/v/v/v) was chosen for optimization. This HEMWat system was optimized to 4:8:2:4 (v/v/v/v) and chosen for HSCCC separation in a tail-to-head elution mode. After the HSCCC scale-up procedure, a withanolides mixture (200.0 mg) was separated within 160 min in a single-step purification process. In total, 78.9 mg of aurelianolide A (up to 95.0% purity) and 54.3 mg of aurelianolide B (up to 88.5% purity) was obtained by this fast sequential liquid–liquid partition process. The isolated withanolides were identified by 1H and 13C NMR spectroscopy (this method has proven to be faster and more efficient than classical procedures (CC and Prep-TLC)).
... They are primarily found in 25 genera of the Solanaceae family, including Jaborosa, Physalis, Vassobia, Withania, Tubocapsicum, etc [1]. In recent years, with the continuous discovery of new structural types of withanolides and the in-depth study of modern pharmacology, some withanolides stand out because of their significant biological activities, which also makes this class of compounds have greater development potential to become drug candidates [2,3]. ...
... And then, we conducted a chemical investigation on the optimized extract of T. anomalum. This investigation has resulted in the discovery of eight new withanolides (1)(2)(3)(4)(5)(6)(7)(8), two artificial withanolides (9)(10), and fifteen previously identified analogues (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). And all the isolated compounds were tested for their antiproliferative effects against various cancer cell lines. ...
... Extracts from Withania somnifera-known by its Sanskrit name "Ashwagandha, " "Indian ginseng, " or "Winter cherry"have been used for over 3000 years in traditional medicine in India within the Ayuvedia system (2). Many of the therapeutic properties of this extract may be associated with the presence of withanolides (3,4). Since the isolation of the first withanolide, withaferin A, by Lavie in 1962 (5,6), this class of natural products has attracted enormous interest from biologists and chemists. ...
... Since the isolation of the first withanolide, withaferin A, by Lavie in 1962 (5,6), this class of natural products has attracted enormous interest from biologists and chemists. To date, almost 1200 withanolides have been isolated and identified largely from the Solanaceae (nightshades) distributed widely among the world's temperate and tropical zones (3). The withanolides are a group of naturally occurring C 28 steroids based on an ergostane skeleton in which C22/C26, or C23/ C26, are oxidized to form a δor γlactone. ...
Withanolides are a group of naturally occurring C 28 steroids based on an ergostane skeleton. They have a high degree of polyoxygenation, and the abundance of O -functional groups has enabled various natural alterations to both the carbocyclic skeleton and the side chain. Consequently, these molecules have intricate structural features that lead to their highly varied display of biological activities including anticancer, anti-inflammatory, and immunomodulating properties. Despite being intriguing leads for further discovery research, synthetic access to the withanolides remains highly challenging—compounds for current biological research are mainly isolated from plants, often inefficiently. Here, we report the divergent synthesis of 11 withanolides in 12 to 20 steps, enabled by a gram-scale route and a series of late-stage functionalizations, most notably a bioinspired photooxygenation-allylic hydroperoxide rearrangement sequence. This approach enables further biological research disconnected from a reliance on minute quantities of the parent natural products or their simple derivatives.
... Withanolides are traditionally used in Ayurvedic medicine and show promise for various health applications such as inflammation, stress, immunity and vitality. Physalin A ( Figure 21) and Physalin B, isolated from Physalis species, are among the known Withanolides with potential therapeutic benefits [176]. ...
... Withanolides are traditionally used in Ayurvedic medicine and show promise for various health applications such as inflammation, stress, immunity and vitality. Physalin A ( Figure 21) and Physalin B, isolated from Physalis species, are among the known Withanolides with potential therapeutic benefits [176]. [177] showed that Physalin A exhibited anti-tumor activity in non-small cell lung cancer (NSCLC) cell lines by targeting the JAK/STAT3 pathway. ...
Michael acceptors represent a class of compounds with potential anti-cancer properties. They act by binding to nucleophilic sites in biological molecules, thereby disrupting cancer cell function and inducing cell death. This mode of action, as well as their ability to be modified and targeted, makes them a promising avenue for advancing cancer therapy. We are investigating the molecular mechanisms underlying Michael acceptors and their interactions with cancer cells, in particular their ability to interfere with cellular processes and induce apoptosis. The anti-cancer properties of Michael acceptors are not accidental but are due to their chemical structure and reactivity. The electrophilic nature of these compounds allows them to selectively target nucleophilic residues on disease-associated proteins, resulting in significant therapeutic benefits and minimal toxicity in various diseases. This opens up new perspectives for the development of more effective and precise cancer drugs. Nevertheless, further studies are essential to fully understand the impact of our discoveries and translate them into clinical practice.
... 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
... Many withanolides frequently exhibit various biological properties such as antitumor, antimicrobial, anti-inflammatory, antioxidant, hepatoprotective, and immunomodulating [2]. ...
... Withanolides are synthesized by W.somnifera, which has been extensively investigated in terms of chemistry and bioactivity profiling. In traditional home medicine, Ashwagandha roots have been commonly used for several kinds of herbal formulations, wherein predominant bioactives are Withaferin A, Withanolide A, and Withanone [2,3]. ...
... 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 highly oxygenated C28-steroidal lactones found in the Solanaceae family, especially in the genera Physalis, Datura, Withania and Nicandra [88]. Lowest binding energy was obtained when Withanolide bound to α-amylase and α-glycosidase in the active site, revealing that it was an inhibitor of α-amylase and α-glycosidase, which is helpful in the treatment of T2DM [89]. ...
Non-alcoholic fatty acid liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) are the fatal liver diseases which encompass a spectrum of disease severity associated with increased risk of type 2 diabetes mellitus (T2DM), a metabolic disorder. Heat shock proteins serve as markers in early prognosis and diagnosis of early stages of liver diseases associated with metabolic disorder. This review aims to comprehensively investigate the significance of HSP90 isoforms in T2DM and liver diseases. Additionally, we explore the collective knowledge on plant-based drug compounds that regulate HSP90 isoform targets, highlighting their potential in treating T2DM-associated liver diseases. Furthermore, this review focuses on the computational systems’ biology and next-generation sequencing technology approaches that are used to unravel the potential medicine for the treatment of pleiotropy of these 2 diseases and to further elucidate the mechanism.
Graphical Abstract
... Ashwagandha is a key ingredient in several important traditional Ayurvedic preparations, including Ashwagandharishta, Ashwagandhaleha, and and antiviral activities (5)(6)(7)(8)(9)(10). Major phytoconstituents identified from the plant, such as alkaloids, flavonoids, and steroidal lactones, including withaferins, withanolides, and withanolide glycosides, known as withanosides, are responsible for its diverse biological activities (11)(12)(13). ...
Background: Withania somnifera (L.) Dunal, belonging to the Solanaceae family and commonly known as Ashwagandha, is a traditional Ayurvedic herb renowned for its adaptogenic properties. It plays a significant role in various classical Ayurvedic formulations and proprietary medicines. Traditionally, the roots of the plant are utilized over the aerial parts, such as leaves and stems. In recent years, a global increase in the use of Ashwagandha roots has been spurred by several modern pharmacological studies supporting its benefits. Methods: This study examined different parts of the herb, including leaves, stems, roots, and seeds, using methods like phytochemical analysis, thin layer chromatography (TLC) analysis, high-performance thin layer chromatography (HPTLC) phytochemical profiling, UV-visible spectral analysis, and 1H nuclear magnetic resonance (NMR) profiling. Results: The findings indicated that phytosterols, triterpenoids, and alkaloids were predominantly found in the leaves and stems, with lower concentrations in the roots and seeds. Ethanol extracts were particularly rich in total flavonoids, whereas aqueous extracts contained higher levels of phenolic compounds. High-performance thin layer chromatography fingerprinting varied for each part of the herb, effectively separating pigment-based components such as chlorophyll at 366 nm in the aerial parts. The 1H NMR spectra showed distinct metabolite profiles for each part of the plant. Conclusions: The analytical methods proposed in this study offer enhanced quality control and evaluation for the medicinal use of W. somnifera roots and its aerial components.
... Therefore, it is necessary to develop drugs for the effective treatment of TNBC. Generally speaking, Solanaceae plants contain a large number of withanolides, a group of highly oxidized C28 ergosterol steroids, which usually have good anticancer activity [29]. As presented in our results, TAMEWs exhibited favorable anti-breast-cancer activity, especially against TNBC. ...
Triple-negative breast cancer (TNBC) is a malignant breast cancer. There is an urgent need for effective drugs to be developed for TNBC. Tubocapsicum anomalum (T. anomalum) has been reported to have an anti-tumor effect, and six novel withanolides were isolated from it and designated as TAMEWs. However, its anti-TNBC effect is still unknown. The results of an MTT assay indicated a higher sensitivity of TNBC cells to TAMEWs compared to other cells. TAMEWs induced apoptosis via mitochondrial dysfunction. They caused increased levels of lipid ROS and Fe2+, with downregulation of GSH and cystine uptake, and it has been confirmed that TAMEWs induced ferroptosis. Additionally, the results of Western blotting indicate that TAMEWs significantly decrease the expressions of ferroptosis-related proteins. Through further investigation, it was found that the knockdown of the p53 gene resulted in a significant reversal of ferroptosis and the expressions of its associated proteins SLC7A11, ASCT2, and GPX4. In vivo, TAMEWs suppressed TNBC growth with no obvious damage. The IHC results also showed that TAMEWs induced apoptosis and ferroptosis in vivo. Our findings provide the first evidence that TAMEWs suppress TNBC growth through apoptosis and ferroptosis.
... ü (Kubwabo et al., 1993) ü (Kubwabo et al., 1993) 7. 8. Physalolactone C ü (Ali et al., 1984) 9. Withaperuvin E, F, G, H ü (Bagchi et al., 1984;Chen et al., 2011;Neogi et al., 1986) 10. Kubwabo et al., 1993) ü (Kubwabo et al., 1993) 23. ...
... Withanolides are a group of naturally occurring steroidal lactones isolated from members of the Solanaceae plant family [9]. Recent evidence has been showing that this class of natural products (NP) has shown promising anticancer properties against multiple tumor types [10][11][12][13][14][15][16][17]. ...
Simple Summary
c-FLIP is a master anti-apoptotic regulator associated with resistance to various therapeutic options in different cancer types. Thus, exploring the combinatorial antitumor effects of a natural product, physachenolide C (PCC) and bortezomib, could lead to an effective, non-toxic therapeutic regimen against KRASmut/P53mut lung cancer cells. Our results showed that the bortezomib–PCC combination was more effective in reducing the viability and inhibiting migration and invasion of cancer cells. Additionally, c-FLIP protein expression was significantly inhibited along with a substantial reduction in the critical parameters of cellular metabolism in cancer cells. Strikingly, tumor growth inhibition was much more effective in tumor xenograft mice models with an enhanced efficacy without causing significant side effects.
Abstract
Background: Defects in apoptosis regulation are one of the classical features of cancer cells, often associated with more aggressiveness and failure to therapeutic options. We investigated the combinatorial antitumor effects of a natural product, physachenolide C (PCC) and bortezomib, in KRASmut/P53mut lung cancer cells and xenograft mice models. Methods: The in vitro anticancer effects of the bortezomib and PCC combination were investigated using cell viability, migration, and invasion assays in 344SQ, H23, and H358 cell lines. Furthermore, the effects of combination treatment on the critical parameters of cellular metabolism, including extracellular acidification rate (ECAR) and mitochondrial oxidative phosphorylation based on the oxygen consumption rate of cancer cells were assessed using Seahorse assay. Finally, the antitumor effect of the bortezomib (1 mg/kg) and PCC (10 mg/kg) combination was evaluated using xenograft mice models. Results: Our data showed that the bortezomib–PCC combination was more effective in reducing the viability of lung cancer cells in comparison with the individual treatments. Similarly, the combination treatment showed a significant inhibition of cell migration and invasion of cancer cells. Additionally, the key anti-apoptotic protein c-FLIP was significantly inhibited along with a substantial reduction in the key parameters of cellular metabolism in cancer cells. Notably, the bortezomib or PCC inhibited the tumor growth compared to the control group, the tumor growth inhibition was much more effective when bortezomib was combined with PCC in tumor xenograft mice models. Conclusion: These findings demonstrate that PCC sensitizes cancer cells to bortezomib, potentially improving the antitumor effects against KRASmut/P53mut lung cancer cells, with an enhanced efficacy of combination treatments without causing significant side effects.
... Moreover, successful metabolic engineering to improve withanolide production requires a complete understanding of the genes involved in the biosynthetic pathway. Structurally, withanolides are C 28 steroids with ergostane skeleton in which C 26 and C 22 , or C 26 and C 23 , are oxidized in order to form a δor γ-lactone (Chen, He and Qiu, 2011). Withanolides have been reported to be derived through the universal phytosterol pathway ( Figure 1). ...
The medicinal properties of Ashwagandha (Withania somnifera L. Dunal) are attributed to withanolides, which belong to the triterpenoid steroidal lactones class of compounds. Though it is proposed that intermediates of the universal phytosterol pathway are utilized by cytochrome P450 (CYP450) enzymes to form withanolides, studies on the functional characterization of these enzymes have been sparse. This study reports the functional characterization of a CYP450 candidate from W. somnifera, WsCYP71B35 that exhibited induced expression in response to methyl jasmonate treatment and showed higher expression in tissues that accumulate withanolides. Biochemical assay with yeast microsomal fraction expressing recombinant WsCYP71B35 indicated no activity when phytosterols and their intermediate 24-methylene cholesterol were used as substrates. However, WsCYP71B35 catalyzed product formation with withaferin A, withanolide A, withanolide B, and withanoside IV among the tested substrates. Moreover, virus-induced gene silencing (VIGS) and transient overexpression of WsCYP71B35 in W. somnifera leaves modulated the levels of withaferin A, withanolide A, and withanolide B, indicating the role of WsCYP71B35 in withanolides pathway. Furthermore, VIGS of WsCYP71B35 in W. somnifera reduced its tolerance to Pseudomonas syringae (DC3000) infection, whereas overexpression enhanced the tolerance to the bacterium in W. somnifera and transgenic tobacco. Overall, these results provide insights into the role of W. somnifera WsCYP71B35 in withanolides biosynthesis and bacterial defence.
... 15 these electrophilic sites react with cysteine residues in proteins and contribute to their bioactivity, whereas other withanolides lack any of the structural groups and are less potent. 16 several studies prove the clinical relevance of Wa as a reliable anti-cancer molecule, as it targets several potential oncogenic targets with almost negligible adverse effects (Figure 1-4). ...
... Moreover, successful metabolic engineering to improve withanolides production requires a complete understanding of the genes involved in the biosynthetic pathway. Structurally, withanolides are C 28 steroids with ergostane skeleton in which C 26 and C 22 , or C 26 and C 23 are oxidized in order to form a δ -or γ -lactone (Chen et al. 2011). Withanolides have been reported to be derived through the universal phytosterol pathway (Figure 1). ...
The medicinal properties of Ashwagandha ( Withania somnifera L. Dunal) are attributed to withanolides, which belong to the triterpenoid steroidal lactones class of compounds. Though it is proposed that intermediates of the universal phytosterol pathway are utilized by cytochrome P450 (CYP450) enzymes to form withanolides, studies on functional characterization of these enzymes has been sparse. This study reports the functional characterization of a CYP450 candidate from W. somnifera (WsCYP71B35) that exhibited induced expression in response to methyl jasmonate treatment and showed higher expression in tissues that accumulate withanolides. Biochemical assay with yeast microsomal fraction expressing recombinant WsCYP71B35 indicated no activity when phytosterols and their intermediate 24-methylene cholesterol were used as substrates. However, WsCYP71B35 catalyzed product formation with withaferin A, withanolide A, withanolide B, and withanoside IV among the tested substrates. Moreover, virus-induced gene silencing (VIGS) and transient overexpression of WsCYP71B35 in W. somnifera leaves modulated the levels of withaferin A, withanolide A, and withanolide B, indicating the role of WsCYP71B35 in withanolides pathway. Furthermore, VIGS of WsCYP71B35 in W. somnifera reduced its tolerance to Pseudomonas syringae (DC3000) infection, whereas overexpression enhanced the tolerance to the bacterium in W. somnifera and transgenic tobacco. Overall, these results provide insights into the role of W. somnifera WsCYP71B35 in withanolides biosynthesis and bacterial defense.
... 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.
... 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.
This article presents a comprehensive overview of recent discoveries and advancements in the field of steroid chemistry, highlighting the isolation and characterization of various steroidal compounds from natural sources. This paper discusses a wide range of steroids, including pregnane steroids, steroidal alkaloids, ketosteroids, and novel triterpenoids, derived from marine organisms, fungi, and plants. Significant findings include the isolation of bioactive compounds such as the cytotoxic erectsterates from microorganisms, soft corals, the unusual tetracyclic steroid penicillitone from a fungal culture, and innovative steroidal derivatives with potential anti-inflammatory and anticancer activities. The synthesis of steroids from microorganisms as a tool for pharmaceutical development is also explored, showcasing the role of microbial biotransformation in generating steroidal drugs. Additionally, this paper emphasizes the ecological and medicinal relevance of these compounds, which are often used in traditional medicine and have potential therapeutic applications in treating diseases like cancer and microbial infections. This article serves as a vital resource for researchers interested in the chemical diversity of steroids and their applications in drug discovery and development.
Cell suspension culture has the potential to be a valuable source for the bioactive compound productions. In this study, an optimized procedure was established for callus and cell suspension culture of Physalis alkekengi for the first time, and the impact of static magnetic field (SMF, 6 mT) was studied on the high-value metabolic compounds through investigation of signaling molecules and gene expressions at the late log-to-stationary phase. Results showed that the growth regulators of 6-benzyl amino purine (BAP, 1.5 mg⁻¹ L) and 1-naphthaleneacetic acid (NAA, 0.4 mg⁻¹ L) induced the highest fresh weight, callus rate, callus index, and total withanolides. Cell suspension culture was established in the liquid MS medium supplied with BAP (1.5 mg⁻¹ L) and NAA (0.1 mg⁻¹ L). SMF application decreased slightly the cell growth and viability and enhanced the number of round-shaped cells. The hydrogen peroxide (H2O2) and nitric oxide (NO) levels increased at an all-time series after SMF exposure, and their maximum contents were observed after 12 h. A significant alteration of malondialdehyde content was also identified after 12 h of SMF exposure. The expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), 1-deoxyD-xylulose 5-phosphate synthase (DXS), squalene synthase (SQS), sterol Δ7-reductase (DWF5), and C-7,8 sterol isomerase (HYD1) genes was upregulated significantly after 24 and 48 h. An increase in the total withanolides was related to more activity of HMGR and DXS enzymes in SMF-exposed cells and the maximum physalin A (12.8 mg g⁻¹ DW) and physalin B (1.92 mg g⁻¹ DW) obtained after 24 h compared to controls. Findings suggest that SMF can play a supportive factor in inducing steroidal compounds in P. alkekengi through modulating H2O2 and NO levels and the related-gene expressions.
Silver (Ag) is a non-essential heavy metal with substantial environmental toxicity but an excellent promotor for
plant organogenesis. It is used as an elicitor for secondary metabolite production and for in planta synthesis of
metal nanoparticles (MNPs). In the present study, the Ag accumulation and reduction capability of in vitro shoots
of Withania somnifera and the toxicity and elicitation effect of Ag on in vitro shoots were explored. In vitro shoot
cultures of W. somnifera were treated with different concentrations of silver nitrate for a specific treatment
period. Growth index, withaferin A, elemental and electron microscopy analyses were done on silver-treated in
vitro shoots of W. somnifera. 1 mM silver nitrate treatment for 12 days period was found to give increased growth
index (1.425 ± 0.05c) and withaferin A (2.568 ± 0.08e mg g 1) content. The concentration of bioaccumulated
Ag in 1 mM silver nitrate treated in vitro shoot was found to be 50.8 ppm. The presence of nano-Ag was also found
in the leaves of 1 mM silver nitrate-treated in vitro shoots. In summary, this is the first report portraying the
bioaccumulation and in planta reduction capability of the in vitro shoot system of W. somnifera, which makes it a
potential medicinal plant of commercial value for silver contaminated soils.
Physalis peruviana L. is an exotic fruit that belongs to the genus Physalis of the family Solanaceae. The fruit is native to South America (Peru, Colombia, and Ecuador) and is currently grown commercially in several tropical and subtropical countries (National Research Council, 1989; Novoa et al., 2006). The fruit is a juicy, ovoid-shaped berry with a diameter of 1.25-2.50 cm and a weight of 4-10 g, containing 100-200 small seeds. It is protected against insects, birds, diseases, and adverse weather conditions by the calyx, or fruit basket, which encloses it completely throughout development and maturation (Tapia & Fries, 2007). This plant has been cultivated since the Incan period (National Research Council, 1989). It is produced in Colombia, Kenya, Zimbabwe, Australia, New Zealand, India, Ecuador, the United States, Brazil, Venezuela, Bolivia, Peru, Chile, Central America, Mexico, Belize, Guatemala, El Salvador, Nicaragua, Costa Rica, Panama, Jamaica, South Africa, Gabon, Egypt, China, Japan, the Philippines, Malaysia, Indonesia, Samoa, Tonga, New Caledonia, Guam, the United Kingdom, Israel, and Portugal (Guine´ et al., 2020). Its nutritional and bioactive properties make P. peruviana highly suitable for the production of functional foods (Campos et al., 2018). The pulp, in particular, is a good source of provitamin A, vitamin C, vitamin B complex, phenolic compounds, and several minerals of nutritional importance (Bazalar Pereda et al., 2019; Nocetti et al., 2020; Obrego´n et al., 2021). Fruit is a rich source of beneficial nutrients, including minerals, vitamins, fibers, carotenoids, proteins, fructose, sucrose, esters, pectins, flavonoids, polyphenols, polyunsaturated fatty acids (PUFAs), and phytosterols (Mazova et al., 2020). The extract contains a variety of chemical compounds, including saponins, withanolides, kaempferol, peruvioses, quercetin, and di- and tri-glycosides (Bernal et al., 2018; Dong et al., 2019; Ocampo et al., 2017); some of which have shown antioxidant (Puente et al., 2011), hypoglycemic, and anticancer properties (Ramadan, 2020; Xu et al., 2017). Consuming this fruit reduces blood sugar after 90 minutes (postprandial glycemia) in young adults, with a further hypoglycemic effect after that time (Ulloa, 2007). This crop is a good alternative for the production sector in many countries because it may have a positive economic impact due to the good prospects and interest in the global trade of fruits and berries, as well as consumer demand for fruits with medicinal properties (Fischer et al., 2011; Oliveira et al., 2016). This review is aimed at presenting updated information on the physicochemical, nutritional, and bioactive properties of various genotypes of P. peruviana L. grown worldwide to assess their utility in the development of functional foods and ingredients, as well as in their fresh consumption.
Molasses is a valuable byproduct in the sugar and citrus fruit processing industries. This versatile substance used in various sectors, including beverage production, acetic acid synthesis, baker’s yeast cultivation, formulation of animal feed components, and even as a fertilizer. Beet molasses is used for creation of diverse bakery and confectionery products. In agriculture, beet sugar molasses is employed to enhance nutrient uptake efficiency and stimulate soil biological activity. Molasses also contributes to human health. Sugarcane molasses serves as a source of iron, containing approximately 0.7% iron by weight. Studies have indicated that molasses can have positive effects on glucose regulation, reducing both the peak and total levels of glucose, enhancing the secretion of insulin, amylin, and gastric inhibitory polypeptide after oral intake. Despite its widespread usage, molasses had its own drawbacks like it causes diseases (molasses toxicity, urea toxicity, and bloat) and increased greenhouse gas emissions.
Withanolides are the class of steroidal molecules getting greater emphasis in recent years. Quality control throughout the manufacturing and storage period is often one of the key problems that have restricted their broad use in India's indigenous and Ayurvedic medical systems for thousands of years. Because of their diverse clinical potential, withanolides have received a great deal of scientific attention. Analytical techniques are being devised for the automated isolation, identification, and estimation of every single protein within the cell as well as in herbal extracts of withanolides, due to which now researchers are interested in determining the effects of metabolism as well as various stimuli on protein expression, which made the study easier. This study discusses the potential use of hyphenated analytical methods that are reliable in understanding the molecular signaling features, proteome evaluation and characterization of withanolides, in addition to examining existing methodological limitations. The choice of analytical techniques for the withanolides analysis, however, relies on the nature of the sample matrix, the aim of the analysis, and the sensitivity of the technique.
Natural products have played a significant role throughout history in the prevention and treatment of numerous diseases, particularly cancers. As a natural product primarily derived from various medicinal plants in the Withania genus, withanolides have been shown in several studies to exhibit potential activities in cancer treatment. Consequently, understanding the molecular mechanism of withanolides could herald the discovery of new anticancer agents. Withanolides have been studied widely, especially in the last 20 years, and attracted the attention of numerous researchers. Currently, over 1200 withanolides have been classified, with approximately a quarter of them having been reported in the literature to be able to modulate the survival and death of cancer cells through multiple avenues. To what extent, though, has the anticancer effects of these compounds been studied? How far are they from being developed into clinical drugs? What are their potential, characteristic features, and challenges? In this review, we elaborate on the current knowledge of natural compounds belonging to this class and provide an overview of their natural sources, anticancer activity, mechanism of action, molecular targets, and implications for anticancer drug research. In addition, direct targets and clinical research to guide the design and implementation of future preclinical and clinical studies to accelerate the application of withanolides have been highlighted.
As the global population ages, osteoporosis is becoming a more common silent disease. Osteoporosis is characterized by decreased bone quality and strength, which increases the risk of fragility fractures in the elderly. According to estimates, 50% of women eventually suffer from an osteoporotic fracture. Due to increasing disability, more frequent hospital hospitalizations, and most critically, fragility fractures have been linked to a reduced quality of life. Osteoporotic fractures have been linked to an increased mortality risk; and must be considered in awareness as a serious health concern. There are anti-osteoporotic medications available that improve bone quality. Considering the availability of various treatment options, still there are a lot of underserved needs in the treatment of fractures and osteoporosis. For example, the application of natural products and herbal resources for fracture healing, because of the androgen-like and antioxidant characteristics of the plants, they can play a crucial for accelerating the repair of bone fractures. In this article, we’ll discuss the herbal remedies that are essential for treating osteoporosis (bone disease).
Ethnopharmacological relevance
Withania somnifera (L.) Dunal; (Solanaceae), commonly known as Ashwagandha, is one of the most significant medicinal herbs in ‘Ayurveda’, a traditional Indian medicine used for centuries with evidence in scriptures. Ashwagandha was mentioned in old Ayurvedic medical literature such as Charaka Samhita and Sushruta Samhita for improving weight and strength, with multiple citations for internal and exterior usage in emaciation and nourishing the body. Ethnopharmacological evidence revealed that it was used to relieve inflammation, reduce abdominal swelling, as a mild purgative, and treat swollen glands. The root was regarded as a tonic, aphrodisiac, and emmenagogue in the Unani tradition of the Indian medicinal system. Further, Ashwagandha has been also described as an Ayurvedic medicinal plant in the Ayurvedic Pharmacopoeia of India extending informed therapeutic usage and formulations. Despite the widespread ethnopharmacological usage of Ashwagandha, clinical pharmacokinetic parameters are lacking in the literature; hence, the findings of this study will be relevant for calculating doses for future clinical evaluations of Ashwagandha root extract.
Aim
This study aimed to develop a validated and highly sensitive bioanalytical method for quantifying withanosides and withanolides of the Ashwagandha root extract in human plasma to explore its bioaccessibility. Further to apply a developed method to perform pharmacokinetics of standardized Withania somnifera (L.) Dunal root extract (WSE; AgeVel®/Witholytin®) capsules in healthy human volunteers.
Methods
A sensitive, reliable, and specific ultra-high pressure liquid chromatography-mass spectrometry (UHPLC-MS/MS) method was developed and validated for the simultaneous quantification of five major withanosides and withanolides (withanoside IV, withanoside V, withanolide A, withaferin A, and 12-deoxy-withastramonolide) in human plasma. Further for the study, eighteen healthy male volunteers (18–45 years) were enrolled in a non-randomized, open-label, single period, single treatment, clinical pharmacokinetic study and given a single dose (500 mg) of WSE (AgeVel®/Witholytin®) capsules containing not less than 7.5 mg of total withanolides under fasting condition. Later, pharmacokinetic profiles were assessed using the plasma concentration of each bioactive constituent Vs. time data.
Results
For all five constituents, the bioanalytical method demonstrated high selectivity, specificity, and linearity. There was no carryover, and no matrix effect was observed. Furthermore, the inter-day and intra-day precision and accuracy results fulfilled the acceptance criteria. Upon oral administration of WSE capsules, Cmax was found to be 0.639 ± 0.211, 2.926 ± 1.317, 2.833 ± 0.981, and 5.498 ± 1.986 ng/mL for withanoside IV, withanolide A, withaferin A, and 12-deoxy-withastramonolide with Tmax of 1.639 ± 0.993, 1.361 ± 0.850, 0.903 ± 0.273, and 1.375 ± 0.510 h respectively. Further, withanoside V was also detected in plasma; but its concentration was found below LLOQ.
Conclusion
The novel and first-time developed bioanalytical method was successfully applied for the quantification of five bio-active constituents in human volunteers following administration of WSE capsules, indicating that withanosides and withanolides were rapidly absorbed from the stomach, have high oral bioavailability, and an optimum half-life to produce significant pharmacological activity. Further, AgeVel®/Witholytin® was found safe and well tolerated after oral administration, with no adverse reaction observed at a 500 mg dose.
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.
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.
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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.
Phytochemical studies on the whole plant of Withania coagulans have resulted in the isolation of five new withanolides, namely coagulins H, I, J, K and L (1-5). Their structures have been established as (17S,20S,22R)-5α6β,14α,15α,17,20-hexahydroxy-1-oxowitha- 2,24-dienolide (1), (14R,17S, 20S,22R)-5α6β,17-trihydroxy-14,20-epoxy-1-oxowitha-2,24-dienolide(2), (14R, 17R,20R,22R)-3β,27-dihydroxy-14,20-epoxy-1-oxowitha-5,24-dienolide (3), (14R,17R,20R,22R)-14,20-epoxy-3β-(O-β-D-glucopyranosyl)-1-oxowitha-5, 24-dienolide (4) and (14R,17S,20S,22R)-14,17,20-trihydroxy-3β-(O-β-D-glucopyranosyl)-1- oxowitha-5,24-dienolide (5), respectively on the basis of spectroscopic techniques.
Four new withanolides, coagulin B (1), coagulin C (2), coagulin D (3) and coagulin E (4) were isolated from the aerial parts of Withania coagulance. The structures (1-4) have been determined through spectroscopic studies.
Two new steroidal lactones of the withanolide group named as withametelinol
(1a) and withametelinone (2) have been isolated from the aerial parts of
Datura innoxia along with withametelin. The structures
of the new constituents have been established as
(20R,22R)-21,24-epoxy-12α-hydroxy-1-oxowitha-2,5,25(27)-trienolide
and
(20R,22R)-21,24-epoxy-1,12-dioxowitha-2,5,25(27)-trienolide
through spectroscopic studies including one- and two-dimensional (COSY-45,
NOESY, HMQC, HMBC) n.m.r. spectroscopy and chemical
transformations.
From seeds of Jaborosa maqellanica (Griseb.) Dusén (Solanaceae), a new withanolide was isolated and studied by nmr and mass spectroscopy.
Two novel lactonic steroids, stoloniolide I and II, were isolated from the Okinawan soft coral, Clavularia viridis Quoy and Gaimard. Their structures were determined by spectroscopic analysis. They each possessed a unique 1,10-secoergostane skeleton unprecedented in the field steroids.
Physalin K was isolated from Physalis alkekengi var. francheti. Spectroscopic studies and chemical correlations, however, revealed that the reported structure of physalin K at the AB ring moiety, namely, 4 alpha,5 alpha-epoxy-6 alpha-hydroxy-2-en-1-one, should be revised to 2 alpha,5 alpha-epidioxy-6 beta-hydroxy-3-en-1-one. A new physalin,named physalin Q, was also isolated and identified as the 2 beta,5 beta-epidioxy diastereomer of physalin K.
C28H3606, Mr=468"59, monoclinic, P2, a=6.919(3), b=17.042, c=10.267(3)A, fl= 93.39 (3) °, v= 1209 (2) A s, z= 2, Dx= 1-288 Mg m -3, 2(Mo Ka) = 0.71073 A, /~ = 0-083 mm -~, F(000) = 504, T= 293 (1) K, R = 0-033 for 2032 observed reflections with I> 300(/). The average bond distances are C(sp3)-C(sp 3) 1.534 (3), C(sp3)-C(sp 2) 1.498 (3), C(spZ)-C(sp 2) 1.481 (3), C=C 1.336 (3), C-C (aromatic) 1.388 (3), C(sp3)-O 1.445 (2), C(sp2)-O 1.342 (3) and C=O 1.221 (2) A. Ring A is essentially planar, the tetrahydrofuranoid ring B has a C(7)-envelope conformation while ring C has a twist-boat and ring D a C(13)-envelope conformation. The lactonic ring E is in a half-chair conformation. Atoms C(18) and 0(4) are/3, and the lactone moiety is a oriented. An hydroxy group is H-bonded to a ketonic O atom (O(61) ...H(O1) 1.96A). Introduction. Our continuing investigations on the withanolides found in Jaborosa magellanica (Griseb.) Drisen (Solanaceae) (Parvez, Fajardo & Shamma, 1988), has led to an usual withanolide, (+)-jaborol, in which the original steroidal ring B has suffered in vivo oxidative cleavage with formation of a phenolic ring A. Chemical and spectroscopic studies led to the proposal of structure (1) for jaborol (Fajardo, Freyer, Minard & Shamma, 1987). The crystal structure of (1) was determined in order to ascertain its conformation and molecular geometry. The absolute configuration was not established by the anomalous-dispersion method. However, the configuration indicated in (1) is derived from the fact that naturally occurring steroidal derivatives generally incorporate a C(18) methyl group which lies above the mean plane of the molecule.
Isotope administration experiments with Nicandra physaloides plants using [3′-C2H3]- and [3′-14C3]-mevalonic acid, analysed by 2H NMR and by degradation, respectively, show that the aromatic ring-D of Nic-1 2is formed by ring-o expansion in a steroid precursor with oxidative inclusion of the C/Dangular methyl.