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The Structure and Pharmacological Functions of Coumarins and Their Derivatives
Abstract
Coumarins are of many different structures. They constitute an important class of pharmacological agents possessing a range of different physiological activities including anti-cancer, anti-oxidant, anti-inflammation, anti-HIV, anticoagulant, anti-bacterial, analgesic and comparative immune-modulation. Recently, coumarins have attracted intense research interest. Of great interest is the possibility that this class of molecules could be a source of drugs for the therapy of several diseases. These include recent insights into inhibiting cell proliferation by interfering with mitotic spindle microtubule function, decrease Matrix Metalloproteinase (MMP) activity, block the cell cycle in the S or G2/M phases to interfere with processes of cell division, suppress O2 - generation in leukocytes, inhibit different protein kinases, modulate the signalings, induce carcinogen-detoxifying enzymes glutathione Stransferases (GSTs) and/or NAD(P)H quinine oxidoreductase (NQO1), suppress the phosphorylation of Akt/PKB as a mechanism inhibiting inflammation, progress in structure modification to increase in anti-fungal action, to broaden against bacteria spectrum, to enhance inhibiting activities of nitric oxide synthase (NOS) and cyclooxygenase (COX), to strengthen anti-oxidant activity and to exhibit a much higher cytotoxicity against human umbilical vein endothelial cell (HUVEC). With fewer non-hemorrhagic side effects than the indanedione derivatives, they can be applied as an oral anticoagulant commonly for preventing venous thromboembolism following orthopedic surgery, recurrent myocardial infarction and the treatment of systemic embolism in atrial fibrillation, together with the significant advances in the basis of drug action. It is therefore useful to build up some correlations with the data available in order to better explore the molecular and cellular mechanism of coumarin action in the treatment of diseases. This review will focus on recent advances in molecular and cellular mechanisms of coumarin action involved with the relationship between structure and activity.
... Apple Academic Press Non Commercial Use six-membered rings fused with one of them being a benzene ring, and the other containing an alkene and ester functional group inside the ring. In coumarin, the two adjacent hydrogen atom of the benzene ring is replaced by a lactone chain (Wu et al., 2009). According to systemic nomenclature, they are called benzopyrone (2H-1-benzopyran-2-one) which is established by IUPAC (International Union of Pure and Applied Chemistry). ...
... Coumarins and their derivatives are also documented in different monocot families, such as Graminae and Orchidaceae. Linear furanocoumarins are primarily found in Rutaceae, Fabaceae, Apiaceae, and Moraceae (Wu et al., 2009). But certain coumarin derivatives can also be plant-specific (Table 8.4). ...
... In Angelica decursiva, the biosynthesis of coumarin begins with the production of phenylalanine through the shikimate pathway followed by conversion into cinnamic acid catalyzed by PAL enzyme. Cinnamic acid is then hydroxylated by the enzyme C4H (cinnamate 4-hydroxylase) to form p-coumaric acid (Wu et al., 2009). The p-coumaric acid can also be directly generated from phenylalanine by the enzyme TAL (tyrosine ammonia-lyase) and converted to p-coumaryl CoA by the aid of enzyme 4CL (4-Coumarate: Coenzyme A Ligase). ...
... The chemical formula of coumarins is C 9 H 6 O 2 , and they can exist in various isomeric forms due to differences in the substitution pattern on the benzene and the pyrone ring (Wu et al., 2009). The presence or absence of particular functional groups confers the coumarin its name and properties, such as simple coumarins which are the basic coumarin metabolites with no additional substituents. ...
... The presence or absence of particular functional groups confers the coumarin its name and properties, such as simple coumarins which are the basic coumarin metabolites with no additional substituents. These include hydroxycoumarins like scopoletin and umbelliferone, methoxycoumarins like esculetin and 7-methoxycoumarin and alkyl coumarins like daphnetin and aesculetin (Wu et al., 2009). Coumarins are variably soluble in most organic solvents or their combinations (Huang et al., 2015) but are freely soluble in ethanol, chloroform, diethyl ether and oils (Jung and Oh, 2011). ...
Introduction: Coumarins are naturally occuring metabolites from plants and a few micro-organisms. They have been widely used in the food and drug industry in their natural or synthetic forms. Numerous coumarins possess several biological activities such as anti-inflammatory, anti-ulcers, anti-tumour, anti-microbial, anti-coagulant. The aim of this study was to assess the bioactivity, and toxicity of coumarins from African medicinal plants.
Methods: We searched online databases and search engines such as PubMed, Google Scholar and Web of Science for key terms such as coumarins, toxicity, bioavailability, bioactivity with appropriate Boolean operators. Only full-length research articles published in English between 1956 to 2023 were reviewed.
Results: We recorded 22 coumarins from 15 plant species from Africa. Most of the plant species (33%) were from North Africa. These were followed by East Africa at 21%, then West, and Central Africa at 18.2% each. Most of the coumarins (21.3%) were isolated from the entire plant and the leaves (19.1%) and most of them (46.7%) had some antimicrobial activity. Five coumarins viz osthole, pseudocordatolide C & calanolide, chartreusin and esculetin had either antitumor or anticancer activity. Six coumarins had varying levels and types of toxicity ranging from inhibiting blood clotting as anticoagulants, to cytotoxic effects, causing hyperventilation, tremor, & photophobia, pulmonary haemorrhage, carcinogenic activity, severe neurotoxicity, hepato- and phototoxicity.
Conclusion: Several African medicinal plants are sources of various coumarins that possess several biological activities as well as toxicities. This calls for more research into their safety and efficacy because of their wide spread applications as therapeutic agents.
... [4,10,19,20]. The search for new plants containing coumarins is important because, in many natural coumarins, including those found in A. macrophylla (scopoletin and fraxetin), an anti-inflammatory activity has been detected [21][22][23][24]. A tight structure-activity relationship has also been documented for coumarins, thus making it possible to use coumarin molecules as the basis for the development of various pharmaceuticals [25,26]. ...
... Both hydroxy and methoxy groups can be attached simultaneously [as in 2-hydroxy-4-methoxycinnamic acid (29), sinapinic acid (35), ferulic acid (37), and isoferulic acid (27)]. Furthermore, when combined with quinic acid, cinnamic acid gives rise to a number of acids: neochlorogenic (22), cryptochlorogenic (21), and accordingly chlorogenic (28) acids. Chlorogenic acid is the most common in nature, but the combination of two different acids in its chemical structure [ester of caffeic acid and (-)-quinic acid] explains the high antioxidant activity [36]. ...
Anemonopsis Siebold et Zucc. is an unstudied single-species genus belonging to the tribe Cimicifugeae (Ranunculaceae). The only species of this genus—Anemonopsis macrophylla Siebold & Zucc.—is endemic to Japan. There are no data on its chemical composition. This work is the first to determine (by liquid chromatography with high-resolution mass spectrometry) the chemical composition of methanol extracts of leaves and flowers of A. macrophylla. More than 100 compounds were identified. In this plant, the classes of substances are coumarins (13 com-pounds), furocoumarins (3), furochromones (2), phenolic acids (21), flavonoids (27), and fatty acids and their derivatives (15 compounds). Isoferulic acid (detected in extracts from this plant) brings this species closer to plants of the genus Cimicifuga: one of the few genera containing this acid and ferulic acid at the same time. Isoferulic acid is regarded as a reference component of a quality indicator of Cimicifuga raw materials. The determined profiles of substances are identical between the leaf and flower methanol extracts. Differences in levels of some identified substances were revealed between the leaf and flower extracts of A. macrophylla; these differences may have a substantial impact on the manifestation of the biological and pharmacological effects of the extracts in question.
... Coumarins are non-flavonoids polyphenols, o-hydroxycinnamic acid lactones (also known as 2H-chromen-2-one1,2-benzopyrone) (Gomez--Pinilla and Nguyen, 2012; Sashidhara et al., 2015), a group of sweet-smelling (aromatic) phytochemicals. Coumarins and their derivatives are structurally distinct (Wu et al., 2009;Sahni et al., 2021) and are being used for the treatment of mental health disorders such as schizophrenia, anxiety, and depression (Irvine et al., 2012;Delogu et al., 2014;Pathak et al., 2016;Abourashed, 2018;Rehuman et al., 2020). Several coumarin derivatives have antidepressant effects e.g., scopoletin, umbelliferone, and 7-hydroxycoumarin (Jo et al., 2002;Qin et al., 2017;Lee et al., 2020b;Nabeel et al., 2021;Heghes et al., 2022;Kılıç, 2022;Sinha et al., 2022). ...
... The different pharmacological activities of coumarins and their derivatives is linked to their ability to suppress myosin light chain kinase; restrict the development of the mitotic spindle, which results in cell death, and reduce tyrosine phosphorylation (Wu et al., 2009), while their antidepressant effects may be attributed to their antioxidant and anti-inflammatory properties (Matés et al., 1999;Sulakhiya et al., 2016;Dhiman et al., 2018;Singh et al., 2020;Hasan et al., 2021;Sharma et al., 2022). ...
Coumarins and their derivatives are non-flavonoids polyphenols with diverse pharmacological activities including anti-depressant effects. This study systematically examines the antidepressant effects of coumarins and their derivatives in relation to time series of research progress in the pharmacological pathways, association with other diseases, toxicity and bliometric analysis. The review was approached using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) coupled with R package using Biblioshiny, a web interface for Bibliometrix analysis and VOSviewer software analytic tools. Literature searches were conducted in Scopus, Web of Science, and PubMed from the inception through January 21, 2023. Coumarins, depression, coumarin derivatives and treatment were the main search terms used which resulted in the inclusion of 46 eligible publications. Scopoletin, psoralen, 7-hydroxycoumarin, meranzin hydrate, osthole, esculetin/umbelliferone were the most studied coumarins with antidepressant effects. Coumarins and their derivatives exerted antidepressant effects with a stronger affinity for monoamine oxidase-B (MAO-B) inhibition and, their inhibitory effect via neurotransmitter pathway on MAO is well-studied. However, epigenetic modification, neuroendocrine, neurotrophic pathways are understudied. Recent research focuses on their antidepressant effects which targeted cytokines and fibromyalgia. There is a link between the gut microbiome, the brain, and depression; meranzin hydrate exerts an antidepressant activity by remodelling the gastrointestinal system. We established that empirical data on some coumarins and their derivatives to support their antidepressant effects are limited. Likewise, the safe dosage range of several coumarins and their derivatives is yet to be fully determined.
... Coumarin and its derivatives are natural and synthetic compounds having biological activity for example antifungal, antitubercular, antibacterial, antioxidant properties, anti-HIV agents, antiviral, anticoagulant, anticancer, anti-inflammatory, antibiotics, anti-malarial and so on [1][2][3][4][5][6][7]. Also, these compounds have been broadly applied in the parts of cosmetics, perfumes, medicine, fluorescent dyes, and microfluidic flow system [1][2][3][4][5]. ...
... Coumarin and its derivatives are natural and synthetic compounds having biological activity for example antifungal, antitubercular, antibacterial, antioxidant properties, anti-HIV agents, antiviral, anticoagulant, anticancer, anti-inflammatory, antibiotics, anti-malarial and so on [1][2][3][4][5][6][7]. Also, these compounds have been broadly applied in the parts of cosmetics, perfumes, medicine, fluorescent dyes, and microfluidic flow system [1][2][3][4][5]. Moreover, numerous coumarins have showed appropriate efficacy in the treatment of several categories of illnesses. ...
Recyclable SnO2 nanoparticles catalyze the Pechmann condensation between phenolic alcohols and β-ketoesters at room temperature in ethanol leading to coumarins. Also, in another study the synthesis of biscoumarins catalyzed by SnO2 nanoparticles in the reaction between 4-hydroxycoumarin and aldehydes under same condition reactions. The corresponding coumarins and biscoumarins were produced efficiently with facility and excellent yields (93–98%). These approaches display the advantages of benign reaction conditions, non-chromatographic purification procedure, appropriate functional group tolerance and valuable process.
... Coumarin and its derivatives possess anticoagulant [11][12][13][14] antimicrobial [15,16], antioxidant [17], anti-inflammatory [18], anticancer [19], anti-HIV [20,21], anti-tuberculosis [22,23], anti-influenza [24], anti-Alzheimer [25,26], antiviral [27], antihyperlipidemic [28,29], antihypertensive [30], anticonvulsant [31,32], antiadipogenic [33,34], cytochrome P 450 inhibiting [35,36], neuroprotective [37], analgesic [38,39], antimalarial [40], antidiabetic [41], antitumor [42], and antipsychotic [43] activities. Coumarins also used for the treatment of multiple sclerosis [44]. ...
... The antibacterial screening for coumarinyl chalcones indicates that the compound (12) with bromo substitution at the 6 th position of coumarin ring and ortho-chloro substitution on "B" ring of chalcone has proved to be potent antibacterial activity. ...
Coumarins and chalcones are potential pharmacological and biologically active molecules obtained from natural source. Coumarins have predominant pharmacological activities such as antidiabetic, antitumor, and anti-inflammatory activity. Chalcones are also one of the naturally occurring pharmacologically vital molecules with different activities such as anti-inflammatory, antitumor, antimicrobial, and antimalarial activity. Literature reveals that a huge number of coumarinyl chalcone derivatives have various pharmacological activities. Coumarinyl chalcone derivatives gained more prominence due to their significant biological activities. This work explains the current information about synthesis techniques, pharmacological importance, and clinical applications of coumarinyl chalcone derivatives.
... As a proposed mechanism, initially, the carbonyl group of the aldehyde is activated by H + from SO 3 The amount of catalyst used in this study was 0.01 g, and the catalyst was reusable five times with only a negligible decrease in its catalytic activity. ...
... Nikpassand et al. synthesized azo-linked biscoumarins via nucleophilic addition reaction of aldehydes with two equivalents of 4-hydroxycoumarin. The reaction was efficiently promoted by recyclable 0.05 g nanosized Fe 3 (Fig. 2). ...
Coumarins (2H-1-benzopyran-2-ones) are an important group of biological heterocyclic compounds present in various parts of many plant species, encompassing an array of biological and pharmaceutical activities. In view of the importance of coumarins in heterocyclic chemistry and biological sciences and recent advances in the design of magnetic nanocatalysts, we present herein recent developments pertaining to their synthesis exclusively using magnetic nanoparticles, which can be retrieved easily and thus conform to the tenets of greener synthesis. The preparation of various types of coumarins such as Pechmann-based coumarins, bis coumarins, pyranocoumarins, and coumarin derivatives bearing amine moiety, linked to nicotinonitriles, N-coumarin-2-furanone, and pyrrole-linked chromene derivatives using nanocatalysts with a Fe3O4 core are described. This review covers the synthetic developments in the recent years 2012–2021 and focuses entirely on the synthesis of coumarins in the presence of magnetic nanocatalysts using greener approaches such as solvent-free conditions or deploying alternative activation methods, namely microwave or ultrasound irradiation.
... They also exhibit a wide range of biological functions, including anti-inflammatory, antioxidant, antibacterial, and anticancer [22]. Among these, scopoletin is a representative coumarin derivative of noni fruit [23]. In this study, all samples contained major iridoid compounds such as deacetylasperulosidic acid, asperulosidic acid, and asperuloside. ...
Morinda citrifolia L. (Noni) has been widely used in traditional medicine in tropical zones and has become increasingly popular globally owing to its health benefits. Most noni fruits are consumed as juice, which is traditionally produced by the natural fermentation of noni fruits. In this study, the metabolic profiles of noni fruit juice (NJ1) and fermented noni fruit juices (NJ2 and NJ3) was compared. A total of 74, 83, and 91 compounds including anthraquinones, coumarins, flavonoids, phenolic acids, phenolics, terpenoids, and miscellaneous (acids, carbohydrates, vitamins, fatty acids, etc.) were tentatively identified from NJ1, NJ2, and NJ3 in both positive and negative electrospray ionization modes. The phenolic compound composition differed significantly between noni juice and fermented noni juice. The results of the unsupervised principal component analysis and hierarchical clustering analysis showed that the non-fermented juice group clustered with the fermented juice groups. Asperulosidic acid, isoasperulosidic acid, and rutin levels were higher in the NJ1 group than those in the NJ2 group. Deacetylasperulosidic acid and monotropein contents in NJ2 were higher than those in NJ1. Similarly, NJ1 had higher asperulosidic acid and isoasperulosidic acid than those in NJ3. The findings from this study have the potential to enhance the quality of fermented noni juice.
... The differentially abundant metabolites of wolfberry fruits subjected to N1, N2, and N3 treatments were analyzed using a Venn diagram, revealing that isofraxidin was a common differentially abundant metabolite influenced by different nitrogen application levels. Isofraxidin is a coumarin-like substance, and coumarins have gained significant attention in recent years for their diverse physiological activities, including anticancer, antioxidation, anti-inflammation, anti-HIV, anticoagulation, antibacterial, analgesic, and immune-regulating properties (Wu et al., 2009). As isofraxidin was the sole common differentially abundant metabolite across all treatments in this study, coumarins may serve as potential biomarkers for the response of wolfberry fruits to nitrogen. ...
Lycium barbarum L., commonly known as wolfberry, is not only a traditional Chinese medicine but also a highly nutritious food. Its main nutrients include L. barbarum polysaccharide, flavonoid polyphenols, carotenoids, alkaloids, and other compounds, demonstrating its wide application value. This study investigated the effects of nitrogen application on the accumulation of the main nutrients and metabolites in wolfberry fruits under three different nitrogen application rates, namely, N1 (20% nitrogen (N) reduction, 540 kg·ha–2), N2 (medium N, 675 kg·ha–2), and N3 (20% nitrogen increase, 810 kg·ha–2,which is a local conventional nitrogen application amount.). Additionally, due to continuous branching, blossoming, and fruiting of wolfberry plants during the annual growth period, this research also explored the variation in nutritional composition among different harvesting batches. The contents of total sugar and polysaccharide in wolfberry fruit were determined by Fehling reagent method and phenol-sulfuric acid method, respectively;The content of betaine in fruit was determined by high-performance liquid chromatography,and the flavonoids and carotene in the wolfberry fruits were determined by spectrophotometry. Analysis of data over three consecutive years revealed that as nitrogen application increased, the total sugar content in wolfberry fruits initially decreased and then increased. The levels of L. barbarum polysaccharides, total flavonoids, and total carotenoids initially increased and then decreased, while the betaine content consistently increased. Different picking batches significantly impacted the nutrient content of wolfberry fruits. Generally, the first batch of summer wolfberry fruits had greater amounts of total sugar and flavonoids, whereas other nutrients peaked in the third batch. By employing a broadly targeted metabolomics approach, 926 different metabolites were identified. The top 20 differentially abundant metabolites were selected for heatmap generation, revealing that the contents of L-citrulline, 2-methylglutaric acid, and adipic acid increased proportionally to the nitrogen gradient. Conversely, the dibutyl phthalate and 2, 4-dihydroxyquinoline contents significantly decreased under high-nitrogen conditions. The remaining 15 differentially abundant metabolites, kaempferol-3-O-sophorosid-7-O-rhamnoside, trigonelline, and isorhamnosid-3-O-sophoroside, initially increased and then decreased with increasing nitrogen levels. Isofraxidin, a common differentially abundant metabolite across all treatments, is a coumarin that may serve as a potential biomarker for wolfberry fruit response to nitrogen. Differentially abundant metabolites were analyzed for GO pathway involvement, revealing significant enrichment in metabolic pathways and biosynthesis of secondary metabolites under different nitrogen treatments. In conclusion, a nitrogen application of 675 kg·ha–2, 20% less than the local farmers’ actual application, was most beneficial for the quality of four-year-old Ningqi 7 wolfberry fruits. Consumers who purchase wolfberry-dried fruit for health benefits should not consider only the first batch of summer wolfberry fruits. These results offer a broader perspective for enhancing the quality and efficiency of the wolfberry industry.
... Beyond alluring scents, citrus coumarins ( Figure 1) unveil an arsenal of potent anti-breast cancer activities. Their versatile structure and diverse substituents enable potent pharmacological effects and the development of active derivatives with enhanced efficacy (Wu et al., 2009) Citrus coumarins (auraptene, imperatorin, phellopterin, scoparone, myrsellin, triphasiol, umbelliferone, citropten) offer a compelling multipronged attack (Kerekes et al., 2022;Prince et al., 2009). ...
The genus Citrus L. belongs to the Rutaceae family of flowering plants and shrubs. Citrus genus has valuable edible fruits such as oranges, lemons, grapefruits, pomelos, and limes. Australia, Melanesia, Southeast Asia, East Asia, and South Asia are the native habitats of the genus Citrus. Indigenous societies in these regions have long utilized and tamed various Citrus species. Citrus fruits and their secondary metabolites have been reported to be useful agents in numerous studies to possess anti-inflammatory, antioxidant, and anticancer properties. This review gives an overview of Citrus species and background information on the potential anticancer properties of the compounds identified, along with the related in vitro and in vivo research. Studies from the past have revealed a variety of biological functions that Citrus compounds can regulate, such as angiogenesis, apoptosis, metastasis, cell cycle regulation, and cell proliferation. These promising data call for more investigation into the chemopreventative activity of Citrus and phytoconstituents.
... Auraptene, a natural citrus coumarin, is found in plants Citrus aurantium and Aegle marmelos extract belonging to the Rutaceae family as depicted in Table 2. Previous research has demonstrated that auraptene possesses a variety of beneficial properties, including antiinflammatory (Okuyama et al., 2013), antioxidant (Prince et al., 2009), anticoagulant (Wu et al., 2009), antimicrobial (Takeda et al., 2007), anti-cancer, neuroprotective (Furukawa et al., 2012), and immunomodulatory (Soltani et al., 2010) properties. In Hela cell line migration was significantly altered at 50, 100 μM auraptene after 6 h of incubation and at 100 μM after 24 h. ...
Monoterpenoids, a sub-class of terpenoids, are secondary metabolites frequently extracted from the essential oils of aromatic plants. Their antitumor properties including antiproliferative, apoptotic, antiangiogenic, and antimetastatic effects along with other biological activities have been the subject of extensive study due to their diverse characteristics. In recent years, numerous investigations have been conducted to understand its potential anticancer impacts, specifically focusing on antiproliferative and apoptotic mechanisms. Metastasis, a malignancy hallmark, can exert either protective or destructive influences on tumor cells. Despite this, the potential antimetastatic and antiangiogenic attributes of monoterpenoids need further exploration. This review focuses on specific monoterpenoids, examining their effects on metastasis and relevant signaling pathways. The monoterpenoids exhibit a high level of complexity as natural products that regulate metastatic proteins through various signaling pathways, including phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin, mitogen-activated protein kinase/extracellular signal-regulated kinase/jun N-terminal kinase, nuclear factor kappa B, vascular endothelial growth factor, and epithelial mesenchymal transition process. Additionally, this review delves into the biosynthesis and classification of monoterpenoids, their potential antitumor impacts on cell lines, the plant sources of monoterpenoids, and the current status of limited clinical trials investigating their efficacy against cancer. Moreover, monoterpenoids depict promising potential in preventing cancer metastasis, however, inadequate clinical trials limit their drug usage. State-of-the-art techniques and technologies are being employed to overcome the challenges of utilizing monoterpenoids as an anticancer agent.
... Their biological activities ascribe their ability to interact with different enzymes and receptors in living cells. Coumarin and its heterocyclic derivatives do employ as an antimicrobial, antitumor, anti-inflammatory, aromatase, anticancer activity, [2] powerful antioxidants, cyclooxygenase, [3] fluorescent probes, scavenge reactive oxygen species, osteoporosis, anti-HIV agent, [4] and cognitive deficits. [5] C-4 substituted coumarin is majorly used in the production of anticancer agents, cytotoxic, [7] & agent of anti-tubulin activities, [8] and C-3 substituted used for anti-inflammatory, cyclooxygenase, selective human carbonic anhydrase, [6] and α-glucosidase, [9] etc. Nowadays; many synthetic procedures have been developed for enhancing the chemical reactivity of coumarins towards the invention of bioactive moieties. ...
Coumarin is a highly proficient scaffold with great effectiveness which uplifts emerging chemists to create coumarin derivatives using cutting‐edge synthetic techniques. However, severe reaction conditions are required to develop substituted coumarin analogous. Notably, the carboxylic acid group in coumarin has emerged as a flexible functionality facilitating the construction of coumarin‐containing building blocks, emphasizing the decarboxylative strategy. Use of the decarboxylative technique has tremendously increased, due to its ability to increase the reactivity of the substrate. Moreover, it is the most extensively investigated synthetic strategy incorporating various functionalities in coumarin nuclei. This review discusses the decarboxylative strategies for creating C‐3 and C‐4 substituted coumarin derivatives. It emphasizes various interactions, including catalyst‐based, catalyst‐free, Michael addition, cyclo addition, three components, oxidative, and photocatalytic system involving the decarboxylation process.
... Many drugs based on natural products have been introduced to the market by the advent of research in medicinal chemistry, to the point that these drugs constitute nearly half of the new chemical entities in the last 30 years (Crane & Gademann, 2016). Coumarins have also been exploited in drug discovery (Wu et al., 2009) as they have diverse pharmacological properties including anti-cancer (El-Gamal & Oh, 2014;Emami & Dadashpour, 2015;Kostova, 2005;Tan et al., 2014;Thakur et al., 2015;Zhao et al., 2014) anti-oxidant (Al-Majedy et al., 2016Kostova et al., 2011;Ozalp et al., 2020), lipid-lowering (Yuce et al., 2009), anti-coagulant (Danis et al., 2010;Weigt et al., 2012) and anticholinesterase activity ( € Ozdemir et al., 2023). Furthermore, coumarins are associated with low toxicity (Belluti et al., 2010;Matos et al., 2015;Venugopala et al., 2013) and they are capable of bearing various substituents (Alparslan & Danı ş, 2015;Anand et al., 2012;Annunziata et al., 2020;Jameel et al., 2016;Singh & Sharma, 2021;Tafesse et al., 2020;Yuce-Dursun et al., 2022). ...
A series of arylcoumarin derivatives and two novel biscoumarin derivatives were investigated for their human recombinant glutathione S-transferase P1-1 (GSTP1-1) enzyme inhibitory activities for the first time. 4-(3,4-Dihydroxyphenyl)-6,7-dihydroxycoumarin (compound 24) was observed to be the most active coumarin derivative (IC50: 0.14 µM). The inhibition was found to be time-dependent and irreversible. Hypothetical binding modes of the ten most active compounds were calculated by molecular docking. Ligand efficiency indices (LEI) were estimated to better understand the binding performance of the coumarin derivatives. Extensive structure-activity relationship studies showed that hydroxy substitution on both the coumarin and the aryl ring enhanced the biological activity and the position of hydroxy group on the coumarin ring is critical for the binding pose and the activity. Top three ligands were subjected to molecular dynamics simulations and MM/PBSA for further investigation. Binding mode of compound 24 suggested that its high inhibitory activity might be attributed to its position between Tyr7 and the cofactor, glutathione (GS-DNB). Exhibiting favorable druglikeness profiles and pharmacokinetics based on ADME studies, compound 5 and 24 can be considered as potential drug leads in future studies for further development.
... On the other hand, chromene (2H-1-benzopyran) derivatives have been extensively used as key intermediates in the synthesis of a large variety of natural products and medicinal agents. This significant class of compounds has garnered considerable interest as an active anticancer and apoptotic scaffold with a variety of suggested pathways [73,74,77]. Because breast cancer is the most frequently diagnosed form of cancer and the leading cause of cancer mortality in women worldwide today [78], several molecules centered on the chromene ring system, including coumarins, have been synthesized and shown to have antiproliferative action against breast cancer [75,76]. ...
Chromene is a naturally abundant heterocyclic compound found in alkaloids, tocopherols, terpenes and other compounds. Its derivatives can be used as a scaffold that exhibits pharmacological activity in the human body. Chromene drugs and related bioactive molecules are the prime focus of this reference. It presents 13 thoroughly researched chapters that comprehensively cover all aspects about the molecule. Starting with a detailed introduction to its role and importance in drug discovery, the book goes into the details of chromene structure, synthesis and pharmacology. Readers can gain knowledge of different commercial medicines based on chromene and its pharmacological activity against different diseases. The elaborate topics in the book will help researchers working on chromene based drugs.
Key highlights of the book include:
- Complete coverage of chromene's role in nature and drug development with references to historical background and current developments
- References to commercial and preclinical drugs and patents of interest
- Explanation of chromene bioacivity in different diseases (antioxidant, antidiabetic, antinflammatory, antibacterial and antifungal activities, antitumour, immunomodulatory activity)
- Explanation of chromene activity against SARS-Cov2
... In addition to traditional multitarget heparin and vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs), FXa inhibitors (such as rivaroxaban, apixaban and edoxaban) and FIIa inhibitors (direct thrombin inhibitors, such as dabigatran) are widely used (Hirsh et al., 2019). VKAs that act as natural anticoagulants, such as coumarins, are an important class of oxygenated heterocyclic compounds that are often found as secondary metabolites in plants (Wu et al., 2009), and its derivative warfarin is more commonly used in clinical practice. Although warfarin is widely used, it is subject to multiple food and drug interactions, unpredictable anticoagulant functions and a narrow therapeutic range that requires regular international normalized ratio (INR) monitoring, as well as a risk of severe bleeding, even in patients with well-controlled anticoagulation. ...
Background:
Anticoagulants are the main drugs used for the prevention and treatment of thrombosis. Currently, anticoagulant drugs are primarily multitarget heparin drugs, single-target FXa inhibitors and FIIa inhibitors. In addition, some traditional Chinese drugs also have anticoagulant effects, but they are not the main direction of treatment at present. But the anticoagulant drugs mentioned above, all have a common side effect is bleeding. Many other anticoagulation targets are under investigation. With further exploration of coagulation mechanism, how to further determine new anticoagulant targets and how to make traditional Chinese medicine play anticoagulant role have become a new field of exploration.
Purpose:
The purpose of the study was to summarize the recent research progress on coagulation mechanisms, new anticoagulant targets and traditional Chinese medicine.
Methods:
A comprehensive literature search was conducted using four electronic databases, including PubMed, Embase, CNKI, Wanfang database and ClinicalTrials.gov, from the inception of the study to 28 Feb 2023. Key words used in the literature search were "anticoagulation", "anticoagulant targets", "new targets", "coagulation mechanisms", "potential anticoagulant", "herb medicine", "botanical medicine", "Chinese medicine", "traditional Chinese medicine", "blood coagulation factor", keywords are linked with AND/OR. Recent findings on coagulation mechanisms, potential anticoagulant targets and traditional Chinese medicine were studied.
Results:
The active components extracted from the Chinese medicinal herbs, Salvia miltiorrhiza, Chuanxiong rhizoma, safflower and Panax notoginseng have obvious anticoagulant effects and can be used as potential anticoagulant drugs, but the risk of bleeding is unclear. TF/FVIIa, FVIII, FIX, FXI, FXII, and FXIII have all been evaluated as targets in animal studies or clinical trials. FIX and FXI are the most studied anticoagulant targets, but FXI inhibitors have shown stronger advantages.
Conclusion:
This review of potential anticoagulants provides a comprehensive resource. Literature analysis suggests that FXI inhibitors can be used as potential anticoagulant candidates. In addition, we should not ignore the anticoagulant effect of traditional Chinese medicine, and look forward to more research and the emergence of new drugs.
... Acenocoumarol is a common anticoagulant agent that is available in the form of quarter-scored film-coated tablets for oral administration. [1][2][3] This medicine has a short half-life ranging from 8 to 24 h. 4,5 Therefore, acenocoumarol therapy is challenging and the patients also exhibit a large variability in their anticoagulant response. ...
Acenocoumarol (anticoagulant agent) is not capable to work fast in some patients due to the narrow range of half-life. Therefore, anticoagulant activity was increased by synthesizing and characterizing the chiral separation of five new imino derivatives (3a-e) of acenocoumarol. These derivatives are racemic and the existing 20 stereoisomers were separated by chiral HPLC with Chiralpak® IB column under normal mobile phase mode. The values of the retention, serration, and resolution factors were 0.11-0.63; 1.11-2.21, and 0.28-2.16, respectively. The absolute configuration of all 20 stereoisomers was determined by ECD and HPLC results. The geometry optimization of all the 20 stereoisomers was done by DFT calculations. The enhanced biological activities were also predicted using DFT calculations. 102 R/Z, 103 R/Z, 104 R/E, 105 R/E, and 106 R/Z stereoisomers are the most stable structures among the twenty stereoisomers studied. The energy difference between EHOMO and ELUMO (-0.1353 to -0.22271 eV) indicated good biological activities of these derivatives. High dipole moment values (7.20-18.8) are an indication of good receptor interactions through non-covalent bonding. The synthesized, characterized, and optically active separated stereoisomers are better anticoagulant agents than acenocoumarol. This work will provide better medication in the future for all patients.
... Coumarins are a phytochemical group, which displayed a high presence in the stems and leaves of the plant. This suggests a large biological potential of these plant parts because coumarins have shown to possess high antioxidant and antibacterial activities and have recently been associated with anti-cancer, anti-inflammatory, and analgesic properties (16). In addition, saponins, phenolics, and glycosides are phytochemical groups which appear frequently in the phytochemical screening. ...
Introduction: Portulacaria afra is a medicinal plant commonly used among African traditional healers to treat skin conditions and dehydration. The aim of this study was to scientifically validate the use of P. afra among traditional healers. Methods: Standard phytochemical colour tests were used to determine the presence of ten phytochemicals, using four solvents of varying polarities (hexane, ethyl acetate, methanol, and water). The antioxidant activity was determined using 1-diphenyl-2-picrylhydrazyl (DPPH) and hydrogen peroxide scavenging assays. An agar-well diffusion assay was used to determine the antibacterial activities of the leaves, stems, and roots of P. afra against Staphylococcus aureus and Escherichia coli. Results: P. afra exhibited a high phytochemical presence in the methanolic extracts, with seven out of the 10 phytochemical groups present. Flavonoids and phlobatannins were absent in all of the plant’s extracts. The methanolic root extract exhibited the highest DPPH scavenging activity (IC50=0.39) whilst the hexane leaf extract (IC50= 14.83) was the only extract to exceed the acceptable upper limit. The scavenging activity of the plant was stronger against hydrogen peroxide than it was against DPPH. The methanolic and hot water stem extracts displayed the largest zone of inhibition (of 20 mm) against E. coli. The cold-water and room-temperature water extracts, of all three plant parts, showed no zone of inhibition against either bacterial strain. Conclusion: P. afra has the capacity to be used as a nutritional supplement for its antioxidant properties, while the antibacterial properties may provide relief against E. coli infections.
... Since then, coumarins have continuously been the focus of scientists and have extensively been studied for biochemical and pharmaceutical properties. [8][9][10] On the other hand, 1,2,4-triazole and thiophene are five-membered nitrogen-and sulfurcontaining heterocyclic molecules, respectively. These molecules adopt a planar structure and are aromatic with the corresponding aromaticity index[0.8 ...
Unlabelled:
Synthesis, characterization and theoretical studies of a novel coumarin-triazole-thiophene hybrid 4-(((4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-6,7-dimethyl-2H-chromen-2-one (1), which was fabricated from 4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazole-3-thiol and 4-(chloromethyl)-6,7-dimethyl-2H-chromen-2-one, are reported. The resulting compound was characterized by microanalysis, IR, 1H, and 13C APT NMR spectroscopy. The DFT calculations examined the structure and electronic properties of 1 in gas phase. Its reactivity descriptors and molecular electrostatic potential revealed the reactivity and the reactive centers of 1. ADMET properties of 1 were evaluated using the respective online tools. It was established that 1 exhibit positive gastrointestinal absorption properties and negative human blood-brain barrier penetration. The Toxicity Model Report revealed that 1 belongs to toxicity class 4. Molecular docking was additionally applied to study the interaction of 1 with some SARS-CoV-2 proteins. It was established that the title compound is active against all the applied proteins with the most efficient interaction with Papain-like protease (PLpro). The interaction of 1 with the applied proteins was also studied using molecular dynamics simulations.
Graphical abstract:
A novel coumarin-triazole-thiophene hybrid 4-(((4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazol-3-yl)thio)methyl)-6,7-dimethyl-2H-chromen-2-one (1) is reported. The structure and electronic properties of 1 were examined by the DFT calculations. ADMET properties of 1 were also evaluated. Molecular docking and molecular dynamics simulations were applied to study interactions of 1 with a series of the SARS-CoV-2 proteins.
Supplementary information:
The online version contains supplementary material available at 10.1007/s12039-022-02127-0.
... Members of the coumarin family have also been isolated from microbes. This moiety is used in many aromas, textile, and medicinal products, particularly as anticoagulants like dicoumarol and warfarin, whose the first synthesis was described in 1882 [17,18]. Since coumarins exhibit selective potency against CYP19/CYP17, it has been a heterocycle of interest. ...
Coumarin is a bicyclic oxygen bearing heterocyclic scaffold formed by fusion of benzene with the pyrone ring. Because of its unique physicochemical characteristics and the ease with which it may be transformed into a wide range of functionalized coumarins during synthesis, coumarin provides a privileged scaffold for medicinal chemists. As a result, many coumarin derivatives have been developed, synthesized, and evaluated to target a variety of therapeutic domains, thereby making it an attractive template for designing novel anti-breast cancer compounds. The main culprit in estrogen overproduction in the estrogen-dependent breast cancer (EDBC), is the enzyme aromatase (AR), and it is thought to be a significant target for the effective treatment of EDBC. Considering coumarins versatility, this review presents a detailed overview of diverse study of aromatase as a target for coumarins. An overview of structure–activity relationship analysis of coumarin core is also included so as to summarize the desired pharmacophoric features essential for design and development of aromatase inhibitors (AIs) using coumarin core. Identification of key synthesis techniques that could aid researchers in designing and developing novel analogues with significant anti-breast cancer properties along with their mechanism of action have also been covered in the current review.
Graphical Abstract
... Coumarins are one of the most significant heterocyclic moieties due to their unique physicochemical features and the versatile and easy modification into different functionalized coumarins. 54 The metal-catalyzed cross dehydrogenative coupling reaction of coumarins with alkenes was explored by different research groups. In 2013, Hong and co-workers developed an efficient and sustainable protocol for the regioselective synthesis of C3-alkenylated coumarins 60 by the cross dehydrogenative coupling reaction between coumarins 58 and alkenes 59 in the presence of Pd(OPiv) 2 (10 mol%) and K 2 CO 3 (3 equiv.) in PivOH at 100°C (Scheme 24). ...
Conjugated dienes have occupied a pivotal position in the field of synthetic organic chemistry and medicinal chemistry. They act as important synthons for the synthesis of various biologically important molecules and therefore, gain tremendous attention worldwide. A wide range of synthetic routes to access these versatile molecules have been developed in the past decades. Transition metal-catalyzed cross-dehydrogenative coupling (CDC) has emerged as one of the utmost front-line research areas in current synthetic organic chemistry due to its high atom economy, efficiency, and viability. In this review, an up-to-date summary including scope, limitations, mechanistic studies, stereoselectivities, and synthetic applications of transition metal-catalyzed double Cvinyl-H bond activation for the synthesis of conjugated dienes has been reported since 2013. The literature reports mentioned in this review have been classified into three different categories, i.e. (a) Cvinyl-Cvinyl bond formation via oxidative homo-coupling of terminal alkenes; (b) Cvinyl-Cvinyl bond formation via non-directed oxidative cross-coupling of linear/cyclic alkenes and terminal/internal alkenes, and (c) Cvinyl-Cvinyl bond formation via oxidative cross-coupling of directing group bearing alkenes and terminal/internal alkenes. Overall, this review aims to provide a concise overview of the current status of the considerable development in this field and is expected to stimulate further innovation and research in the future.
... Coumarins, also known as 1, 2-benzopyrones, are another important class of isoflavonoids and are widely distributed in fruits such as cherries and berries (Kumar et al. 2021;Wu et al. 2009). The only phenylcoumarin isolated from the Millettia species Phytochem Rev considered in this review was 4-hydroxy-5, 6, 7-trimethoxy-3-(3',4'-methylenedioxy)phenylcoumarin (146) (Fig. 7). ...
There are approximately 260 known species in the genus Millettia, many of which are used in traditional medicine to treat human and other animal ailments in various parts of the world. Being in the Leguminosae (Fabaceae) family, Millettia species are rich sources of isoflavonoids. In the past three decades alone, several isoflavonoids originating from Millettia have been isolated, and their pharmacological activities have been evaluated against major diseases, such as cancer, inflammation, and diabetes. Despite such extensive research, no recent and comprehensive review of the phytochemistry and pharmacology of Millettia isoflavonoids is available. Furthermore, the structural diversity of isoflavonoids in Millettia species has rarely been reported. In this review, we comprehensively summarized the structural diversity of Millettia isoflavonoids, the methods used for their extraction and isolation protocols, and their pharmacological properties. According to the literature, 154 structurally diverse isoflavonoids were isolated and reported from the various tissues of nine well-known Millettia species. Prenylated isoflavonoids and rotenoids were the most dominant subclasses of isoflavonoids reported. Other subclasses of reported isoflavonoids include isoflavans, aglycone isoflavones, glycosylated isoflavones, geranylated isoflavonoids, phenylcoumarins, pterocarpans and coumaronochromenes. Although some isolated molecules showed promising pharmacological properties, such as anticancer, anti-inflammatory, estrogenic, and antibacterial activities, others remained untested. In general, this review highlights the potential of Millettia isoflavonoids and could improve their utilization in drug discovery and medicinal use processes.
Supplementary information:
The online version contains supplementary material available at 10.1007/s11101-022-09845-w.
Within the realm of cancer therapeutics, coumarin derivatives stand out as a promising class of compounds, exhibiting a wide array of biological effects and demonstrating significant potential for anticancer activity while minimizing detrimental side effects. This comprehensive study endeavours to navigate through the broad spectrum of coumarin derivatives, offering a thorough exploration of their synthetic methodologies, target cancer cell lines and the intricate interplay between chemical structure and biological activity. Through an unbiased analysis, this research aims to unravel the complex structure–activity relationships that govern the anticancer efficacy of coumarin derivatives, shedding light on their underlying mechanisms of action within cellular pathways. By highlighting the recent research findings it provides a holistic understanding of the therapeutic potential of coumarin derivatives, offering insights that could pave the way for their future application in cancer therapy.
Herein, we report a viable protocol to access furo[3,2-c]chromen-4-ones engaging easily accessible 4-hydroxy coumarins as a three-atom CCO unit and thioamides as a C2 coupling partner mediated by phenyliodine(III) diacetate...
Regulation of pH plays an essential role in orchestrating the delicate cellular machinery responsible for life as we know it. Its abnormal values are indicative of aberrant cellular behavior and associated with pathologies including cancer progression or solid tumors. Here, we report a series of bent and linear aminobenzocoumarins decorated with different substituents. We investigate their photophysical properties and demonstrate that the probes display strong pH‐responsive fluorescence “turn on” behavior in highly acidic environments, with enhancement up to 300‐fold. In combination with their low cytotoxicity, this behavior enabled their application in bioimaging of acidic lysosomes in live human cells. We believe that these molecules serve as attractive lead structures for future rational design of novel biocompatible fluorescent pH probes.
Leishmaniasis is a neglected parasitic tropical disease with numerous clinical manifestations. One of the causative agents of cutaneous leishmaniasis (CL) is Leishmania tropica (L. tropica) known for causing ulcerative lesions on the skin. The adverse effects of the recommended available drugs, such as amphotericin B and pentavalent antimonial, and the emergence of drug resistance in parasites, mean the search for new safe and effective anti-leishmanial agents is crucial. Miltefosine (MIL) was the first recommended oral medication, but its use is now limited because of the rapid emergence of resistance. Pharmaceutical cocrystallization is an effective method to improve the physicochemical and biological properties of active pharmaceutical ingredients (APIs). Herein, we describe the cocrystallization of coumarin-3-carboxylic acid (CU, 1a; 2-oxobenzopyrane-3-carboxylic acid, C10H6O4) with five coformers [2-amino-3-bromopyridine (1b), 2-amino-5-(trifluoromethyl)-pyridine (1c), 2-amino-6-methylpyridine (1d), p-aminobenzoic acid (1e) and amitrole (1f)] in a 1:1 stoichiometric ratio via the neat grinding method. The cocrystals 2–6 obtained were characterized via single-crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry and thermogravimetric analysis, as well as Fourier transform infrared spectroscopy. Non-covalent interactions, such as van der Waals, hydrogen bonding, C—H⋯π and π⋯π interactions contribute significantly towards the packing of a crystal structure and alter the physicochemical and biological activity of CU. In this research, newly synthesized cocrystals were evaluated for their anti-leishmanial activity against the MIL-resistant L. tropica and cytotoxicity against the 3T3 (normal fibroblast) cell line. Among the non-cytotoxic cocrystals synthesized (2–6), CU:1b (2, IC50 = 61.83 ± 0.59 µM), CU:1c (3, 125.7 ± 1.15 µM) and CU:1d (4, 48.71 ± 0.75 µM) appeared to be potent anti-leishmanial agents and showed several-fold more anti-leishmanial potential than the tested standard drug (MIL, IC50 = 169.55 ± 0.078 µM). The results indicate that cocrystals 2–4 are promising anti-leishmanial agents which require further exploration.
Background
Frederico José de Santa-Anna Nery (1848–1901) was a Brazilian Baron who referred to himself as a "volunteer propagandist" for Brazil in Europe, serving as an immigration agent to publicize the living conditions in the Amazon region, advocating for its development and modernization at the end of the nineteenth century. Santa-Anna Nery’s most famous book is "Le Pays des Amazones" (The Lands of the Amazons), first published in 1885, which the author dedicated a chapter to introduce and report on the Amazonian useful plant species and its relationship with humans. The aim of this work is to understand the historical context and ethnobotanical value of the plant species in the Brazilian Amazon at the end of the nineteenth century through an analysis of the book “Le Pays des Amazones” (1885) by Baron de Santa-Anna Nery, as well as to bring to light the historical importance of this very influential propagandist, who has been forgotten nowadays.
Methods
The original book “Le Pays des Amazones” (1885), as well as the original 3rd edition and its translated version into Portuguese, was carefully analyzed and all information about plants was systematized, with botanical names being updated. Finally, using the scientific name of medicinal plants alone or in combination with their traditional use, a search was carried out in databases in order to indicate current pharmacological studies that provide evidence about the described traditional uses.
Results
A total of 156 plant species were identified in the book, although 132 species had their scientific names updated. These species belong to 45 different families, with Fabaceae and Arecaceae the most represented, and 109 plants are Brazilian native. Considering only the 36 medicinal plants, the main medicinal indications reported were astringent, purgative/laxative, stimulant and tonic, vermifuge, febrifuge, sudorific, emetic, diuretic and antidysenteric. Regarding other useful plants (non-medicinal), 97 species were cited for food, constructions and buildings, spices and condiments, ornaments and objects, carpentry, textile fibers, gums, oils, balms and essences, pigments and tanning, hunting and fishing.
Conclusions
When the book “Le Pays des Amazones” is analyzed from a timeless perspective, with a particular focus on historical ethnobotany, it is possible to observe the economic, social, and political importance of many useful plants for the Amazon at the end of the nineteenth century and how the relationship between local people, indigenous communities, and immigrants was established with plant biodiversity.
Geijera Schott is a plant genus of the Rutaceae Juss. (rue and citrus) family, comprising six species which are all native to Oceania. Of the plants belonging to this genus, the most significant species that has a customary use is Geijera parviflora, which was used by Indigenous Australians, primarily as a pain reliever. Herein, a comprehensive review of the literature published on the genus Geijera from 1930 to 2023 was conducted. This is the first review for this plant genus, and it highlights the chemical constituents reported to date, together with the range of pharmacological properties described from the various species and different parts of the plant. These properties include anti-inflammatory, anti-microbial, anti-parasitic, insect repellent, analgesic, neuroactive, and anti-cancer activities. Finally, a reflection on some of the important areas for future focused studies of this plant genus is provided.
New chalcones (2a-e) were prepared by Claisen-Schmidt condensation from 3-acetyl-4-hydroxycoumarin, which was used as a key intermediate in this synthesis. However, we can easily obtain compounds (3a-e) by refluxing chalcone (2a-e) with 4-hydroxycoumarin in the presence of ammonium acetate and glacial acetic acid. Multinuclear NMR (¹H and ¹³C), IR and elemental analysis characterized the structure of the final compound. The antibacterial activity of the obtained products against various bacterial strains was tested in vitro. The antioxidant properties of the same synthesized compounds were also studied using DPPH (2,2-diphenyl-1-trinitrophenylhydrazine) and hydroxyl radical scavenging tests. Furthemore a study was conducted to highlight the nature of the effects produced by screening 2a-e and 3a-e products on colon cancer cell lines (HCT-116) and hepatocellular carcinoma cell lines (HepG-2). Good cytotoxic activity against standard vinblastine was observed for compound 3a.
•3-acetyl-4-hydroxycoumarin as a simple coumarinic ketone was modified to coumarins-bonded chalcones.
•Modification was performed through two steps reaction.
•Final products exhibited free radical scavenging activity and Good cytotoxic
The concise syntheses of the coumarin natural product, minutuminolate (1), and its related natural products, 7-methoxy-8-(2-acetoxy-3-methyl-1-oxobut-2-enyl) coumarin (2) and muralatin I (3), were accomplished for the first time in 4–5 steps from the commercially available umbelliferone. The key step involves a palladium-catalyzed oxidative rearrangement reaction to assemble the α-acyloxyenone moiety in 1 and 2. The incorporation of this functionality enables the successful synthesis of coumarin 3 through an acidic hydrolysis reaction. The anti-inflammatory activities of the compounds were also evaluated against tumor necrosis factor-alpha production in lipopolysaccharides-stimulated RAW264.7 cells. Our developed synthetic route will facilitate the development of analogues and derivatives of 1–3 with potent anti-inflammatory activities.
Osthole is a coumarin derived natural compound which is an essential ingredient of Traditional Chinese Medicine (TMC) which is widely distributed in nature in plants like Cnidium monnieri (L) Cusson and Angelica pubescens. Current study presents a critical review on description of pharmacological importance of osthole, which is reported to exhibit anticancer, antioxidant, osteogenic, hepatoprotective, neuroprotective, cardiovascular protective, antimicrobial, immuno-modulatory and inflammatory activities. Till date, the reports include pharmacological properties, brief chemistry or on advanced methods to explore osthole content in variety of plants. Present review seeks to highlight the sources, biosynthesis, extraction methods, pharmacological properties of the molecule and its derivatives. A brief discussion on patents recently published and granted on the molecule has also been highlighted. Thus the overview of the literature presents the analysis about future possible modalities of the research on this molecule.
Background: The unprecedented overuse and illogical prescribing of antibiotics for various illnesses has accelerated the evolution of antibiotic-resistant bacteria, which has contributed to the resurgence of pathogenic strains with strengthened resistance to conventional therapies. Rising resistance has threatened human health and increased the expense of treating diseases, compromising the treatment procedure for a wide range of antibiotics. Microbes are diversifying quickly due to rapid evolution, which makes it difficult to develop management strategies. This favours the use of plant-derived antimicrobials obtained from medicinal plants to treat diseases. Over the last two decades, an abundance of plant-derived antimicrobials with a wide spectrum of activity against numerous pathogens that cause human infections have been discovered via extensive research. There are various compounds with active components that have been found and are marketed. They have great antibacterial power and can be utilised as antibiotic resistance modifiers or antimicrobials. The current study focuses on the characteristics of plant antimicrobials, their mechanisms of action in combating the rise in microbial resistance, and, in particular, the varied impacts of plant compounds on virulence factors, which are crucial for pathogenicity within the host. Creating new alternatives is necessary due to the very challenging condition of antibiotic resistance that develops amongst bacteria exposed to antibiotics. Due to their high antibacterial action, plant-based antimicrobials have the potential to be utilized in the manufacturing of medicines.
Psoralea corylifolia L. (P. corylifolia) has attracted increasing attention because of its potential hepatotoxicity. In this study, we used network analysis (toxic component and hepatotoxic target prediction, proteinprotein interaction, GO enrichment analysis, KEGG pathway analysis, and molecular docking) to predict the components and mechanism of P. corylifolia-induced hepatotoxicity and then selected 4-hydroxylonchocarpin and corylifol A for experimental verification. HepG2 cells were treated with low, medium, and high concentrations of 4-hydroxylonchocarpin or corylifol A. The activities of ALT, AST, and LDH in cell culture media and the MDA level, SOD activity, and GSH level in cell extracts were measured. Moreover, apoptosis, ROS levels, and mitochondrial membrane potential were evaluated. The results showed that the activities of ALT, AST, and LDH in the culture medium increased, and hepatocyte apoptosis increased. The level of MDA increased, and the activity of SOD and level of GSH decreased, and the ROS level increased with 4-hydroxylonchocarpin and corylifol A intervention. Furthermore, the mitochondrial membrane potential decreased in the 4-hydroxylonchocarpin and corylifol A groups. This study suggests that 4-hydroxylonchocarpin and corylifol A cause hepatocyte injury and apoptosis by inducing oxidative stress and mitochondrial dysfunction, suggesting that these compounds may be the potential hepatotoxic components of P. corylifolia.
Background:
Neurodegenerative diseases are among the diseases that cause the foremost burden on the health system of the world. The diseases are multifaceted and difficult to treat because of their complex pathophysiology, which includes protein aggregation, neurotransmitter breakdown, metal dysregulation, oxidative stress, neuroinflammation, excitotoxicity, etc. None of the currently available therapies has been found to be significant in producing desired responses without any major side effects; besides, they only give symptomatic relief otherwise indicated off-episode relief. Targeting various pathways, namely choline esterase, monoamine oxidase B, cannabinoid system, metal chelation, -secretase, oxidative stress, etc., may lead to neurodegeneration. By substituting various functional moieties over the coumarin nucleus, researchers are trying to produce safer and more effective neuroprotective agents.
Objectives:
This study aimed to review the current literature to produce compounds with lower side effects using coumarin as a pharmacophore.
Methods:
In this review, we have attempted to compile various synthetic strategies that have been used to produce coumarin and various substitutional strategies used to produce neuroprotective agents from the coumarin pharmacophore. Moreover, structure-activity relationships of substituting coumarin scaffold at various positions, which could be instrumental in designing new compounds, were also discussed.
Results:
The literature review suggested that coumarins and their derivatives can act as neuroprotective agents following various mechanisms.
Conclusion:
Various studies have demonstrated the neuroprotective activity of coumarin due to an oxaheterocyclic loop, which allows binding with a broad array of proteins, thus motivating researchers to explore its potential as a lead against various neurodegenerative diseases.
In order to develop drugs against cancer, which is one of the deadliest diseases in the world, hybridiz-ing structures with known anticancer activity can provide a dual activity for the treatment of cancer cases. For this purpose, a series of novel hybrid compounds combining lonidamine and 7-hydroxy-4-methylcoumarin via different linker modifications have been synthesized in this study. The chemical structures of the novel compound were elucidated with 1 H and 13 C NMR and mass spectrometry (HRMS) methods. All the synthesized compounds were screened for anticancer activity against MCF-7 and A549 cells. Among them, compound 2 appeared to be the most potent compound on MCF-7 lines; and IC 50 dose was determined as 33.12 μM. IC 50 of Compound 6 was determined as 139.6 μM for A549 cells. Considering anticancer activity studies, compounds 2 and 6 have potential to lead to the development of novel hybrid compounds for cancer therapy. Further studies to identify mechanistic explanations of the bioactivity of these molecules are ongoing and will be reported in due course.
5,7-Dihydroxy-4-methylcoumarin (D4M) is attributed to free radical scavenging effects, with wide application for anti-oxidation. This work aimed to assess D4M's impact on cisplatin-induced ototoxicity. The cell viability was estimated with CCK-8 assay. Apoptosis was detected by the Annexin V-FITC and PI assay. The reactive oxygen species (ROS) level was determined by MitoSOX-Red and CellROX-Green probes. Mitochondrial membrane potential was analyzed with TMRM staining. Immunofluorescence was utilized for hair cells and spiral ganglion neuron detection. Apoptosis-associated proteins were assessed by cleaved caspase-3 and TUNEL staining. These results showed that D4M pretreatment protected hair cells from cisplatin-induced damage, increased cell viability, and decreased apoptosis in House Ear Institute-Organ of Corti1 (HEI-OC1) cells and neonatal mouse cochlear explants. D4M significantly inhibited cisplatin-induced mitochondrial apoptosis and reduced ROS accumulation. In addition, the protective effect of D4M on cisplatin-induced ototoxicity was also confirmed in cochlear hair cells and spiral ganglion neurons in neonatal mice. Mechanistic studies showed that D4M markedly downregulated p-JNK and elevated the expression ratio of p-FoxO1/FoxO1, thereby reducing cisplatin-induced caspase-dependent apoptosis. Meanwhile, D4M-related protection of HEI-OC1 cells was significantly blunted by JNK signaling induction with anisomycin. This study supports the possibility that D4M may be used as a new compound to prevent cisplatin-related hearing loss.
Natural bioactive compounds are molecules’ treasure trove for nutraceuticals, food additives, and functional foods, as they exhibit several structures and activities. Some of these chemicals, such as polyphenols, can be found in high concentrations in nature. However, others are present in such low concentrations that significant harvesting is vital to achieving sufficient quantities, and chemical synthesis is unprofitable due to their structural diversity and complexity. Because screening and synthesizing these compounds are complex, new technologies have been created. The most common approach is traditional liquid or solid–liquid extraction also termed solvent extraction, although modern approaches comprise supercritical and subcritical extractions, pressured liquid extraction, along with microwave and ultrasound-assisted extractions. Such technologies could give a novel technique for increasing the construction of bioactive and usage of such particular compounds as nutraceuticals or as ingredients in functional foods.KeywordsPressured liquid extractionBioactive componentsSolid–liquid extractionFunctional potential
Bioactive compounds isolated from plant sources are the secondary metabolites that have toxicological or pharmacological properties depending upon their structure. Recently, these compounds have received more attention due to their diverse role in providing protection against various types of pathogenic and non-pathogenic diseases. These miraculous bioactive compounds also pursue pharmacological activities against several microbial pathogens and are also known to exhibit antidiabetic, antipyretic, anticancerous, antidiuretic, and antioxidant properties. Some bioactive compounds extracted from plants such as phenolic compounds, anthocyanidins, flavonoids, tannins, and flavones are found in significantly high concentration in the biosphere, and certain others are present in less amount but their pharmacological as well as commercial importance cannot be denied. The activities of bioactive compounds like flavonoids, polyphenols, not only functions to inhibit microbial growth but also they act synergistically with other drugs which make them ideal for alternative cancer remedies. This chapter provides a general insight into secondary metabolites having antimicrobial and anticancerous properties, their plant source, and their mode of actions.KeywordsBioactive compoundsAntimicrobialAnticancerousHuman health
One of the most critical uses in the food business is the encapsulation of food components. Bioactive components are being used in food applications due to growing consumer interest in natural ingredients. Encapsulation is a promising method for improving the stability of bioactive components while allowing for regulated release. This chapter presents an overview of various encapsulation procedures, viz. spray drying, freeze-drying, extrusion, emulsification, coacervation, cocrystallisation, supercritical fluid method, and different encapsulated bioactive compounds, which have been used to fortify food components and deliver them into various functional foods.
frequency of tongue carcinoma was also decreased (100 ppm auraptene, 100% reduction, P < 0.001; 500 ppm auraptene, 74% reduction, P < 0.01). The incidences of tongue severe dysplasia in these groups were significantly smaller than those in carcinogen controls (P < 0.05). There were no pathological alterations in rats treated with 500 ppm auraptene alone or those in an untreated control group. Dietary administration of auraptene significantly decreased BrdU-labelling index and polyamine concentrations in the oral mucosa (P < 0.05). In addition, auraptene administration significantly increased the activities of GST and QR in the liver and tongue. Although dose-dependent effect was not found, citrus auraptene is effective in inhibiting the development of oral neoplasms induced by 4-NQO. Thus, suppression by the initiation-feeding of auraptene might relate to elevation in the phase II enzymes GST and QR of the liver and tongue, and inhibition occurring during the post-initiation might be related to suppression of increased cell proliferation caused by 4-NQO in the oral mucosa.
Aims/hypothesis
The effect of the benzopyran derivative T33, a novel non-thiazolidinedione agent, was studied on peroxisome proliferator-activated receptors (PPARs), insulin signalling and glucose uptake in adipocytes and skeletal muscle. We hypothesised that T33 could activate PPARγ and exert a beneficial effect on insulin action on glucose uptake and lipid metabolism.
Materials and methods
Using a cell-based reporter gene assay, T33 was identified as a PPARα/γ dual agonist, which activated human PPARγ and PPARα with EC50 values of 19 and 148 nmol/l, respectively. The effect of T33 on glucose metabolism was studied in cultured 3T3-L1 adipocytes and L6 myotubes. In vivo effects of T33 on skeletal muscle were determined in ob/ob mice treated with 8 mg/kg T33. The effect of T33 on metabolic abnormalities was observed in diet-induced obese mice.
Results
Exposure of 3T3-L1 adipocytes to T33 for 4 days increased basal and insulin-stimulated glucose uptake, with no effect noted in L6 myotubes. Treatment of ob/ob mice for 20 days with T33 normalised basal and insulin-stimulated glucose uptake and increased phosphorylation of Akt and p38 mitogen-activated protein kinase in skeletal muscle. In contrast, phosphorylation of AMP-activated protein kinase was unaltered. Moreover, T33 improved insulin sensitivity and lipid metabolism in diet-induced obese mice.
Conclusions/interpretation
T33 is non-thiazolidinedione PPARα/γ dual agonist which directly increases basal and insulin-stimulated glucose uptake in adipocytes and secondarily improves insulin action on insulin signalling and glucose metabolism in skeletal muscle from diabetic ob/ob mice.
The biosynthesis of linear and angular furanocoumarins is still poorly understood at the molecular level, with only psoralen
synthase (CYP71AJ1) identified from Ammi majus. Using cDNA probes inferred from CYP71AJ1, three orthologs were isolated from Apium graveolens (CYP71AJ2) and Pastinaca sativa (CYP71AJ3 and -4) and functionally expressed in yeast cells. CYP71AJ2 and CYP71AJ3 displayed psoralen synthase activity, whereas CYP71AJ4
only catalyzed the conversion of (+)-columbianetin to angelicin and negligible amounts of a hydroxylated columbianetin by-product.
CYP71AJ4 thus constitutes the first fully characterized P450 monooxygenase specific for the angular furanocoumarin pathway.
The angelicin synthase exhibited an apparent Km of 2.1 ± 0.4 μm for (+)-columbianetin and a kcat of 112 ± 14 min–1. Moreover, the use of 3′-deuterated (+)-columbianetin as substrate led to an almost complete “metabolic switch,” resulting
in the synthesis of anti-3′-hydroxy-3′-deuterated(+)-columbianetin. This confirms that angelicin synthase attacks columbianetin by syn-elimination of hydrogen from C-3′. Sequence comparison between psoralen synthase (CYP71AJ3) and angelicin synthase (CYP71AJ4)
showed 70% identity, whereas the identity dropped to 40% in those regions thought to provide the substrate recognition sites.
Accordingly, CYP71AJ3 and CYP71AJ4 might be derived from a common ancestor of unknown functionality by gene duplication and
subsequent molecular evolution.
Coumarins (1,2-benzopyrones) are
ubiquitously found in higher plants where they
originate from the phenylpropanoid pathway.
They contribute essentially to the persistence of
plants being involved in processes such as defense
against phytopathogens, response to abiotic stresses,
regulation of oxidative stress, and probably
hormonal regulation. Despite their importance,
major details of their biosynthesis are still largely
unknown and many P450-dependent enzymatic
steps have remained unresolved. Ortho-hydroxylation
of hydroxycinnamic acids is a pivotal step
that has received insufficient attention in the
literature. This hypothetical P450 reaction is
critical for the course for the biosynthesis of
simple coumarin, umbelliferone and other
hydroxylated coumarins in plants. Multiple P450
enzymes are also involved in furanocoumarin
synthesis, a major class of phytoalexins derived
from umbelliferone. Several of them have been characterized at the biochemical level but no
monooxygenase gene of the furanocoumarin
pathway has been identified yet. This review
highlights the major steps of the coumarin pathway
with emphasis on the cytochrome P450
enzymes involved. Recent progress and the outcomes
of novel strategies developed to uncover
coumarin-committed CYPs are discussed.
In the present study, we investigated the inhibitory effect of the known oxycoumarins poncitrin (3), osthol (4), and xanthoxyletin (5), newly isolated from Clausena guillauminii (Rutaceae), together with the known carbazoles heptaphylline (1) and 7-methoxyheptaphylline (2) on inducible-nitric oxide synthase (iNOS) expression induced by lipopolysaccharide (LPS) and the NO generation in RAW 264.7 mouse macrophages. Isolation of active oxycoumarins was guided by Western blot analysis of iNOS protein expression. These oxycoumarins showed an inhibitory effect on iNOS protein expression at 10 microM. Further examination of the inhibitory effects of these compounds on inflammation mediators revealed that the synthesis of nitric oxide (NO) and the protein expression of tumor necrosis factor-alpha (TNF-alpha) and cyclooxygenase-2 (COX-2) were inhibited by 5. It was expected that these compounds show anti-inflammatory activities.
Coumarins, an old class of natural and synthetic benzopyrene derivatives, attract an intense interest because of their diverse pharmacological use. The biochemical properties and therapeutic applications of simple coumarins strongly depend upon the molecular structure of these compounds. Recently their antioxidant effects were extensively examined in connection with possibilities for control over the oxidative stress. Latter is being implicated in many diseases curable by therapy with coumarin-containing drugs. In this review, experimental data for antioxidant properties of coumarins are presented. It was observed that different coumarins may act as antioxidants by scavenging free radicals, by acting as enzymes modulators and by bonding free metal cations in helate complexes. The antioxidant activities are discussed in relation with their molecular structure.
The coumarin (benzopyran-2-one, or chromen-2-one) ring system, present in natural products (such as the anticoagulant warfarin) that display interesting pharmacological properties, has intrigued chemists and medicinal chemists for decades to explore the natural coumarins or synthetic analogs for their applicability as drugs. Many molecules based on the coumarin ring system have been synthesized utilizing innovative synthetic techniques. The diversity oriented synthetic routes have led to interesting derivatives including the furanocoumarins, pyranocoumarins, and coumarin sulfamates (COUMATES), which have been found to be useful in photochemotherapy, antitumor and anti-HIV therapy, and as stimulants for central nervous system, antibacterials, anti-inflammatory, anti-coagulants, and dyes. Of particular interest in breast cancer chemotherapy, some coumarins and their active metabolite 7-hydroxycoumarin analogs have shown sulfatase and aromatase inhibitory activities. Coumarin based selective estrogen receptor modulators (SERMs) and coumarin-estrogen conjugates have also been described as potential antibreast cancer agents. Since breast cancer is the second leading cause of death in American women behind lung cancer, there is a strong impetus to identify potential new drug treatments for breast cancer. Therefore, the objective of this review is to focus on important coumarin analogs with antibreast cancer activities, highlight their mechanisms of action and structure-activity relationships on selected receptors in breast tissues, and the different methods that have been applied in the construction of these pharmacologically important coumarin analogs.
Cinnamate 4-hydroxylase [CA4H; trans-cinnamate,NADPH:oxygen oxidoreductase (4-hydroxylating), EC 1.14.13.11] is a cytochrome P450 that catalyzes the first oxygenation step of the general phenylpropanoid metabolism in higher plants. The compounds formed are essential for lignification and defense against predators and pathogens. We recently reported the purification of this enzyme from Mn(2+)-induced Jerusalem artichoke (Helianthus tuberosus L.) tuber tissues. Highly selective polyclonal antibodies raised against the purified protein were used to screen a lambda gt11 cDNA expression library from wound-induced Jerusalem artichoke, allowing isolation of a 1130-base-pair insert. Typical P450 domains were identified in this incomplete sequence, which was used as a probe for the isolation of a 1.7-kilobase clone in a lambda gt10 library. A full-length open reading frame of 1515 base pairs, encoding a P450 protein of 505 residues (M(r) = 57,927), was sequenced. The N terminus, essentially composed of hydrophobic residues, matches perfectly the microsequenced N terminus of the purified protein. The calculated pI is 9.78, in agreement with the chromatographic behavior and two-dimensional electrophoretic analysis of CA4H. Synthesis of the corresponding mRNA is induced in wounded plant tissues, in correlation with CA4H enzymatic activity. This P450 protein exhibits the most similarity (28% amino acid identity) with avocado CYP71, but also good similarity with CYP17 and CYP21, or with CYP1 and CYP2 families. According to current criteria, it qualifies as a member of a new P450 family.
For Abstract see ChemInform Abstract in Full Text.
When 3-acetyl coumarin derivatives are treated with bromine, 3-(w-bromoacetyl) coumarin derivatives are obtained. The reaction of 3-(w-bromoacetyl) coumarin derivatives with thiourea or with amines for two hours leads to the formation of 2-Amino-4-(3-coumarinyl) thiazole or 3-(w-aminoacetyl) coumarin derivatives, respectively. While 3-(w-bromoacetyl) coumarin derivatives react with amines for 5–8 hours to yield imino derivatives of 3-(w-aminoacetyl) coumarin. The antimicrobial activity ofIa-b, IIa-c, IVc-f, IVh andVc, f, h, k, m, andq was studied.
Fifty-three new 3-(2-diethylaminoethyl)-4-methyl-7-substituted coumarins were synthesized by four different routes utilizing commercially available 3-(2-diethylaminoethyl)-7-hydroxy-4-methylcoumarin hydrochloride. Their antifungal activities were measured against a phytopathologic fungi, Botrytis cinerea. Some compounds with a substituted benzoyloxy, benzoyloxyethoxy, methylbenzoylaminoethoxy, or benzoylaminophenoxy group at the 7-position had an inhibitory effect (MIC: <50 ppm) on the germination of spores in an in vitro screening system. Among them, eight derivatives had interest activities. The highest level of activity (MIC: 7.8 ppm) was observed for the coumarin with a 7-[4-(2,4,6-trichlorobenzoylamino) phenoxy] substitution. This derivative also inhibited the germination of four other plant pathogens, Colletotrichum orbiculare, Alternaria mali, Phytophthora capsici, and Pyricularia oryzae.
Coumarin, a widely used fragrance ingredient, is a rat liver and mouse lung toxicant. Species differences in toxicity are metabolism-dependent, with injury resulting from the cytochrome P450-mediated formation of coumarin 3,4-epoxide (CE). In this study, the enzymes responsible for coumarin activation in liver and lung were determined. Recombinant human and rat CYP1A forms and recombinant human CYP2E1 readily catalyzed CE production. Coinhibition with CYP1A1/2 and CYP2E1 antibodies blocked CE formation by 38, 84, and 67 to 92% ( n = 3 individual samples) in mouse, rat, and human hepatic microsomes, respectively. Although CYP1A and 2E forms seem to be the most active catalysts of CE formation in liver, studies conducted with the mechanism-based inhibitor 5-phenyl-pentyne demonstrated that CYP2F2 is responsible for up to 67% of CE formation in whole mouse lung microsomes. In contrast to the CE pathway, coumarin 3-hydroxylation is a minor product of coumarin in liver microsomes from mice, rats, and humans and is catalyzed predominately by CYP3A and CYP1A forms, confirming that CE and 3-hydroxycoumarin are formed via distinct metabolic pathways.
Abstract Using root tips of Allium cepa as a model system, coumarin, 7-hydroxycoumarin, 4-hydroxycoumarin, psoralen, and xanthotoxin inhibited mitosis. 7-Hydroxycoumarin caused the most marked changes in karyokinesis, which led to chromatin condensation and shortening of chromosomes, as well as disorganisation of microtubules. Other coumarins influenced mostly cytokinesis, causing aberrations in fragmoplast formation and displacement of the middle lamella. The cell wall between sister cells was aberrant, with telophase bridges often occurring late in the post-telophase stage. In the cytoplasm, changes were noted in the mitochondrial structure, ER arrangement and separation of parts of the cytoplasm, in which autolysis was observed. After treatment with 7-hydroxycoumarin the ER became hypertrophic, with cisternae of the rough ER still narrow and arranged in complexes of parallel sheets. After treatment with the psoralens the ER dilated and fragmented into small vesicles. Swollen and dividing megamitochondria suggest that cells may be under stress from oxygen deficiency.
For Abstract see ChemInform Abstract in Full Text.
Feeding experiments of tobacco tissue cultures with (U)-14C-phenylalanine, 2-14C-cinnamic acid, 2-14C-glucosidoferulic acid and methyl-14C-methionine were carried out over periods from 3 min to 10 hr. The use of short feedings enabled us to study the kinetic aspect of the biosynthesis and to demonstrate the following main pathway: phenylalanine → free cinnamic acid → free p-coumaric acid → free caffeic acid → free ferulic acid → scopoletin → scopolin. Turn-over rates of free forms were shown to be much higher than those of the corresponding bound forms.
α-Chymotrypsin is rapidly and irreversibly inactivated by 3,4-dihydro-3,4-dibromo-6-bromo-methylcoumarin (VII) at neutral pH. The inactivation is pH dependent between pH 5 and 7 and is delayed when the active site of the enzyme is protected by acetylation of the active serine-195 or by binding of a competitive inhibitor.
This dihydrocoumarin VII and its 6-methyl analogue are substrates for α-chymotrypsin, but when the ester bond in VII is broken during formation of the acyl-enzyme, a reactive p-hydroxybenzylbromide group is generated in situ within the active site. This newly formed group then alkylates one histidine residue (probably histidine-57), as shown by amino acid analysis of the modified enzyme on acid hydrolysis. A model non-enzymic reaction shows that the dihydrocoumarin VII is able to alkylate imidazole in aqueous solution at pH 7, yielding the N-substituted imidazole, 3-bromo-6-(imidazol-1-yl-methyl)coumarin (XI).
The modified enzyme has practically no activity against a specific substrate and seems no longer to have its intact active site. However its binding site is at least partly free for it is still able to bind proflavin.
α-Chymotrypsin is also inactivated by 6-bromomethylcoumarin, the ester bond of which is stable, but the mode of inactivation and the properties of the modified enzyme are different from those found in the study with the dihydrocoumarin VII.
Esculetin, a coumarin compound, has been shown to exhibit antioxidant and anti-inflammatory effects. In the present study, esculetin was found to inhibit the survival of human promyelocytic leukemia HL-60 cells in a concentration-dependent and time-dependent manner. HL-60 cells underwent internucleosomal DNA fragmentation and morphological changes characteristic of apoptosis after a 24-h treatment with esculetin (100 μM). Flow cytometric analysis showed that the hypodiploid nuclei of HL-60 cells were increased to 40.93% after a 36-h treatment with esculetin (100 μM). Further investigation showed that esculetin induced the release of cytochrome c from mitochondria into cytosol in a time-dependent and concentration-dependent manner. Moreover, esculetin application reduced Bcl-2 protein expression to 58% after 9 h as compared with that time at 0. Cysteine protease 32 kDa proenzyme (CPP32), a caspase 3, was activated and its substrate, poly (adenosine diphosphate-ribose) polymerase, was cleaved after a 24-h treatment of HL-60 cells with esculetin. These data suggest that esculetin induces apoptosis in human leukemia cells by increasing cytosolic translocation of cytochrome c and activation of CPP32.
Coumarin is an active principle found in several vegetable species with a characteristic smell of vanilla. It is widely used as a perfume fixer, paint and spray additive, and in cleaning products. It also possesses clinical value due to antibiotic and analgesic properties, besides its potential use in the treatment of cancer and AIDS. The objective of this work was to obtain solubility data for coumarin under several conditions, as well as to evaluate process parameters for its extraction from emburana seeds with supercritical CO2. The process parameters studied were temperature, pressure, CO2 flow rate and particle size of the seeds. The solubility in supercritical CO2 was correlated using the Peng–Robinson equation. Solid-supercritical fluid and liquid-supercritical fluid equilibria were considered and correlated separately, with L-SC presenting better results due to the effect of the melting point depression of coumarin under high pressure. The results showed significant effects of pressure and temperature on the extraction yield and also, the smaller the particle size of the seeds, the better the yield.
The enzymatic transfer of acetyl groups from acetylated xenobiotics to specific proteins is a relatively grey area in the evergreen field of biotransformation of foreign compounds. In this paper, we have documented evidence for the existence of a transacetylase in liver microsomes that catalyses the transfer of acetyl groups from 7,8-diacetoxy-4-methylcoumarin (DAMC) to glutathione S-transferase (GST), either purified or present in cytosol leading to the irreversible inhibition of GST. A simple procedure is described for the assay of transacetylase by preincubation of DAMC with liver microsomes and pure GST/liver cytosol, followed by the addition of 1-chloro-2, 4-dinitrobenzene (CDNB) and reduced glutathione (GSH) in order to quantify GST activity by the conventional procedure. The extent of inhibition of GST by DAMC under the conditions of the assay is indicative of DAMC:protein transacetylase activity. Following the assay procedure described here, the transacetylase was shown to exhibit hyperbolic kinetics. The bimolecular nature of the transacetylase reaction was apparent by the demonstration of Km and νmax values. 7,8-Dihydroxy-4-methylcoumarin (DHMC), one of the products of transacetylase reaction was identified and quantified using the partially purified enzyme. The fact that p-hydroxymercuribenzoate (PHMB) and iodoacetamide abolished irreversible inhibition of GST upon the action of transacetylase on DAMC strongly characterized transacetylase as a protein containing thiol group at the active site. In addition, the relative specificities of acetoxy 4-methylcoumarins to transacetylase have been demonstrated.
The anticonvulsant activity of furanocoumarins, coumarin mixture and the essential oil obtained from the fruits of Heracleum crenatifolium was examined against maximal electroshock (MES)-induced seizures in mice. Bergapten showed significant anticonvulsant activity. The furanocoumarins isolated from the fruits of the plant were identified using thin-layer chromatography, melting points and spectroscopic methods (IR, MS, 1H NMR) as isobergapten (1), pimpinellin (2), bergapten (3), isopimpinellin (4), sphondin (5) and byak-angelicol (6). The essential oil content of the fruits were found as 5.5%. Twenty-two compounds representing 99.3% of the essential oil obtained from the fruits of H. crenatifolium were determined and the major components were identified as octanol and octyl acetate (3.1% and 88.4% respectively) by GC and GC–MS.
The induction of phase II detoxifying enzymes is an important defense mechanism against intake of xenobiotics. While this group of enzymes is believed to be under the transcriptional control of antioxidant response elements (AREs), this contention is experimentally unconfirmed. Since the ARE resembles the binding sequence of erythroid transcription factor NF-E2, we investigated the possibility that the phase II enzyme genes might be regulated by transcription factors that also bind to the NF-E2 sequence. The expression profiles of a number of transcription factors suggest that an Nrf2/small Maf heterodimer is the most likely candidate to fulfill this rolein vivo.To directly test these questions, we disrupted the murinenrf2 genein vivo.While the expression of phase II enzymes (e.g., glutathione S-transferase and NAD(P)H: quinone oxidoreductase) was markedly induced by a phenolic antioxidantin vivoin both wild type and heterozygous mutant mice, the induction was largely eliminated in the liver and intestine of homozygousnrf2-mutant mice. Nrf2 was found to bind to the ARE with high affinity only as a heterodimer with a small Maf protein, suggesting that Nrf2/small Maf activates gene expression directly through the ARE. These results demonstrate that Nrf2 is essential for the transcriptional induction of phase II enzymes and the presence of a coordinate transcriptional regulatory mechanism for phase II enzyme genes. Thenrf2-deficient mice may prove to be a very useful model for thein vivoanalysis of chemical carcinogenesis and resistance to anti-cancer drugs.
Carrots, celery, coriander, fennel and parsley of the Umbelliferae family have been used as common vegetables and spices in many different cultures of the world. In this study, we evaluated the immunomodulatory activities of coumarins and flavonoids obtained from the above foods on human peripheral blood mononuclear cells (PBMC). Studies were conducted on lymphocyte transformation, ELISA assay and flow cytometry. Results provided the evidence of a health-modulating effect of these vegetables and spices which possessed a direct role in immunomodulatory function. Some of non-nutritional constituents of these foods such as coumarins and flavonoids also exhibited a similar immunomodulatory activity. At non-cytotoxic concentrations, the above phytoconstituents exhibited three types of immunomodulation including type 1 of PHA, ConA and quercetin (increased lymphocyte activation and IFN-γ secretion); type 2 of isopimpinellin (enhanced lymphocyte activation) and type 3 of rutin, bergapten and xanthotoxin (elevated IFN-γ secretion). The augmentation of lymphocyte proliferation was closely correlated to an increase in the number of lymphocyte cells including CD8+ T cells and activated PBMC, whereas elevation of IFN-γ secretion was due to the activated CD8+ T cells.
Microtubules are a proven target for anticancer drug development because they are critical for mitotic spindle formation and the separation of chromosomes at mitosis. We here report a novel synthetic microtubule inhibitor 7-diethylamino-3(2'-benzoxazolyl)-coumarin (DBC). DBC causes destabilization of microtubules, leading to a cell cycle arrest at G(2)/M stage. In addition, human cancer cells are more sensitive to DBC (IC(50) 44.8-475.2nM) than human normal fibroblast (IC(50) 7.9microM), and DBC induces apoptotic cell death of cancer cells. Furthermore, our data show that DBC is a poor substrate of drug efflux pumps and effective against multidrug resistant (MDR) cancer cells. Taken together, these results describe a novel pharmacological property of DBC as a microtubule inhibitor, which may make it an attractive new agent for treatment of MDR cancer.
Naturally occurring coumarins possess anti-carcinogenic activities in part by inducing carcinogen-detoxifying enzymes glutathione S-transferase (GST) and/or NAD(P)H quinone oxidoreductase (NQO1). Our goal was to determine whether citrus coumarins induce hepatic GST and/or NQO1 via activation of Nrf2 and the antioxidant response element (ARE). First, HepG2 cells stably transfected with the ARE and a green fluorescent protein (GFP) reporter were treated with increasing concentrations of coumarins and compared to positive controls. tert-Butylhydroquinone (TBHQ) and oltipraz increased GFP fluorescence, as did coumarin, limettin, auraptene, imperatorin, and 7,8-benzoflavone, suggesting that they activate the ARE, whereas isopimpinellin did not increase GFP fluorescence. Next, the effects of orally administered coumarins and oltipraz on hepatic GST and NQO1 activities were compared in Nrf2 knockout mice or Nrf2 heterozygous mice exhibiting the wild-type phenotype. Oltipraz, auraptene, imperatorin, isopimpinellin, and auraptene all significantly increased liver cytosolic GST activities in Nrf2 heterozygous mice. This effect was abrogated in Nrf2(-/-) mice dosed with oltipraz, attenuated in mice Nrf2(-/-) mice treated with auraptene and imperatorin, and still significant in Nrf2(-/-) mice treated with isopimpinellin. Of these compounds, only isopimpinellin significantly increased liver cytosolic NQO1 activities, and this effect was not attenuated in Nrf2(-/-) mice. These results strongly suggest that imperatorin and auraptene induce murine liver cytosolic GST activities via the Nrf2/ARE mechanism. Although structurally similar, isopimpinellin did not appear to activate HepG2-ARE-GFP and the Nrf2 knockout mouse study suggests that isopimpinellin may induce GST and NQO1 via additional mechanisms.
Cytochrome P450 2A13-catalyzed alpha-hydroxylation is a critical step in the activation of the tobacco carcinogens 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and (S)-N'-nitrosonornicotine [(S)-NNN]. In the enzyme's active site, a single polar residue, Asn297, can influence substrate binding, orientation, and metabolism. We determined the effects of N297A mutation on enzyme kinetics and specificity for NNK, NNN, and coumarin metabolism. [5-(3)H]-NNK, [5-(3)H]-(S)-NNN, [(14)C]coumarin, and radioflow high-performance liquid chromatography analysis were used to quantify metabolites. Cytochrome P450 (P450) 2A13 N297A catalyzed NNK alpha-hydroxylation, with a 3-fold preference for methylene versus methyl hydroxylation, similar to wild type. Docking studies using the P450 2A13 crystal structure predicted that when the pyridine ring of NNK cannot hydrogen bond to residue 297 it tilts and orients NNK in positions unfavorable for alpha-hydroxylation. The N297A mutation resulted in a 5- and 4-fold decrease in catalytic efficiency of NNK and NNN metabolism, respectively, primarily because of increased K(m) values. The N297A mutation strikingly affected coumarin metabolism. The ratio of coumarin 7-hydroxylation to coumarin 3,4-epoxidation is approximately equal for wild-type enzyme, whereas the ratio was 1:9 for the N297A mutant. Coumarin 3,4-epoxidation was significantly underestimated unless the epoxide was trapped and quantified as its glutathione conjugate. The K(m) value for this reaction was 4-fold greater for the mutant enzyme; the V(max) value increased nearly 40-fold. The observed shift toward coumarin 3,4-epoxidation is consistent with docking studies. In summary, Asn297 in P450 2A13 is important for orienting NNK and coumarin in the active site, changing this residue to Ala results in altered enzyme kinetics for NNK, NNN, and coumarin.
Coumarin (1,2-benzopyrone) is a naturally occurring fragrant compound found in a variety of plants and spices. Coumarins have attracted intense interest in recent years because of their diverse pharmacological activities. This study examines the antioxidant coumarin 7,8-diacetoxy-4-methylcoumarin (DAMC) and its thiocoumarin derivative 7,8-diacetoxy-4-methylthiocoumarin (DAMTC) for their effect on human non-small cell lung cancer A549 cells. Here we show that both DAMC and DAMTC not only inhibited cell proliferation, but also induced apoptosis with an IC(50) of 160 microg/ml as confirmed by morphological examination, annexin-V assay and flow cytometric analysis. Interestingly, it was observed that these two coumarin compounds exhibited little cytotoxicity towards peripheral blood mononuclear cells but induced apoptosis in malignant cells. DAMC/DAMTC treatment also resulted in pronounced release of apoptogenic cytochrome c from mitochondria to cytosol, alteration of mitochondrial membrane potential (DeltaPsi(m)), and activation of caspase-9 and caspase-3. Although an increase in the levels of reactive oxygen species (ROS) was observed, pre-treatment with antioxidant showed no protective effect against DAMC/DAMTC-induced apoptosis. Results of present study suggest that downregulation of Bcl-xl, Cox-2 and mitogen activated protein kinase pathway and upregulation of p53, Akt and NF-kappaB pathway are involved in the underlying molecular mechanism of apoptosis induction by DAMC and DAMTC in A549 cells.
Cassava (Manihot esculenta Crantz) is an important starch-rich crop, but the storage roots only have a short shelf-life due to post-harvest physiological deterioration (PPD), which includes the over-production and polymerisation of hydroxycoumarins. Key aspects of coumarin secondary-metabolite biosynthesis remain unresolved. Here we exploit the accumulation of hydroxycoumarins to test alternative pathways for their biosynthesis. Using isotopically labelled intermediates (p-coumarate-2-(13)C, caffeate-2-(13)C, ferulate-2-(13)C, umbelliferone-2-(18)O and esculetin-2-(18)O), we show that the major biosynthetic pathway to scopoletin and its glucoside, scopolin, in cassava roots during PPD is through p-coumaric, caffeic and then ferulic acids. An alternate pathway through 2',4'-dihydroxycinnamate and umbelliferone leads to esculetin and esculin. We have used C(18)O(2)-carboxylate-labelled cinnamic and ferulic acids, and feeding experiments under an atmosphere of (18)O(2), to investigate the o-hydroxylation and cyclisation steps. We demonstrate that the major pathway is through o-hydroxylation and not via a proposed spirolactone-dienone intermediate.
Coumarin is bioactivated via 3,4-epoxidation resulting in formation of the hepatotoxic o-hydroxyphenylacetaldehyde (oHPA) and detoxified by cytochrome P450 2A6 (CYP2A6) hydroxylation leading to 7-hydroxycoumarin. The present study defines physiologically based biokinetic (PBBK) models to predict liver levels of the toxic oHPA metabolite of coumarin in rats and in human subjects with normal or deficient CYP2A6 catalyzed coumarin 7-hydroxylation. The results reveal that the predicted maximum tissue concentration (C(max)) of oHPA in the liver of wild type human subjects and of subjects deficient in CYP2A6 catalyzed 7-hydroxylation are, respectively, three and one order of magnitude lower than the values predicted for rat liver. Another difference between CYP2A6 deficient and wild type human subjects is a 500-fold difference in the area under the curve 0-24h (AUC(0-24h)) for the time-dependent oHPA liver concentration pointing at a relative higher percentage of the original dose converted in time through this pathway when CYP2A6 is deficient. For wild type human subjects and the subjects with completely deficient coumarin 7-hydroxylation the AUC(0-24h) values for oHPA in the liver are, respectively, three and one order of magnitude lower than that for rat liver. Even when 7-hydroxylation is deficient, the chances on formation of the hepatotoxic oHPA metabolite will be significantly lower in the liver of humans than those expected in the liver of rats when exposed to a similar dose on a body-weight basis. This conclusion should be taken into account when extrapolating data from experimental studies in sensitive animals, i.e., rats, to the general human population.
The barks and roots of Edgeworthia chrysantha LINDL., which have been used as the folk medicine "Zhu shima" in southern China due to their detumescence and acesodyne effects, were investigated for their anti-inflammatory and analgesic activities using a xylene-induced ear edema assay in mice and Freund's complete adjuvant-induced paw edema as inflammation models, and the acetic acid-induced writhing test as an analgesic model. Fractions effective in terms of anti-inflammatory and analgesic activities were obtained from E. chrysantha. The chloroform-soluble fraction (CHF) showed significant anti-inflammatory (p<0.01-0.001) and analgesic (p<0.01) effects. On further purification by silica gel, three major coumarins, edgeworin (EdN), edgeworosides A and C (EdeA and EdeC), were isolated from the chloroform fraction and both anti-inflammatory and analgesic activities were evaluated. EdN and EdeA had anti-inflammatory (p<0.05-0.01) and analgesic (p<0.001) effects, while EdeC only showed an analgesic effect. The results of this study thus demonstrated that the coumarins EdN, EdeA and EdeC in this plant may be active constituents that contribute to the anti-inflammatory and analgesic effects.
A CHCl3-soluble fraction of 70% EtOH extract of the flower of Kayea assamica from Myanmar exhibited 100% preferential cytotoxicity (PC(100)) against human pancreatic cancer PANC-1 cells under nutrient-deprived conditions at 1 microg/mL. Bioassay-guided fractionation and isolation afforded nine new coumarins, kayeassamins A (8), B (9), and C-I (1-7), together with nine known coumarins (10-18). The structures of these compounds were identified by extensive spectroscopic techniques as well as by comparison with published data. Absolute configuration at C-1' of 1 was established as S-configuration by the modified Mosher method. All the isolates were evaluated for their in vitro preferential cytotoxicity using novel anti-austerity strategy. Among them, the novel coumarins, kayeassamins A (8), B (9), D (2), E (3), and G (5) exhibited the most potent preferential cytotoxicity (PC(100) 1 microM) in a concentration- and time-dependent manner and induced apoptosis-like morphological changes of PANC-1 cells within 24 h of treatment. Based on the observed cytotoxicity, structure-activity relationships have been established.
Eight new coumarin compounds (1-8) were isolated by anti-HIV bioassay-guided fractionation of an extract of Calophyllum lanigerum. The structures of calanolide A (1), 12-acetoxycalanolide A (2), 12-methoxycalanolide A (3), calanolide B (4), 12-methoxycalanolide B (5), calanolide C (6) and related derivatives 7 and 8 were solved by extensive spectroscopic analyses, particularly HMQC, HMBC, and difference NOE NMR experiments. The absolute stereochemistry of calanolide A (1) and calanolide B (4) was established by a modified Mosher's method. Calanolides A (1) and B (4) were completely protective against HIV-1 replication and cytopathicity (EC50 values of 0.1 microM and 0.4 microM, respectively), but were inactive against HIV-2. Some of the related compounds also showed evidence of anti-HIV-1 activity. Studies with purified bacterial recombinant reverse transcriptases (RT) revealed that the calanolides are HIV-1 specific RT inhibitors. Moreover, calanolide A was active not only against the AZT-resistant G-9106 strain of HIV-1 but also against the pyridinone-resistant A17 strain. This was of particular interest since the A17 virus is highly resistant to previously known HIV-1 specific, non-nucleoside RT inhibitors (e.g., TIBO; BI-RG-587; L693,593) which comprise a structurally diverse but apparently common pharmacologic class. The calanolides represent a substantial departure from the known class and therefore provide a novel new anti-HIV chemotype for drug development.
Steroid hydroxylation specificities were determined for 11 forms of human cytochrome P450, representing four gene families and eight subfamilies, that were synthesized in human hepatoma Hep G2 cells by means of cDNA-directed expression using vaccinia virus. Microsomes isolated from the P450-expressing Hep G2 cells were isolated and then assayed for their regioselectivity of hydroxylation toward testosterone, androstenedione, and progesterone. Four of the eleven P450s exhibited high steroid hydroxylase activity (150-900 pmol hydroxysteroid/min/mg Hep G2 microsomal protein), one was moderately active (30-50 pmol/min/mg) and six were inactive. In contrast, 10 of the P450s effectively catalyzed O-deethylation of 7-ethoxycoumarin, a model drug substrate, while only one (P450 2A6) catalyzed significant coumarin 7-hydroxylation. Human P450 4B1, which is expressed in lung but not liver, catalyzed the 6 beta-hydroxylation of all three steroids at similar rates and with only minor formation of other hydroxylated products. Three members of human P450 family 3A, which are expressed in liver and other tissues, also catalyzed steroid 6 beta-hydroxylation as their major activity but, additionally, formed several minor products that include 2 beta-hydroxy and 15 beta-hydroxy derivatives in the case of testosterone. These patterns are similar to those exhibited by rat family 3A P450s. Although several rodent P450s belonging to subfamilies 2A, 2B, 2C, 2D are active steroid hydroxylases, four of five human P450s belonging to these subfamilies exhibited very low activity or were inactive, as were the human 1A and 2E P450s examined in the present study. These studies demonstrate that individual human cytochrome P450 enzymes can hydroxylate endogenous steroid hormones with a high degree of stereospecificity and regioselectivity, and that some, but not all of the human cytochromes exhibit metabolite profiles similar to their rodent counterparts.
A series of 18 2,4-diamino-5-[(1,2,3,4-tetrahydro-6-quinolyl)methyl]pyrimidines has been prepared by the condensation of 2,4-diamino-5-(hydroxymethyl)pyrimidine with 1,2,3,4-tetrahydroquinolines in acidic medium. Several derivatives were catalytically aromatized; others were synthesized from these by routine aromatic substitution or by condensations of (anilinomethyl)pyrimidines to give quinolinylmethyl analogues. Compounds with 4-methyl-8-methoxy substitution are closely related to trimethoprim (1a) in structure and are excellent inhibitors of bacterial dihydrofolate reductase, with activity at least equivalent to that of 1a. The highest degree of inhibition was achieved with the rigid aromatic series, but greater specificity was accomplished among the tetrahydroquinoline derivatives. This was directly related to N-1 substitution of 4-methyl-8-methoxy derivatives. The spatial relationships around N-1 and protonation at this site may both affect selectivity. Such compounds also had excellent broad-spectrum in vitro antibacterial activity.
The relative efficacy of 10 flavonoid compounds and some common antioxidants in inhibiting 12-lipoxygenase of fish gill was determined. Lipoxygenase activity was measured by oxygen consumption with polarography and formation of hydroxy fatty acid using thin layer chromatography with autoradiography. Generally, the inhibition of 12-lipoxygenase by flavonoids was noncompetitive. The lipoxygenase product pattern did not change in the presence of flavonoids. Fisetin (3,3',4',7-tetrahydroxyflavone) and quercetin (3,3',4',5,7-pentahydroxyflavone) were the most potent inhibitors of 12-lipoxygenase, with IC50's of 0.25 and 0.4 microM respectively. These were compared with IC50's values of 5,1000 microM for BHA (t-butylhydroxyanisole) and BHT (t-butylhydroxytoluene) respectively. Possible inhibitory mechanisms and relationships between flavonoid structure and inhibitory potencies are discussed.