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Sample records for natural product inhibitors

  1. Natural Products as Aromatase Inhibitors

    PubMed Central

    Balunas, Marcy J.; Su, Bin; Brueggemeier, Robert W.; Kinghorn, A. Douglas

    2010-01-01

    With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating also the potential of natural products as AIs. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. Natural products that have been used traditionally for nutritional or medicinal purposes (e.g., botanical dietary supplements) may also afford AIs with reduced side effects. A thorough review of the literature regarding natural product extracts and secondary metabolites of plant, microbial, and marine origin that have been shown to exhibit aromatase inhibitory activity is presented herein. PMID:18690828

  2. Marine Natural Products with P-Glycoprotein Inhibitor Properties

    PubMed Central

    Lopez, Dioxelis; Martinez-Luis, Sergio

    2014-01-01

    P-glycoprotein (P-gp) is a protein belonging to the ATP-binding cassette (ABC) transporters superfamily that has clinical relevance due to its role in drug metabolism and multi-drug resistance (MDR) in several human pathogens and diseases. P-gp is a major cause of drug resistance in cancer, parasitic diseases, epilepsy and other disorders. This review article aims to summarize the research findings on the marine natural products with P-glycoprotein inhibitor properties. Natural compounds that modulate P-gp offer great possibilities for semi-synthetic modification to create new drugs and are valuable research tools to understand the function of complex ABC transporters. PMID:24451193

  3. Natural products from Garcinia brasiliensis as Leishmania protease inhibitors.

    PubMed

    Pereira, Ivan O; Assis, Diego M; Juliano, Maria A; Cunha, Rodrigo L O R; Barbieri, Clara L; do Sacramento, Luis V S; Marques, Marcos J; dos Santos, Marcelo H

    2011-06-01

    The infections by protozoans of the genus Leishmania are a major worldwide health problem, with high endemicity in developing countries. The drugs of choice for the treatment of leishmaniasis are the pentavalent antimonials, which cause renal and cardiac toxicity. As part of a search for new drugs against leishmaniasis, we evaluated the in vitro Leishmania protease inhibition activity of extracts (hexanic, ethyl-acetate, and ethanolic) and fukugetin, a bioflavonoid purified from the ethyl-acetate extract of the pericarp of the fruit of Garcinia brasiliensis, a tree native to Brazilian forests. The isolated compound was characterized by using spectral analyses with nuclear magnetic resonance, mass spectroscopy, ultraviolet, and infrared techniques. The ethyl-acetate extract and the compound fukugetin showed significant activity as inhibitors of Leishmania's proteases, with mean (±SD) IC(50) (50% inhibition concentration of protease activity) values of 15.0±1.3 μg/mL and 3.2±0.5 μM/mL, respectively, characterizing a bioguided assay. In addition, this isolated compound showed no activity against promastigote and amastigote forms of L. (L.) amazonensis and mammalian cells. These results suggest that fukugetin is a potent protease inhibitor of L. (L.) amazonensis and does not cause toxicity in mammalian or Leishmania cells in vitro. This study provides new perspectives on the development of novel drugs that have leishmanicidal activity obtained from natural products and that target the parasite's proteases. PMID:21554130

  4. Identifying HER2 Inhibitors from Natural Products Database

    PubMed Central

    Yang, Shun-Chieh; Chang, Su-Sen; Chen, Calvin Yu-Chian

    2011-01-01

    The relationship between abnormal HER2 expression and cancer is important in cancer therapeutics. Formation and spread of cancer cells may be restricted by inhibiting HER2. We conducted ligand-based and structure-based studies to assess the potency of natural compounds as potential HER2 inhibitors. Multiple linear regression (MLR) and support vector machine (SVM) models were constructed to predict biological activities of natural compounds, and molecular dynamics (MD) was used to assess their stability with HER2 under a dynamic environment. Predicted bioactivities of the natural compounds ranged from 6.014–9.077 using MLR (r2 = 0.7954) and 5.122–6.950 using SVM (r2 = 0.8620). Both models were in agreement and suggest bioactivity based on candidate structure. Conformation changes caused by MD favored the formation of stabilizing H-bonds. All candidates had higher stability than Lapinatib, which may be due to the number and spatial distribution of additional H-bonds and hydrophobic interactions. Amino acids Lys724 and Lys736 are critical for binding in HER2, and Thr798, Cys805, and Asp808 are also important for increased stability. Candidates may block the entrance to the ATP binding site located within the inner regions and prevent downstream activation of HER2. Our multidirectional approach indicates that the natural compounds have good ligand efficacy in addition to stable binding affinities to HER2, and should be potent candidates of HER2 inhibitors. With regard to drug design, designing HER2 inhibitors with carboxyl or carbonyl groups available for H-bond formation with Lys724 and Lys736, and benzene groups for hydrophobic contact with Cys805 may improve protein-ligand stability. PMID:22174899

  5. Marine Natural Product Inhibitors of Neutrophil-Associated Inflammation.

    PubMed

    Chen, Chun-Yu; Tsai, Yung-Fong; Chang, Wen-Yi; Yang, Shun-Chin; Hwang, Tsong-Long

    2016-01-01

    Neutrophils are widely recognized to play an important role in acute inflammatory responses, and recent evidence has expanded their role to modulating chronic inflammatory and autoimmune diseases. Reactive oxygen species (ROS) and microbicidal compounds released from neutrophils that are recruited to the site of inflammation contribute to the pathogenesis of multiple inflammation-associated diseases such as chronic obstructive pulmonary disease, atherosclerosis, and hepatitis. Marine organisms are a valuable source of bioactive compounds with potential for industrial and pharmaceutical application. Marine natural products that inhibit neutrophil activation could be used as drugs for the treatment of inflammatory diseases. Numerous studies investigating marine natural products have reported novel anti-inflammatory agents. Nevertheless, the detailed mechanisms underlying their actions, which could facilitate our understanding of the molecular events occurring in neutrophils, have not been reported in most of the associated research studies. Therefore, in this review, we will present marine products that inhibit neutrophil-associated inflammation. Furthermore, we will be limiting the detailed discussion to agents with well-investigated molecular targets. PMID:27472345

  6. Marine Natural Product Inhibitors of Neutrophil-Associated Inflammation

    PubMed Central

    Chen, Chun-Yu; Tsai, Yung-Fong; Chang, Wen-Yi; Yang, Shun-Chin; Hwang, Tsong-Long

    2016-01-01

    Neutrophils are widely recognized to play an important role in acute inflammatory responses, and recent evidence has expanded their role to modulating chronic inflammatory and autoimmune diseases. Reactive oxygen species (ROS) and microbicidal compounds released from neutrophils that are recruited to the site of inflammation contribute to the pathogenesis of multiple inflammation-associated diseases such as chronic obstructive pulmonary disease, atherosclerosis, and hepatitis. Marine organisms are a valuable source of bioactive compounds with potential for industrial and pharmaceutical application. Marine natural products that inhibit neutrophil activation could be used as drugs for the treatment of inflammatory diseases. Numerous studies investigating marine natural products have reported novel anti-inflammatory agents. Nevertheless, the detailed mechanisms underlying their actions, which could facilitate our understanding of the molecular events occurring in neutrophils, have not been reported in most of the associated research studies. Therefore, in this review, we will present marine products that inhibit neutrophil-associated inflammation. Furthermore, we will be limiting the detailed discussion to agents with well-investigated molecular targets. PMID:27472345

  7. Marine Natural Products as Breast Cancer Resistance Protein Inhibitors

    PubMed Central

    Cherigo, Lilia; Lopez, Dioxelis; Martinez-Luis, Sergio

    2015-01-01

    Breast cancer resistance protein (BCRP) is a protein belonging to the ATP-binding cassette (ABC) transporter superfamily that has clinical relevance due to its multi-drug resistance properties in cancer. BCRP can be associated with clinical cancer drug resistance, in particular acute myelogenous or acute lymphocytic leukemias. The overexpression of BCRP contributes to the resistance of several chemotherapeutic drugs, such as topotecan, methotrexate, mitoxantrone, doxorubicin and daunorubicin. The Food and Drugs Administration has already recognized that BCRP is clinically one of the most important drug transporters, mainly because it leads to a reduction of clinical efficacy of various anticancer drugs through its ATP-dependent drug efflux pump function as well as its apparent participation in drug resistance. This review article aims to summarize the different research findings on marine natural products with BCRP inhibiting activity. In this sense, the potential modulation of physiological targets of BCRP by natural or synthetic compounds offers a great possibility for the discovery of new drugs and valuable research tools to recognize the function of the complex ABC-transporters. PMID:25854646

  8. Marine natural products as breast cancer resistance protein inhibitors.

    PubMed

    Cherigo, Lilia; Lopez, Dioxelis; Martinez-Luis, Sergio

    2015-04-01

    Breast cancer resistance protein (BCRP) is a protein belonging to the ATP-binding cassette (ABC) transporter superfamily that has clinical relevance due to its multi-drug resistance properties in cancer. BCRP can be associated with clinical cancer drug resistance, in particular acute myelogenous or acute lymphocytic leukemias. The overexpression of BCRP contributes to the resistance of several chemotherapeutic drugs, such as topotecan, methotrexate, mitoxantrone, doxorubicin and daunorubicin. The Food and Drugs Administration has already recognized that BCRP is clinically one of the most important drug transporters, mainly because it leads to a reduction of clinical efficacy of various anticancer drugs through its ATP-dependent drug efflux pump function as well as its apparent participation in drug resistance. This review article aims to summarize the different research findings on marine natural products with BCRP inhibiting activity. In this sense, the potential modulation of physiological targets of BCRP by natural or synthetic compounds offers a great possibility for the discovery of new drugs and valuable research tools to recognize the function of the complex ABC-transporters. PMID:25854646

  9. Anti-cancer glycosidase inhibitors from natural products: a computational and molecular modelling perspective.

    PubMed

    Singh, Ashona; Mhlongo, Ndumiso; Soliman, Mahmoud E S

    2015-01-01

    The implementation of computational tools in pharmaceutics has proven an effectual strategy in creating harmony between the physical and chemical aspects of proteins and potential inhibitors. This is achieved by bringing to life the three dimensional retrospect of biological systems, which takes into consideration computational approaches such as quantum mechanics and molecular dynamics to facilitate drug design and discovery. In this work, we aim to provide a summary of the computational aspects of naturally derived anti-cancer inhibitors targeting the enzyme family of glycosidases. Our study offers insight into the evolution of drug discovery, molecular modelling and molecular binding modes of natural product inhibitors associated with glycosidase enzymes. PMID:25706917

  10. Identification of diverse natural products as falcipain-2 inhibitors through structure-based virtual screening.

    PubMed

    Wang, Liyan; Zhang, Shoude; Zhu, Junsheng; Zhu, Lili; Liu, Xiaofeng; Shan, Lei; Huang, Jin; Zhang, Weidong; Li, Honglin

    2014-03-01

    Ten natural compounds are successfully identified as falcipain-2 (FP-2) inhibitors from our in-house natural products database using structure-based virtual screening, which show moderate inhibitory activities against FP-2 with IC50 values ranging from 3.18 to 68.19 μM. While one of the inhibitors (compound 5) also exhibits in vitro antiplasmodial activity against chloroquine sensitive strain (3D7) and chloroquine resistant strain (Dd2) of Plasmodium falciparum in the micromolar range (IC50s=5.54 μM and 4.05 μM against 3D7 cells and Dd2 cells, respectively). Furthermore, the predicted binding poses are analyzed to explain the structure-activity relationships, which will be helpful for further structural modifications. PMID:24530004

  11. Screening natural products for inhibitors of quinone reductase-2 using ultrafiltration LC-MS

    PubMed Central

    Choi, Yongsoo; Jermihov, Katherine; Nam, Sang-Jip; Sturdy, Megan; Maloney, Katherine; Qiu, Xi; Chadwick, Lucas R.; Main, Matthew; Chen, Shao-Nong; Mesecar, Andrew D.; Farnsworth, Norman R.; Pauli, Guido F.; Fenical, William; Pezzuto, John M.; van Breemen, Richard R.

    2011-01-01

    Inhibitors of quinone reductase-2 (NQO2; QR-2) can have anti-malarial activity and anti-tumor activities or can function as chemoprevention agents by preventing the metabolic activation of toxic quinones such as menadione. To expedite the search for new natural product inhibitors of QR-2, we developed a screening assay based on ultrafiltration liquid chromatography-mass spectrometry that is compatible with complex samples such as bacterial or botanical extracts. Human QR-2 was prepared recombinantly, and the known QR-2 inhibitor, resveratrol, was used as a positive control and as a competitive ligand to eliminate false positives. Ultrafiltration LC-MS screening of extracts of marine sediment bacteria resulted in the discovery of tetrangulol methyl ether as an inhibitor of QR-2. When applied to the screening of hop extracts from the botanical, Humulus lupulus L., xanthohumol and xanthohumol D were identified as ligands of QR-2. Inhibition of QR-2 by these ligands was confirmed using a functional enzyme assay. Furthermore, binding of xanthohumol and xanthohumol D to the active site of QR-2 were confirmed using X-ray crystallography. Ultrafiltration LC-MS was shown to be a useful assay for the discovery of inhibitors of QR-2 in complex matrices such as extracts of bacteria and botanicals. PMID:21192729

  12. SARS-CoV protease inhibitors design using virtual screening method from natural products libraries.

    PubMed

    Liu, Bing; Zhou, Jiaju

    2005-04-15

    Two natural products databases, the marine natural products database (MNPD) and the traditional Chinese medicines database (TCMD), were used to find novel structures of potent SARS-CoV protease inhibitors through virtual screening. Before the procedure, the databases were filtered by Lipinski's ROF and Xu's extension rules. The results were analyzed by statistic methods to eliminate the bias in target-based database screening toward higher molecular weight compounds for enhancing the hit rate. Eighteen lead compounds were recommended by the screening procedure. They were useful for experimental scientists in prioritizing drug candidates and studying the interaction mechanism. The binding mechanism was also analyzed between the best screening compound and the SARS protein. PMID:15693056

  13. An overview on the potential of natural products as ureases inhibitors: A review☆

    PubMed Central

    Modolo, Luzia V.; de Souza, Aline X.; Horta, Lívia P.; Araujo, Débora P.; de Fátima, Ângelo

    2014-01-01

    Ureases, enzymes that catalyze urea hydrolysis, have received considerable attention for their impact on living organisms’ health and life quality. On the one hand, the persistence of urease activity in human and animal cells can be the cause of some diseases and pathogen infections. On the other hand, food production can be negatively affected by ureases of soil microbiota that, in turn, lead to losses of nitrogenous nutrients in fields supplemented with urea as fertilizer. In this context, nature has proven to be a rich resource of natural products bearing a variety of scaffolds that decrease the ureolytic activity of ureases from different organisms. Therefore, this work compiles the state-of-the-art researches focused on the potential of plant natural products (present in extracts or as pure compounds) as urease inhibitors of clinical and/or agricultural interests. Emphasis is given to ureases of Helicobacter pylori, Canavalia ensiformis and soil microbiota although the active site of this class of hydrolases is conserved among living organisms. PMID:25685542

  14. Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis

    PubMed Central

    Green, Nora S.; Foss, Ted R.; Kelly, Jeffery W.

    2005-01-01

    The misfolding of transthyretin (TTR), including rate-limiting tetramer dissociation and partial monomer denaturation, is sufficient for TTR misassembly into amyloid and other abnormal quaternary structures associated with three amyloid diseases: senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. Small molecules can bind to one or both of the unoccupied TTR thyroid hormone-binding sites, stabilizing the native tetramer more than the dissociative transition state, thereby raising the kinetic barrier for tetramer dissociation. Herein we demonstrate that genistein, the major isoflavone natural product in soy, works in this fashion and is an excellent inhibitor of transthyretin tetramer dissociation and amyloidogenesis, reducing acid-mediated fibril formation to <10% of that exhibited by TTR alone. Genistein also inhibits the amyloidogenesis of the most common familial amyloid polyneuropathy and familial amyloid cardiomyopathy mutations in TTR: V30M and V122I, respectively. Genistein additionally inhibits tetramer dissociation under physiological conditions thought to lead to slow amyloidogenesis in humans. Furthermore, this natural product exhibits highly selective binding to TTR in plasma over all of the other plasma proteins. Isothermal titration calorimetry shows that genistein binds to TTR with negative cooperativity (Kd1 = 40 nM, Kd2 = 1.4 μM). The benefits of using a nutraceutical such as genistein to treat orphan diseases such as the TTR amyloidoses include known oral bioavailability and safety data. It is conceivable that some patients could benefit from simply increasing their intake of soy products or supplements. PMID:16195386

  15. Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis.

    PubMed

    Green, Nora S; Foss, Ted R; Kelly, Jeffery W

    2005-10-11

    The misfolding of transthyretin (TTR), including rate-limiting tetramer dissociation and partial monomer denaturation, is sufficient for TTR misassembly into amyloid and other abnormal quaternary structures associated with three amyloid diseases: senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. Small molecules can bind to one or both of the unoccupied TTR thyroid hormone-binding sites, stabilizing the native tetramer more than the dissociative transition state, thereby raising the kinetic barrier for tetramer dissociation. Herein we demonstrate that genistein, the major isoflavone natural product in soy, works in this fashion and is an excellent inhibitor of transthyretin tetramer dissociation and amyloidogenesis, reducing acid-mediated fibril formation to <10% of that exhibited by TTR alone. Genistein also inhibits the amyloidogenesis of the most common familial amyloid polyneuropathy and familial amyloid cardiomyopathy mutations in TTR: V30M and V122I, respectively. Genistein additionally inhibits tetramer dissociation under physiological conditions thought to lead to slow amyloidogenesis in humans. Furthermore, this natural product exhibits highly selective binding to TTR in plasma over all of the other plasma proteins. Isothermal titration calorimetry shows that genistein binds to TTR with negative cooperativity (K(d1) = 40 nM, K(d2) = 1.4 microM). The benefits of using a nutraceutical such as genistein to treat orphan diseases such as the TTR amyloidoses include known oral bioavailability and safety data. It is conceivable that some patients could benefit from simply increasing their intake of soy products or supplements. PMID:16195386

  16. Salinosporamide Natural Products: Potent 20S Proteasome Inhibitors as Promising Cancer Chemotherapeutics

    PubMed Central

    Gulder, Tobias A. M.

    2010-01-01

    Proteasome inhibitors are rapidly evolving as potent treatment options in cancer therapy. One of the most promising drug candidates of this type is salinosporamide A from the bacterium Salinispora tropica. This marine natural product possesses a complex, densely functionalized γ-lactam-β-lactone pharmacophore, which is responsible for its irreversible binding to its target, the β subunit of the 20S proteasome. Salinosporamide A entered phase I clinical trials for the treatment of multiple myeloma only three years after its discovery. The strong biological activity and the challenging structure of this compound have fueled intense academic and industrial research in recent years, which has led to the development of more than ten syntheses, the elucidation of its biosynthetic pathway, and the generation of promising structure–activity relationships and oncological data. Salinosporamide A thus serves as an intriguing example of the successful interplay of modern drug discovery and biomedical research, medicinal chemistry and pharmacology, natural product synthesis and analysis, as well as biosynthesis and bioengineering. PMID:20927786

  17. Discovery of Mycobacterium tuberculosis Protein Tyrosine Phosphatase B (PtpB) Inhibitors from Natural Products

    PubMed Central

    Chiaradia-Delatorre, Louise Domeneghini; Menegatti, Angela Camila Orbem; Monache, Franco Delle; Ferrari, Franco; Yunes, Rosendo Augusto; Nunes, Ricardo José; Terenzi, Hernán; Botta, Bruno; Botta, Maurizio

    2013-01-01

    Protein tyrosine phosphatase B (PtpB) is one of the virulence factors secreted into the host cell by Mycobacterium tuberculosis. PtpB attenuates host immune defenses by interfering with signal transduction pathways in macrophages and, therefore, it is considered a promising target for the development of novel anti-tuberculosis drugs. Here we report the discovery of natural compound inhibitors of PtpB among an in house library of more than 800 natural substances by means of a multidisciplinary approach, mixing in silico screening with enzymatic and kinetics studies and MS assays. Six natural compounds proved to inhibit PtpB at low micromolar concentrations (< 30 µM) with Kuwanol E being the most potent with Ki = 1.6 ± 0.1 µM. To the best of our knowledge, Kuwanol E is the most potent natural compound PtpB inhibitor reported so far, as well as it is the first non-peptidic PtpB inhibitor discovered from natural sources. Compounds herein identified may inspire the design of novel specific PtpB inhibitors. PMID:24155919

  18. High-Throughput Screen of Natural Product Libraries for Hsp90 Inhibitors

    PubMed Central

    Davenport, Jason; Balch, Maurie; Galam, Lakshmi; Girgis, Antwan; Hall, Jessica; Blagg, Brian S. J.; Matts, Robert L.

    2014-01-01

    Hsp90 has become the target of intensive investigation, as inhibition of its function has the ability to simultaneously incapacitate proteins that function in pathways that represent the six hallmarks of cancer. While a number of Hsp90 inhibitors have made it into clinical trials, a number of short-comings have been noted, such that the search continues for novel Hsp90 inhibitors with superior pharmacological properties. To identify new potential Hsp90 inhibitors, we have utilized a high-throughput assay based on measuring Hsp90-dependent refolding of thermally denatured luciferase to screen natural compound libraries. Over 4,000 compounds were screen with over 100 hits. Data mining of the literature indicated that 51 compounds had physiological effects that Hsp90 inhibitors also exhibit, and/or the ability to downregulate the expression levels of Hsp90-dependent proteins. Of these 51 compounds, seven were previously characterized as Hsp90 inhibitors. Four compounds, anthothecol, garcinol, piplartine, and rottlerin, were further characterized, and the ability of these compounds to inhibit the refolding of luciferase, and reduce the rate of growth of MCF7 breast cancer cells, correlated with their ability to suppress the Hsp90-dependent maturation of the heme-regulated eIF2α kinase, and deplete cultured cells of Hsp90-dependent client proteins. Thus, this screen has identified an additional 44 compounds with known beneficial pharmacological properties, but with unknown mechanisms of action as possible new inhibitors of the Hsp90 chaperone machine. PMID:24833337

  19. Applications of Integrated Data Mining Methods to Exploring Natural Product Space for Acetylcholinesterase Inhibitors

    PubMed Central

    Schuster, Daniela; Kern, Lisa; Hristozov, Dimitar P.; Terfloth, Lothar; Bienfait, Bruno; Laggner, Christian; Kirchmair, Johannes; Grienke, Ulrike; Wolber, Gerhard; Langer, Thierry; Stuppner, Hermann; Gasteiger, Johann; Rollinger, Judith M.

    2013-01-01

    Nature, especially the plant kingdom, is a rich source for novel bioactive compounds that can be used as lead compounds for drug development. In order to exploit this resource, the two neural network-based virtual screening techniques novelty detection with self-organizing maps (SOMs) and counterpropagation neural network were evaluated as tools for efficient lead structure discovery. As application scenario, significant descriptors for acetylcholinesterase (AChE) inhibitors were determined and used for model building, theoretical model validation, and virtual screening. Top-ranked virtual hits from both approaches were docked into the AChE binding site to approve the initial hits. Finally, in vitro testing of selected compounds led to the identification of forsythoside A and (+)-sesamolin as novel AChE inhibitors. PMID:20214575

  20. Identification of a natural product-like STAT3 dimerization inhibitor by structure-based virtual screening

    PubMed Central

    Liu, L-J; Leung, K-H; Chan, D S-H; Wang, Y-T; Ma, D-L; Leung, C-H

    2014-01-01

    STAT3 regulates a variety of genes involved with cell proliferation, differentiation, apoptosis, angiogenesis, metastasis, inflammation, and immunity. The purpose of this study was to apply molecular docking techniques to identify STAT3 inhibitors from a database of over 90 000 natural product and natural product-like compounds. The virtual screening campaign furnished 14 hit compounds, from which compound 1 emerged as a top candidate. Compound 1 inhibited STAT3 DNA-binding activity in vitro and attenuated STAT3-directed transcription in cellulo with selectivity over STAT1 and with comparable potency to the well-known STAT3 inhibitor S3I-201. Furthermore, compound 1 inhibited STAT3 dimerization and decreased STAT3 phosphorylation in cells without affecting STAT1 dimerization and phosphorylation. Compound 1 also exhibited selective anti-proliferative activity against cancer cells over normal cells in vitro. Molecular docking analysis suggested that compound 1 might putatively function as an inhibitor of STAT3 dimerization by binding to the SH2 domain. This study also validates the use of in silico techniques to identify inhibitors of protein–protein interactions, which are typically considered difficult to target with small molecules. PMID:24922077

  1. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors from Natural Products: Discovery of Next-Generation Antihyperglycemic Agents.

    PubMed

    Choi, Chang-Ik

    2016-01-01

    Diabetes mellitus is a chronic condition associated with the metabolic impairment of insulin actions, leading to the development of life-threatening complications. Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia, weight gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safer antidiabetic drugs. Since the important roles of the sodium-glucose cotransporter 2 (SGLT2) for glucose homeostasis in the kidney were recently elucidated, pharmacological inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes. Since the discovery of the first natural SGLT2 inhibitor, phlorizin, several synthetic glucoside analogs have been developed and introduced into the market. Furthermore, many efforts to find new active constituents with SGLT2 inhibition from natural products are still ongoing. This review introduces the history of research on the development of early-generation SGLT2 inhibitors, and recent progress on the discovery of novel candidates for SGLT2 inhibitor from several natural products that are widely used in traditional herbal medicine. PMID:27618891

  2. Depsidones from Lichens as Natural Product Inhibitors of M-Phase Phosphoprotein 1, a Human Kinesin Required for Cytokinesis.

    PubMed

    Talapatra, Sandeep K; Rath, Oliver; Clayton, Eddie; Tomasi, Sophie; Kozielski, Frank

    2016-06-24

    M-Phase Phosphoprotein 1 (MPP1), a microtubule plus end directed kinesin, is required for the completion of cytokinesis. Previous studies have shown that MPP1 is upregulated in various types of bladder cancer. This article describes inhibitor screening leading to the identification of a new class of natural product inhibitors of MPP1. Two compounds with structural similarity, norlobaridone (1) and physodic acid (2), were found to inhibit MPP1. Physodic acid is not competitive with ATP, indicating the presence of an allosteric inhibitor-binding pocket. Initial drug-like property screening indicates that physodic acid is more soluble than norlobaridone and has more favorable lipophilicity. However, both suffer from high clearance in human microsomal stability assays mediated by the lability of the lactone ring as well as hydroxylation of the alkyl chains as shown by metabolite identification studies. In cell-based assays physodic acid is a weak inhibitor with EC50 values of about 30 μM in a range of tumor cell lines. The two depsidones identified and characterized here could be used for future improvement of their activity against MPP1 and will be useful chemical probes for studying this unique molecular motor in more depth. PMID:27300079

  3. Focused library with a core structure extracted from natural products and modified: application to phosphatase inhibitors and several biochemical findings.

    PubMed

    Hirai, Go; Sodeoka, Mikiko

    2015-05-19

    Synthesis of a focused library is an important strategy to create novel modulators of specific classes of proteins. Compounds in a focused library are composed of a common core structure and different diversity structures. In this Account, we describe our design and synthesis of libraries focused on selective inhibitors of protein phosphatases (PPases). We considered that core structures having structural and electronic features similar to those of PPase substrates, phosphate esters, would be a reasonable choice. Therefore, we extracted core structures from natural products already identified as PPase inhibitors. Since many PPases share similar active-site structures, such phosphate-mimicking core structures should interact with many enzymes in the same family, and therefore the choice of diversity structures is pivotal both to increase the binding affinity and to achieve specificity for individual enzymes. Here we present case studies of application of focused libraries to obtain PPase inhibitors, covering the overall process from selection of core structures to identification and evaluation of candidates in the focused libraries. To synthesize a library focused on protein serine-threonine phosphatases (PPs), we chose norcantharidin as a core structure, because norcantharidin dicarboxylate shows a broad inhibition profile toward several PPs. From the resulting focused library, we identified a highly selective PP2B inhibitor, NCA-01. On the other hand, to find inhibitors of dual-specificity protein phosphatases (DSPs), we chose 3-acyltetronic acid extracted from natural product RK-682 as a core structure, because its structure resembles the transition state in the dephosphorylation reaction of DSPs. However, a highly selective inhibitor was not found in the resulting focused library. Furthermore, an inherent drawback of compounds having the highly acidic 3-acyltetronic acid as a core structure is very weak potency in cellulo, probably due to poor cell membrane

  4. Eriocitrin and Apigenin as New Carbonic Anhydrase VA Inhibitors from a Virtual Screening of Calabrian Natural Products.

    PubMed

    Gidaro, Maria Concetta; Alcaro, Francesca; Carradori, Simone; Costa, Giosuè; Vullo, Daniela; Supuran, Claudiu T; Alcaro, Stefano

    2015-04-01

    In this work, we performed a structure-based virtual screening against five carbonic anhydrase isoforms using, as a ligand library, natural components of Citrus bergamia (Bergamot) and Allium cepa var. Tropea (red onion) sources, which are some typical Calabrian products. The most relevant Bergamot and red onion components, identified as potentially new hits by means of the computational work, were submitted to in vitro tests in order to confirm the ability to exert the predicted biological activity. Apigenin and eriocitrin were identified as new potent inhibitors of human carbonic anhydrase VA isozyme. PMID:25590364

  5. Olive leaf extracts are a natural source of advanced glycation end product inhibitors.

    PubMed

    Kontogianni, Vassiliki G; Charisiadis, Pantelis; Margianni, Evangelia; Lamari, Fotini N; Gerothanassis, Ioannis P; Tzakos, Andreas G

    2013-09-01

    Advanced glycation end products (AGEs), which are readily formed and accumulated with sustained hyperglycemia, contribute to the development of diabetic complications. As a consequence, inhibition of AGE formation constitutes an attractive therapeutic/preventive target. In the current study, we explored the phytochemical composition and the in vitro effect of two different olive leaf extracts (an aqueous and a methanolic) on AGE formation. The methanolic olive leaf extract inhibited fluorescent AGE formation in a bovine serum albumin (BSA)-ribose system, whereas the aqueous extract had no effect in both BSA-fructose and BSA-ribose systems. The phytochemical profile was investigated with liquid chromatography-ultraviolet-visible (UV-Vis) diode array coupled to electrospray ionization multistage mass spectrometry (LC/DAD/ESI-MS(n)). Quantification of the major phenolic compounds was performed with high performance liquid chromatography with UV-Vis diode array detection and nuclear magnetic resonance spectroscopy. Among the major phenolic components (luteolin, hydroxytyrosol, luteolin-4'-O-β-D-glucopyranoside, luteolin-7-O-β-D-glucopyranoside, and oleuropein), luteolin and luteolin-4'-O-β-D-glucopyranoside were assigned as potent inhibitors of AGE formation. The extraction procedure greatly affects the composition and therefore the anti-glycation potential of olive leaves. PMID:24044491

  6. Olive Leaf Extracts Are a Natural Source of Advanced Glycation End Product Inhibitors

    PubMed Central

    Charisiadis, Pantelis; Margianni, Evangelia; Lamari, Fotini N.; Gerothanassis, Ioannis P.

    2013-01-01

    Abstract Advanced glycation end products (AGEs), which are readily formed and accumulated with sustained hyperglycemia, contribute to the development of diabetic complications. As a consequence, inhibition of AGE formation constitutes an attractive therapeutic/preventive target. In the current study, we explored the phytochemical composition and the in vitro effect of two different olive leaf extracts (an aqueous and a methanolic) on AGE formation. The methanolic olive leaf extract inhibited fluorescent AGE formation in a bovine serum albumin (BSA)-ribose system, whereas the aqueous extract had no effect in both BSA-fructose and BSA-ribose systems. The phytochemical profile was investigated with liquid chromatography-ultraviolet-visible (UV-Vis) diode array coupled to electrospray ionization multistage mass spectrometry (LC/DAD/ESI-MSn). Quantification of the major phenolic compounds was performed with high performance liquid chromatography with UV-Vis diode array detection and nuclear magnetic resonance spectroscopy. Among the major phenolic components (luteolin, hydroxytyrosol, luteolin-4′-O-β-D-glucopyranoside, luteolin-7-O-β-D-glucopyranoside, and oleuropein), luteolin and luteolin-4′-O-β-D-glucopyranoside were assigned as potent inhibitors of AGE formation. The extraction procedure greatly affects the composition and therefore the anti-glycation potential of olive leaves. PMID:24044491

  7. Natural Products Screening for the Identification of Selective Monoamine Oxidase-B Inhibitors

    PubMed Central

    Zarmouh, Najla O.; Messeha, Samia S.; Elshami, Faisel M.; Soliman, Karam F. A.

    2016-01-01

    Aims Monoamine oxidase-B inhibitors (MAO-BIs) are used for the initial therapy of Parkinson’s disease. Also, MAO-BIs have shown to be effective neuroprotective agents in several neurodegenerative diseases. However, some concerns exist regarding the long-term use of these compounds. Meanwhile, natural compounds showed potential MAO-B selective inhibitions. To date, few selective natural MAO-BIs have been identified. Therefore, the current study is designed to identify plants with potent and specific MAO-B inhibition. Study Design In this work, we utilized high throughput screening to evaluate the different plants ethanolic extract for their effectiveness to inhibit recombinant human (h)MAO-A and hMAO-B and to determine the relative selectivity of the top MAO-BI. Methodology Recombinant human isozymes were verified by Western blotting, and the 155 plants were screened. A continuous fluorometric screening assay was performed followed by two separate hMAO-A and hMAO-B microtiter screenings and IC50 determinations for the top extracts. Results In the screened plants, 9% of the extracts showed more than 1.5-fold relative inhibition of hMAO-B (RIB) and another 9% showed more than 1.5-fold relative inhibition of hMAO-A. The top extracts with the most potent RIBs were Psoralea corylifolia seeds, Phellodendron amurense bark, Glycyrrhiza uralensis roots, and Ferula assafoetida roots, with the highest RIB of 5.9-fold. Furthermore, extensive maceration of the promising extracts led to increase inhibitory effects with a preserved RIB as confirmed with luminescence assay. The top four extracts hMAO-BIs were equally potent (IC50= 1.3 to 3.8 μg/mL) with highly significant relative selectivities to inhibit hMAO-B (4.1- to 13.4-fold). Conclusion The obtained results indicate that Psoralea corylifolia seeds, Ferula assafoetida, Glycyrrhiza uralensis roots, and Phellodendron amurense ethanolic extracts have selective inhibitions for human MAO-B. Investigating these plant extracts as

  8. Titration-based screening for evaluation of natural product extracts: identification of an aspulvinone family of luciferase inhibitors

    SciTech Connect

    Cruz, P.G.; Auld, D.S.; Schultz, P.J.; Lovell, S.; Battaile, K.P.; MacArthur, R.; Shen, M.; Tamayo-Castillo, G.; Inglese, J.; Sherman, D.H.

    2011-11-28

    The chemical diversity of nature has tremendous potential for the discovery of molecular probes and medicinal agents. However, sensitivity of HTS assays to interfering components of crude extracts derived from plants, and macro- and microorganisms has curtailed their use in lead discovery. Here, we describe a process for leveraging the concentration-response curves obtained from quantitative HTS to improve the initial selection of actives from a library of partially fractionated natural product extracts derived from marine actinomycetes and fungi. By using pharmacological activity, the first-pass CRC paradigm improves the probability that labor-intensive subsequent steps of reculturing, extraction, and bioassay-guided isolation of active component(s) target the most promising strains and growth conditions. We illustrate how this process identified a family of fungal metabolites as potent inhibitors of firefly luciferase, subsequently resolved in molecular detail by X-ray crystallography.

  9. Ultra High Throughput Screening of Natural Product Extracts to Identify Pro-apoptotic Inhibitors of Bcl-2 Family Proteins

    PubMed Central

    Hassig, Christian A.; Zeng, Fu-Yue; Kung, Paul; Kiankarimi, Mehrak; Kim, Sylvia; Diaz, Paul W.; Zhai, Dayong; Welsh, Kate; Morshedian, Shana; Su, Ying; O'Keefe, Barry; Newman, David J.; Rusman, Yudi; Kaur, Harneet; Salomon, Christine E.; Brown, Susan G.; Baire, Beeraiah; Michel, Andrew R.; Hoye, Thomas R.; Francis, Subhashree; Georg, Gunda I.; Walters, Michael A.; Divlianska, Daniela B.; Roth, Gregory P.; Wright, Amy E.; Reed, John C.

    2015-01-01

    Anti-apoptotic Bcl-2 family proteins are validated cancer targets comprised of six related proteins. From a drug discovery perspective, these are challenging targets that exert their cellular functions through protein-protein interactions (PPIs). While several isoform-selective inhibitors have been developed using structure-based design or high throughput screening (HTS) of synthetic chemical libraries, no large scale screen of natural product collections has been reported. A competitive displacement fluorescence polarization (FP) screen of nearly 150,000 natural product extracts was conducted against all six anti-apoptotic Bcl-2 family proteins using fluorochrome-conjugated peptide ligands that mimic functionally-relevant PPIs. The screens were conducted in 1,536-well format and displayed satisfactory overall HTS statistics, with Z’-factor values ranging from 0.72 to 0.83, and a hit confirmation rate between 16-64%. Confirmed active extracts were orthogonally tested in a luminescent assay for caspase-3/7 activation in tumor cells. Active extracts were resupplied and effort toward the isolation of pure active components was initiated through iterative bioassay-guided fractionation. Several previously described altertoxins were isolated from a microbial source and the pure compounds demonstrate activity in both Bcl-2 FP and caspase cellular assays. The studies demonstrate the feasibility of ultra high throughput screening using natural product sources and highlight some of the challenges associated with this approach. PMID:24870016

  10. Screening of the Pan-African Natural Product Library Identifies Ixoratannin A-2 and Boldine as Novel HIV-1 Inhibitors

    PubMed Central

    Tietjen, Ian; Ntie-Kang, Fidele; Mwimanzi, Philip; Onguéné, Pascal Amoa; Scull, Margaret A.; Idowu, Thomas Oyebode; Ogundaini, Abiodun Oguntuga; Meva’a, Luc Mbaze; Abegaz, Berhanu M.; Rice, Charles M.; Andrae-Marobela, Kerstin; Brockman, Mark A.; Brumme, Zabrina L.; Fedida, David

    2015-01-01

    The continued burden of HIV in resource-limited regions such as parts of sub-Saharan Africa, combined with adverse effects and potential risks of resistance to existing antiretroviral therapies, emphasize the need to identify new HIV inhibitors. Here we performed a virtual screen of molecules from the pan-African Natural Product Library, the largest collection of medicinal plant-derived pure compounds on the African continent. We identified eight molecules with structural similarity to reported interactors of Vpu, an HIV-1 accessory protein with reported ion channel activity. Using in vitro HIV-1 replication assays with a CD4+ T cell line and peripheral blood mononuclear cells, we confirmed antiviral activity and minimal cytotoxicity for two compounds, ixoratannin A-2 and boldine. Notably, ixoratannin A-2 retained inhibitory activity against recombinant HIV-1 strains encoding patient-derived mutations that confer resistance to protease, non-nucleoside reverse transcriptase, or integrase inhibitors. Moreover, ixoratannin A-2 was less effective at inhibiting replication of HIV-1 lacking Vpu, supporting this protein as a possible direct or indirect target. In contrast, boldine was less effective against a protease inhibitor-resistant HIV-1 strain. Both ixoratannin A-2 and boldine also inhibited in vitro replication of hepatitis C virus (HCV). However, BIT-225, a previously-reported Vpu inhibitor, demonstrated antiviral activity but also cytotoxicity in HIV-1 and HCV replication assays. Our work identifies pure compounds derived from African plants with potential novel activities against viruses that disproportionately afflict resource-limited regions of the world. PMID:25830320

  11. Targeting FASN in Breast Cancer and the Discovery of Promising Inhibitors from Natural Products Derived from Traditional Chinese Medicine

    PubMed Central

    Cheng, Chien-shan; Wang, Zhiyu; Chen, Jianping

    2014-01-01

    Molecular targeted therapy has been developed for cancer chemoprevention and treatment. Cancer cells process a fundamental change in its bioenergetic metabolism from normal cells on an altered lipid metabolism, also known as the de novo fatty acid synthesis, for sustaining their high proliferation rates. Fatty acid synthesis is now associated with clinically aggressive tumor behavior and tumor cell growth and has become a novel target pathway for chemotherapy development. Although the underlying mechanisms of the altered de novo fatty acid synthesis still remains unclear, recent progress has shown that by targeting Fatty acid synthase (FASN), a key enzyme that catalyzes the synthesis of endogenous long chain fatty acid could be a critical target for drug discovery. However, relatively few FASN inhibitors have been discovered. With the long history of clinical practices and numerous histological case study reports, traditional Chinese medicine enjoys an important role in seeking bioactive anticancer natural compounds. Herein, we will give an overall picture of the current progress of molecular targeted therapy in cancer fatty acid synthesis, describe the advances in the research on natural products-derived FASN inhibitors and their potential for enhancing our understanding of fatty acids in tumor biology, and may provide new therapeutic moieties for breast cancer patient care. PMID:24778702

  12. Identification of a Series of Tricyclic Natural Products as Potent Broad-Spectrum Inhibitors of Metallo-β-Lactamases

    PubMed Central

    Payne, David J.; Hueso-Rodríguez, Juan Antonio; Boyd, Helen; Concha, Néstor O.; Janson, Cheryl A.; Gilpin, Martin; Bateson, John H.; Cheever, Christy; Niconovich, Nancy L.; Pearson, Stewart; Rittenhouse, Stephen; Tew, David; Díez, Emilio; Pérez, Paloma; de la Fuente, Jesus; Rees, Michael; Rivera-Sagredo, Alfonso

    2002-01-01

    This work describes the discovery and characterization of a novel series of tricyclic natural product-derived metallo-β-lactamase inhibitors. Natural product screening of the Bacillus cereus II enzyme identified an extract from a strain of Chaetomium funicola with inhibitory activity against metallo-β-lactamases. SB236050, SB238569, and SB236049 were successfully extracted and purified from this extract. The most active of these compounds was SB238569, which possessed Ki values of 79, 17, and 3.4 μM for the Bacillus cereus II, Pseudomonas aeruginosa IMP-1, and Bacteroides fragilis CfiA metallo-β-lactamases, respectively, yet none of the compounds exhibited any inhibitory activity against the Stenotrophomonas maltophilia L-1 metallo-β-lactamase (50% inhibitory concentration > 1,000 μM). The lack of activity against angiotensin-converting enzyme and serine β-lactamases demonstrated the selective nature of these compounds. The crystal structure of SB236050 complexed in the active site of CfiA has been obtained to a resolution of 2.5 Å. SB236050 exhibits key polar interactions with Lys184, Asn193, and His162 and a stacking interaction with the indole ring of Trp49 in the flap, which is in the closed conformation over the active site groove. SB236050 and SB238569 also demonstrate good antibacterial synergy with meropenem. Eight micrograms of SB236050 per ml gave rise to an eightfold drop in the MIC of meropenem for two clinical isolates of B. fragilis producing CfiA, making these strains sensitive to meropenem (MIC ≤ 4 μg/ml). Consequently, this series of metallo-β-lactamase inhibitors exhibit the most promising antibacterial synergy activity so far observed against organisms producing metallo-β-lactamases. PMID:12019104

  13. Identification of a series of tricyclic natural products as potent broad-spectrum inhibitors of metallo-beta-lactamases.

    PubMed

    Payne, David J; Hueso-Rodríguez, Juan Antonio; Boyd, Helen; Concha, Néstor O; Janson, Cheryl A; Gilpin, Martin; Bateson, John H; Cheever, Christy; Niconovich, Nancy L; Pearson, Stewart; Rittenhouse, Stephen; Tew, David; Díez, Emilio; Pérez, Paloma; De La Fuente, Jesus; Rees, Michael; Rivera-Sagredo, Alfonso

    2002-06-01

    This work describes the discovery and characterization of a novel series of tricyclic natural product-derived metallo-beta-lactamase inhibitors. Natural product screening of the Bacillus cereus II enzyme identified an extract from a strain of Chaetomium funicola with inhibitory activity against metallo-beta-lactamases. SB236050, SB238569, and SB236049 were successfully extracted and purified from this extract. The most active of these compounds was SB238569, which possessed K(i) values of 79, 17, and 3.4 microM for the Bacillus cereus II, Pseudomonas aeruginosa IMP-1, and Bacteroides fragilis CfiA metallo-beta-lactamases, respectively, yet none of the compounds exhibited any inhibitory activity against the Stenotrophomonas maltophilia L-1 metallo-beta-lactamase (50% inhibitory concentration > 1,000 microM). The lack of activity against angiotensin-converting enzyme and serine beta-lactamases demonstrated the selective nature of these compounds. The crystal structure of SB236050 complexed in the active site of CfiA has been obtained to a resolution of 2.5 A. SB236050 exhibits key polar interactions with Lys184, Asn193, and His162 and a stacking interaction with the indole ring of Trp49 in the flap, which is in the closed conformation over the active site groove. SB236050 and SB238569 also demonstrate good antibacterial synergy with meropenem. Eight micrograms of SB236050 per ml gave rise to an eightfold drop in the MIC of meropenem for two clinical isolates of B. fragilis producing CfiA, making these strains sensitive to meropenem (MIC < or = 4 microg/ml). Consequently, this series of metallo-beta-lactamase inhibitors exhibit the most promising antibacterial synergy activity so far observed against organisms producing metallo-beta-lactamases. PMID:12019104

  14. Exploration of natural product ingredients as inhibitors of human HMG-CoA reductase through structure-based virtual screening

    PubMed Central

    Lin, Shih-Hung; Huang, Kao-Jean; Weng, Ching-Feng; Shiuan, David

    2015-01-01

    Cholesterol plays an important role in living cells. However, a very high level of cholesterol may lead to atherosclerosis. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase is the key enzyme in the cholesterol biosynthesis pathway, and the statin-like drugs are inhibitors of human HMG-CoA reductase (hHMGR). The present study aimed to virtually screen for potential hHMGR inhibitors from natural product to discover hypolipidemic drug candidates with fewer side effects and lesser toxicities. We used the 3D structure 1HWK from the PDB (Protein Data Bank) database of hHMGR as the target to screen for the strongly bound compounds from the traditional Chinese medicine database. Many interesting molecules including polyphenolic compounds, polisubstituted heterocyclics, and linear lipophilic alcohols were identified and their ADMET (absorption, disrtibution, metabolism, excretion, toxicity) properties were predicted. Finally, four compounds were obtained for the in vitro validation experiments. The results indicated that curcumin and salvianolic acid C can effectively inhibit hHMGR, with IC50 (half maximal inhibitory concentration) values of 4.3 µM and 8 µM, respectively. The present study also demonstrated the feasibility of discovering new drug candidates through structure-based virtual screening. PMID:26170618

  15. Virtual screening for novel Staphylococcus Aureus NorA efflux pump inhibitors from natural products.

    PubMed

    Thai, Khac-Minh; Ngo, Trieu-Du; Phan, Thien-Vy; Tran, Thanh-Dao; Nguyen, Ngoc-Vinh; Nguyen, Thien-Hai; Le, Minh-Tri

    2015-01-01

    NorA is a member of the Major Facilitator Superfamily (MFS) drug efflux pumps that have been shown to mediate antibiotic resistance in Staphylococcus aureus (SA). In this study, QSAR analysis, virtual screening and molecular docking were implemented in an effort to discover novel SA NorA efflux pump inhibitors. Originally, a set of 47 structurally diverse compounds compiled from the literature was used to develop linear QSAR models and another set of 15 different compounds were chosen for extra validation. The final model which was estimated by statistical values for the full data set (n = 45, Q(2) = 0.80, RMSE = 0.20) and for the external test set (n = 15, R(2) = 0.60, |res|max = 0.75, |res|min = 0.02) was applied on the collection of 182 flavonoides and the traditional Chinese medicine (TCM) database to screen for novel NorA inhibitors. Finally, 33 lead compounds that met the Lipinski's rules of five/three and had good predicted pIC50 values from in silico screening process were employed to analyze the binding ability by docking studies on NorA homology model in place of its unavailable crystal structures at two active sites, the central channel and the Walker B. PMID:25181985

  16. Marine natural products as acetylcholinesterase inhibitor: comparative quantum mechanics and molecular docking study.

    PubMed

    Farrokhnia, Maryam; Nabipour, Iraj

    2014-03-01

    Alzheimer's disease (AD) is the most common form of dementia which affects the elderly population throughout the world. The inhibition of acetylcholinesterase (AChE) has appeared as one of the most promising strategies for the AD treatment. In this study, the density functional theory and molecular docking studies have been carried out on seven halogenated sesquiterpenes derived from the Persian Gulf sea hare, Aplysia dactylomela, to reveal their electronic, structural and chemical properties. Moreover, influences of these properties on their AChE-inhibition properties have been investigated theoretically. The results indicate that these compounds have several interactions with important residues of AChE active sites. Three of the investigated molecules correlate better to well-known AD drugs such as huperzine A, galanthamine and donepezil which represent possible AChE inhibitors against Alzheimer disease. In conclusion, the information obtained from this theoretical study may aid in the discovery of new potential AChE inhibitors with marine origin. PMID:24712383

  17. Screening of mammalian target of rapamycin inhibitors in natural product extracts by capillary electrophoresis in combination with high performance liquid chromatography-tandem mass spectrometry.

    PubMed

    Zhang, Yanmei; Li, Feng; Li, Mingxia; Kang, Jingwu

    2015-04-01

    In this study, capillary electrophoresis (CE) combined with HPLC-MS/MS were used as a powerful platform for screening of inhibitors of mammalian target of rapamycin (mTOR) in natural product extracts. The screening system has been established by using 5-carboxyfluorescein labeled substrate peptide F-4EBP1, a known mTOR inhibitor AZD8055, and a small chemical library consisted of 18 natural product extracts. Biochemical screening of natural product extracts was performed by CE with laser induced fluorescence detection. The CE separation allowed a quantitative measurement of the phosphorylated product, hence the quantitation of enzymatic inhibition as well as inhibition kinetics. The hits are readily identified as long as the peak area of the phosphorylated product is reduced in comparison with the negative control. Subsequent assay-guided isolation of the active natural product extract was performed with HPLC-MS/MS to track the particular active components. The structures of the identified active components were elucidated by the molecular ions and fragmentation information provided by MS/MS analysis. The CE-based assay method only requires minute pure compounds, which can be readily purified by HPLC. Therefore, the combination of CE and HPLC-MS/MS provides a high-throughput platform for screening bioactive compounds from the crude nature extracts. By taking the advantage of the screening system, salvianolic acid A and C in extract of Salvia miltiorrhiza were discovered as the new mTOR inhibitors. PMID:25725958

  18. Discovery of a Potential HER2 Inhibitor from Natural Products for the Treatment of HER2-Positive Breast Cancer.

    PubMed

    Li, Jianzong; Wang, Haiyang; Li, Junjie; Bao, Jinku; Wu, Chuanfang

    2016-01-01

    Breast cancer is one of the most lethal types of cancer in women worldwide due to the late stage detection and resistance to traditional chemotherapy. The human epidermal growth factor receptor 2 (HER2) is considered as a validated target in breast cancer therapy. Even though a substantial effort has been made to develop HER2 inhibitors, only lapatinib has been approved by the U.S. Food and Drug Administration (FDA). Side effects were observed in a majority of the patients within one year of treatment initiation. Here, we took advantage of bioinformatics tools to identify novel effective HER2 inhibitors. The structure-based virtual screening combined with ADMET (absorption, distribution, metabolism, excretion and toxicity) prediction was explored. In total, 11,247 natural compounds were screened. The top hits were evaluated by an in vitro HER2 kinase inhibition assay. The cell proliferation inhibition effect of identified inhibitors was evaluated in HER2-overexpressing SKBR3 and BT474 cell lines. We found that ZINC15122021 showed favorable ADMET properties and attained high binding affinity against HER2. Moreover, ZINC15122021 showed high kinase inhibition activity against HER2 and presented outstanding cell proliferation inhibition activity against both SKBR3 and BT474 cell lines. Results reveal that ZINC15122021 can be a potential HER2 inhibitor. PMID:27376283

  19. Discovery of a Potential HER2 Inhibitor from Natural Products for the Treatment of HER2-Positive Breast Cancer

    PubMed Central

    Li, Jianzong; Wang, Haiyang; Li, Junjie; Bao, Jinku; Wu, Chuanfang

    2016-01-01

    Breast cancer is one of the most lethal types of cancer in women worldwide due to the late stage detection and resistance to traditional chemotherapy. The human epidermal growth factor receptor 2 (HER2) is considered as a validated target in breast cancer therapy. Even though a substantial effort has been made to develop HER2 inhibitors, only lapatinib has been approved by the U.S. Food and Drug Administration (FDA). Side effects were observed in a majority of the patients within one year of treatment initiation. Here, we took advantage of bioinformatics tools to identify novel effective HER2 inhibitors. The structure-based virtual screening combined with ADMET (absorption, distribution, metabolism, excretion and toxicity) prediction was explored. In total, 11,247 natural compounds were screened. The top hits were evaluated by an in vitro HER2 kinase inhibition assay. The cell proliferation inhibition effect of identified inhibitors was evaluated in HER2-overexpressing SKBR3 and BT474 cell lines. We found that ZINC15122021 showed favorable ADMET properties and attained high binding affinity against HER2. Moreover, ZINC15122021 showed high kinase inhibition activity against HER2 and presented outstanding cell proliferation inhibition activity against both SKBR3 and BT474 cell lines. Results reveal that ZINC15122021 can be a potential HER2 inhibitor. PMID:27376283

  20. Structure of Trypanosoma cruzi glycosomal glyceraldehyde-3-phosphate dehydrogenase complexed with chalepin, a natural product inhibitor, at 1.95 A resolution.

    PubMed

    Pavão, F; Castilho, M S; Pupo, M T; Dias, R L A; Correa, A G; Fernandes, J B; da Silva, M F G F; Mafezoli, J; Vieira, P C; Oliva, G

    2002-06-01

    The structure of the glycosomal glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) from Trypanosoma cruzi complexed with chalepin, a natural product from Pilocarpus spicatus, has been determined by X-ray crystallography to 1.95 A resolution. The structure is in the apo form without cofactors in the subunits of the tetrameric gGAPDH in the asymmetric unit. Unequivocal density corresponding to the inhibitor was clearly identified in one monomer. The final refined model of the complex shows extensive conformational changes when compared with the native structure. The mode of binding of chalepin to gGAPDH and its implications for inhibitor design are discussed. PMID:12044862

  1. Identification of resveratrol oligomers as inhibitors of cystic fibrosis transmembrane conductance regulator by high-throughput screening of natural products from chinese medicinal plants.

    PubMed

    Zhang, Yaofang; Yu, Bo; Sui, Yujie; Gao, Xin; Yang, Hong; Ma, Tonghui

    2014-01-01

    Inhibitors of cystic fibrosis transmembrane conductance regulator (CFTR) have been widely used for characterizing CFTR function in epithelial fluid transport and in diseases such as secretory diarrhea, polycystic kidney disease and cystic fibrosis. Few small molecule CFTR inhibitors have been discovered so far from combinatorial compound library. In the present study, we used a high throughput screening (HTS)-based natural product discovery strategy to identify new CFTR inhibitors from Chinese medicinal herbs. By screening 40,000 small molecule fractions from 500 herbal plants, we identified 42 positive fractions from 5 herbs and isolated two compounds that inhibited CFTR conductance from Chinese wild grapevine (Vitis amurensis Rupr). Mass spectrometry (MS) and nuclear magnetic resonance (NMR) studies determined the two active compounds as trans-ε-viniferin (TV) and r-2-viniferin (RV), respectively. Both compounds dose-dependently blocked CFTR-mediated iodide influx with IC50 around 20 μM. Further analysis by excised inside-out patch-clamp indicated strong inhibition of protein kinase A (PKA)-activated CFTR chloride currents by TV and RV. In ex vivo studies, TV and RV inhibited CFTR-mediated short-circuit Cl- currents in isolated rat colonic mucosa in a dose-dependent manner. In a closed-loop mouse model, intraluminal applications of TV (2.5 μg) and RV (4.5 μg) significantly reduced cholera toxin-induced intestinal fluid secretion. The present study identified two resveratrol oligomers as new CFTR inhibitors and validates our high-throughput screening method for discovery of bioactive compounds from natural products with complex chemical ingredients such as herbal plants. PMID:24714160

  2. Development of Fourth Generation ABC Inhibitors from Natural Products: A Novel Approach to Overcome Cancer Multidrug Resistance.

    PubMed

    Karthikeyan, Subburayan; Hoti, Sugeerappa Laxmanappa

    2015-01-01

    Multidrug resistance (MDR) in cancer caused due to overexpression of ABC drug transporters is a major problem in modern chemotherapy. Molecular investigations on MDR have revealed that the resistance is due to various transport proteins of the ABC superfamily which include Phosphoglycoprotein (P-gp/MDR1/ ABCB1), multidrug resistance-associated protein-1 (MRP1), and the breast cancer resistance protein (BCRP). They have been characterized functionally and are considered as major players in the development of MDR in cancer cells. These ATP-dependent transporter proteins cause MDR either by decreased uptake of the drug or increased efflux of the drug from the target organelles. Several MDR-reversing agents are being developed and are in various stages of clinical trials. The first three generations of ABC modulators such as quinine, verapamil, cyclosporine-A, tariquitor, PSC 833, LY335979, and GF120918 required to be administered in high doses to reverse MDR and were associated with adverse effects. Additionally, these modulators non-selectively inhibit ABC and adversely accumulate chemotherapeutic drugs in brain and kidney. Currently, research has stepped up towards reversing MDR by using natural products which exhibitted potential as chemosensitizers. Globally, there is a rich biodiversity of natural products which can be sourced for developing drugs. These products may provide more lead compounds with superior activity, foremost to the development of more effective therapies for MDR cancer cells. Here, we briefly review the status of natural products for reversing MDR modulators, and discuss the long term goal of MDR strategies in current clinical settings. PMID:25584696

  3. The natural product dihydrotanshinone I provides a prototype for uncharged inhibitors that bind specifically to the acetylcholinesterase peripheral site with nanomolar affinity.

    PubMed

    Beri, Veena; Wildman, Scott A; Shiomi, Kazuro; Al-Rashid, Ziyad F; Cheung, Jonah; Rosenberry, Terrone L

    2013-10-22

    Cholinergic synaptic transmission often requires extremely rapid hydrolysis of acetylcholine by acetylcholinesterase (AChE). AChE is inactivated by organophosphates (OPs) in chemical warfare nerve agents. The resulting accumulation of acetylcholine disrupts cholinergic synaptic transmission and can lead to death. A potential long-term strategy for preventing AChE inactivation by OPs is based on evidence that OPs must pass through a peripheral site or P-site near the mouth of the AChE active site gorge before reacting with a catalytic serine in an acylation site or A-site at the base of the gorge. An ultimate goal of this strategy is to design compounds that bind tightly at or near the P-site and exclude OPs from the active site while interfering minimally with the passage of acetylcholine. However, to target the AChE P-site with ligands and potential drugs that selectively restrict access, much more information must be gathered about the structure-activity relationships of ligands that bind specifically to the P-site. We apply here an inhibitor competition assay that can correctly determine whether an AChE inhibitor binds to the P-site, the A-site, or both sites. We have used this assay to examine three uncharged, natural product inhibitors of AChE, including aflatoxin B1, dihydrotanshinone I, and territrem B. The first two of these inhibitors are predicted by the competition assay to bind selectively to the P-site, while territrem B is predicted to span both the P- and A-sites. These predictions have recently been confirmed by X-ray crystallography. Dihydrotanshinone I, with an observed binding constant (KI) of 750 nM, provides a good lead compound for the development of high-affinity, uncharged inhibitors with specificity for the P-site. PMID:24040835

  4. Ectopic NGAL expression can alter sensitivity of breast cancer cells to EGFR, Bcl-2, CaM-K inhibitors and the plant natural product berberine

    PubMed Central

    Chappell, William H.; Abrams, Stephen L.; Franklin, Richard A.; LaHair, Michelle M.; Montalto, Giuseppe; Cervello, Melchiorre; Martelli, Alberto M.; Nicoletti, Ferdinando; Candido, Saverio; Libra, Massimo; Polesel, Jerry; Talamini, Renato; Milella, Michele; Tafuri, Agostino; Steelman, Linda S.; McCubrey, James A.

    2012-01-01

    Neutrophil gelatinase-associated lipocalin (NGAL, a.k.a Lnc2) is a member of the lipocalin family and has diverse roles. NGAL can stabilize matrix metalloproteinase-9 from autodegradation. NGAL is considered as a siderocalin that is important in the transport of iron. NGAL expression has also been associated with certain neoplasias and is implicated in the metastasis of breast cancer. In a previous study, we examined whether ectopic NGAL expression would alter the sensitivity of breast epithelial, breast and colorectal cancer cells to the effects of the chemotherapeutic drug doxorubicin. While abundant NGAL expression was detected in all the cells infected with a retrovirus encoding NGAL, this expression did not alter the sensitivity of these cells to doxorubicin as compared with empty vector-transduced cells. We were also interested in determining the effects of ectopic NGAL expression on the sensitivity to small-molecule inhibitors targeting key signaling molecules. Ectopic NGAL expression increased the sensitivity of MCF-7 breast cancer cells to EGFR, Bcl-2 and calmodulin kinase inhibitors as well as the natural plant product berberine. Furthermore, when suboptimal concentrations of certain inhibitors were combined with doxorubicin, a reduction in the doxorubicin IC50 was frequently observed. An exception was observed when doxorubicin was combined with rapamycin, as doxorubicin suppressed the sensitivity of the NGAL-transduced MCF-7 cells to rapamycin when compared with the empty vector controls. In contrast, changes in the sensitivities of the NGAL-transduced HT-29 colorectal cancer cell line and the breast epithelial MCF-10A cell line were not detected compared with empty vector-transduced cells. Doxorubicin-resistant MCF-7/DoxR cells were examined in these experiments as a control drug-resistant line; it displayed increased sensitivity to EGFR and Bcl-2 inhibitors compared with empty vector transduced MCF-7 cells. These results indicate that NGAL expression

  5. "One-shot" analysis of PDE-5 inhibitors and analogues in counterfeit herbal natural products using an LC-DAD-QTOF system.

    PubMed

    Bortolini, Claudio; Pivato, Antonio; Bogialli, Sara; Pastore, Paolo

    2015-08-01

    A highly selective and robust method for simultaneous screening and confirmation of target and non-target phosphodiesterase type 5 (PDE-5) inhibitor analogues within a single chromatographic run in counterfeit herbal products was developed. The protocol, based on an easy and rapid extraction with a water/acetonitrile 1 % formic acid solution, followed by sonication and centrifugation, exploits an LC-diode array detector-quadrupole-time-of-flight (DAD-QTOF) system. The extraction method was optimized both at high concentrations and at trace levels. These two situations are typically encountered in pharmaceutical formulations and herbal food supplements. Carryover effects, never reported before and occurring mainly for vardenafil, were overcome using a polymer-based column. An in-house validation was carried out using five blanks of different bulk matrices spiked with seven standard analytes, namely yohimbine, sildenafil, vardenafil, tadalafil, homosildenafil, pseudovardenafil and hydroxyhomovardenafil. Reliable quantitation was possible using a conventional standard solution for all the pharmaceutical and herbal samples considered, as matrix effects were eliminated. Accuracy ranged from 80.9 to 108.1 % with overall relative standard deviation (RSD) <11 % (N = 15), measured at 1.0, 5.0 and 10.0 μg/g. Limits of detection (LODs) obtained ensured the determination of cross contaminations at nanogram per gram levels. A database with 82 PDE-5 inhibitor analogues was implemented for automatic non-target analysis. Among the 26 samples of dietary supplements and herbal remedies bulk marketed for erectile dysfunctions, three samples were found to be contaminated with both registered and unregistered synthetic PDE-5 inhibitors, i.e. yohimbine, sildenafil, dimethylsildenafil and thiodimethylsildenafil or thiomethisosildenafil. The occurrence of such contaminations, both at trace levels and at pharmaceutical dosage, indicates the illicit use of synthetic PDE-5 analogues

  6. Ligand-based virtual screening and inductive learning for identification of SIRT1 inhibitors in natural products

    PubMed Central

    Sun, Yunan; Zhou, Hui; Zhu, Hongmei; Leung, Siu-wai

    2016-01-01

    Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent deacetylase, and its dysregulation can lead to ageing, diabetes, and cancer. From 346 experimentally confirmed SIRT1 inhibitors, an inhibitor structure pattern was generated by inductive logic programming (ILP) with DMax Chemistry Assistant software. The pattern contained amide, amine, and hetero-aromatic five-membered rings, each of which had a hetero-atom and an unsubstituted atom at a distance of 2. According to this pattern, a ligand-based virtual screening of 1 444 880 active compounds from Chinese herbs identified 12 compounds as inhibitors of SIRT1. Three compounds (ZINC08790006, ZINC08792229, and ZINC08792355) had high affinity (−7.3, −7.8, and −8.6 kcal/mol, respectively) for SIRT1 as estimated by molecular docking software AutoDock Vina. This study demonstrated a use of ILP and background knowledge in machine learning to facilitate virtual screening. PMID:26805727

  7. Inhibitory effects of respiration inhibitors on aflatoxin production.

    PubMed

    Sakuda, Shohei; Prabowo, Diyan Febri; Takagi, Keiko; Shiomi, Kazuro; Mori, Mihoko; Ōmura, Satoshi; Nagasawa, Hiromichi

    2014-04-01

    Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A) inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III) and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control. PMID:24674936

  8. Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

    PubMed Central

    Sakuda, Shohei; Prabowo, Diyan Febri; Takagi, Keiko; Shiomi, Kazuro; Mori, Mihoko; Ōmura, Satoshi; Nagasawa, Hiromichi

    2014-01-01

    Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A) inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III) and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control. PMID:24674936

  9. Total synthesis and structural confirmation of the marine natural product Dysinosin A: a novel inhibitor of thrombin and Factor VIIa.

    PubMed

    Hanessian, Stephen; Margarita, Roberto; Hall, Adrian; Johnstone, Shawn; Tremblay, Martin; Parlanti, Luca

    2002-11-13

    The structure and absolute configuration of the marine antithrombotic product dysinosin A was confirmed by total synthesis. The strategy involved disconnections to three subunits, of which two were synthesized from the readily available l-glutamic acid, d-leucine, and d-mannitol. The Grubbs olefin metathesis carbocyclization reaction was utilized to prepare two intermediates. PMID:12418860

  10. High Throughput Screen Identifies Natural Product Inhibitor of Phenylalanyl-tRNA Synthetase from Pseudomonas aeruginosa and Streptococcus pneumoniae.

    PubMed

    Hu, Yanmei; Palmer, Stephanie O; Munoz, Hector; Bullard, James M

    2014-01-01

    Pseudomonas aeruginosa and Streptococcus pneumoniae are causative agents in a wide range of infections. Genes encoding proteins corresponding to phenylalanyl-tRNA synthetase (PheRS) were cloned from both bacteria. The two forms of PheRS were kinetically evaluated and the K(m)'s for P. aeruginosa PheRS with its three substrates, phenylalanine, ATP and tRNA(Phe) were determined to be 48, 200, and 1.2 µM, respectively, while the K(m)'s for S. pneumoniae PheRS with respect to phenylalanine, ATP and tRNA(Phe) were 21, 225 and 0.94 µM, respectively. P. aeruginosa and S. pneumoniae PheRS were used to screen a natural compound library and a single compound was identified that inhibited the function of both enzymes. The compound inhibited P. aeruginosa and S. pneumoniae PheRS with IC50's of 2.3 and 4.9 µM, respectively. The compound had a K(I) of 0.83 and 0.98 µM against P. aeruginosa and S. pneumoniae PheRS, respectively. The minimum inhibitory concentration (MIC) of the compound was determined against a panel of Gram positive and negative bacteria including efflux pump mutants and hyper-sensitive strains. MICs against wild-type P. aeruginosa and S. pneumoniae cells in culture were determined to be 16 and 32 µg/ml, respectively. The mechanism of action of the compound was determined to be competitive with the amino acid, phenylalanine, and uncompetitive with ATP. There was no inhibition of cytoplasmic protein synthesis, however, partial inhibition of the human mitochondrial PheRS was observed. PMID:25601215

  11. DNA Methyltransferases Inhibitors from Natural Sources.

    PubMed

    Zwergel, Clemens; Valente, Sergio; Mai, Antonello

    2016-01-01

    DNA methyltransferases (DNMTs) catalyze the methylation at cytosine-C5 mainly in a CpG dinucleotide context. Although DNA methylation is essential for fundamental processes like embryonic development or differentiation, aberrant expression and/or activities of DNMTs are involved in several pathologies, from neurodegeneration to cancer. DNMTs inhibition can arrest tumor growth, cells invasiveness and induce differentiation, whereas their increased expression is shown in numerous cancer types. Moreover, hypermethylated promoters of tumor suppressor genes lead to their silencing. Hence, the use of specific inhibitors of DNMT might reactivate those genes and stop or even reverse the aberrant cell processes. To date, the only approved DNMTs inhibitors for therapy belong to the nucleoside-based family of drugs, but they display relevant side effects as well as high chemical instability. Thus, there is a keen interest actually exists to develop novel, potent and safe inhibitors possessing a nonnucleoside structure. Increasing literature evidence is highlighting that natural sources could help the researchers to achieve this goal. Indeed, several polyphenols, flavonoids, antraquinones, and others are described able to inhibit DNMTs activity and/or expression, thus decreasing the methylation/silencing of different genes involved in tumorigenesis. These events can lead to re-expression of such genes and to cell death in diverse cancer cell lines. Epigallocatechin-3-gallate (1) and laccaic acid A (11) resulted the most effective DNMT1 inhibitors with submicromolar IC50 values, acting as competitive inhibitors. Compound 1 and 11 both displayed gene demethylation and re-activation in several cancers. However, all of the natural compounds described in this review showed important results, from gene reactivation to cell growth inhibition. Moreover, some of them displayed interesting activity even in rodent cancer models and very recently entered clinical trials. PMID:26303417

  12. Structure-based hybridization of the bioactive natural products rhizonin A and ternatin leading to a selective fat-accumulation inhibitor against 3T3-L1 adipocytes.

    PubMed

    Shimokawa, Kenichiro; Yamada, Kaoru; Uemura, Daisuke

    2009-02-01

    Based on the structural similarity between the naturally occurring cyclic heptapeptides rhizonin A and ternatin, two novel analogues were designed. The synthetic analogues were assessed with regard to their fat-accumulation inhibitory effect against 3T3-L1 adipocytes, and this led to the discovery of a potent and selective fat-accumulation inhibitor compared to the parent compound rhizonin A. PMID:19097891

  13. Natural Product Total Synthesis in the Organic Laboratory: Total Synthesis of Caffeic Acid Phenethyl Ester (CAPE), a Potent 5-Lipoxygenase Inhibitor from Honeybee Hives

    ERIC Educational Resources Information Center

    Touaibia, Mohamed; Guay, Michel

    2011-01-01

    Natural products play a critical role in modern organic synthesis and learning synthetic techniques is an important component of the organic laboratory experience. In addition to traditional one-step organic synthesis laboratories, a multistep natural product synthesis is an interesting experiment to challenge students. The proposed three-step…

  14. An optimized micro-assay of myosin II ATPase activity based on the molybdenum blue method and its application in screening natural product inhibitors.

    PubMed

    Chen, Hong-Lin; Zhao, Jing; Zhang, Guan-Jun; Kou, Jun-Ping; Yu, Bo-Yang

    2016-06-01

    Myosin II plays multiple roles in physiological and pathological functions through its ATPase activity. The present study was designed to optimize a micro-assay of myosin II ATPase activity based on molybdenum blue method, using a known myosin II ATPase inhibitor, blebbistatin. Several parameters were observed in the enzymatic reaction procedure, including the concentrations of the substrate (ATP) and calcium chloride, pH, and the reaction and incubation times. The proportion of coloration agent was also investigated. The sensitivity of this assay was compared with the malachite green method and bioluminescence method. Additionally, 20 natural compounds were studied for myosin II ATPase inhibitory activity using the optimized method. Our results showed that ATP at the concentration of 5 mmol·L(-1) and ammonium molybdate : stannous chloride at the ratio of 15 : 1 could greatly improve the sensitivity of this method. The IC50 of blebbistatin obtained by this method was consistent with literature. Compound 8 was screened with inhibitory activity on myosin II ATPase. The optimized method showed similar accuracy, lower detecting limit, and wider linear range, which could be a promising approach to screening myosin II ATPase inhibitors in vitro. PMID:27473959

  15. Use of a Recombinant Fluorescent Substrate with Cleavage Sites for All Botulinum Neurotoxins in High-Throughput Screening of Natural Product Extracts for Inhibitors of Serotypes A, B, and E▿ †

    PubMed Central

    Hines, Harry B.; Kim, Alexander D.; Stafford, Robert G.; Badie, Shirin S.; Brueggeman, Ernst E.; Newman, David J.; Schmidt, James J.

    2008-01-01

    The seven serotypes of botulinum neurotoxin (BoNTs) are zinc metalloproteases that cleave and inactivate proteins critical for neurotransmission. The synaptosomal protein of 25 kDa (SNAP-25) is cleaved by BoNTs A, C, and E, while vesicle-associated membrane protein (VAMP) is the substrate for BoNTs B, D, F, and G. BoNTs not only are medically useful drugs but also are potential bioterrorist and biowarfare threat agents. Because BoNT protease activity is required for toxicity, inhibitors of that activity might be effective for antibotulinum therapy. To expedite inhibitor discovery, we constructed a hybrid gene encoding (from the N terminus to the C terminus, with respect to the expressed product) green fluorescent protein, then a SNAP-25 fragment encompassing residues Met-127 to Gly-206, and then VAMP residues Met-1 to Lys-94. Cysteine was added as the C terminus. The expressed product, which contained the protease cleavage sites for all seven botulinum serotypes, was purified and coupled covalently through the C-terminal sulfhydryl group to maleimide-activated 96-well plates. The substrate was readily cleaved by BoNTs A, B, D, E, and F. Using this assay and an automated 96-well pipettor, we screened 528 natural product extracts for inhibitors of BoNT A, B, and E protease activities. Serotype-specific inhibition was found in 30 extracts, while 5 others inhibited two serotypes. PMID:18083881

  16. Natural Products for Antithrombosis

    PubMed Central

    Chen, Cen; Zhang, Qian; Wang, Feng-Qin; Hu, Yuan-Jia; Xia, Zhi-Ning

    2015-01-01

    Thrombosis is considered to be closely related to several diseases such as atherosclerosis, ischemic heart disease and stroke, as well as rheumatoid arthritis, hyperuricemia, and various inflammatory conditions. More and more studies have been focused on understanding the mechanism of molecular and cellular basis of thrombus formation as well as preventing thrombosis for the treatment of thrombotic diseases. In reality, there is considerable interest in the role of natural products and their bioactive components in the prevention and treatment of thrombosis related disorders. This paper briefly describes the mechanisms of thrombus formation on three aspects, including coagulation system, platelet activation, and aggregation, and change of blood flow conditions. Furthermore, the natural products for antithrombosis by anticoagulation, antiplatelet aggregation, and fibrinolysis were summarized, respectively. PMID:26075003

  17. Natural products as photoprotection.

    PubMed

    Saewan, Nisakorn; Jimtaisong, Ampa

    2015-03-01

    The rise in solar ultraviolet radiation on the earth's surface has led to a depletion of stratospheric ozone over recent decades, thus accelerating the need to protect human skin against the harmful effects of UV radiation such as erythema, edema, hyperpigmentation, photoaging, and skin cancer. There are many different ways to protect skin against UV radiation's harmful effects. The most popular way to reduce the amount of UV radiation penetrating the skin is topical application of sunscreen products that contain UV absorbing or reflecting active molecules. Based on their protection mechanism, the active molecules in sunscreens are broadly divided into inorganic and organic agents. Inorganic sunscreens reflect and scatter UV and visible radiation, while organic sunscreens absorb UV radiation and then re-emit energy as heat or light. These synthetic molecules have limited concentration according to regulation concern. Several natural compounds with UV absorption property have been used to substitute for or to reduce the quantity of synthetic sunscreen agents. In addition to UV absorption property, most natural compounds were found to act as antioxidants, anti-inflammatory, and immunomodulatory agents, which provide further protection against the damaging effects of UV radiation exposure. Compounds derived from natural sources have gained considerable attention for use in sunscreen products and have bolstered the market trend toward natural cosmetics. This adds to the importance of there being a wide selection of active molecules in sunscreen formulations. This paper summarizes a number of natural products derived from propolis, plants, algae, and lichens that have shown potential photoprotection properties against UV radiation exposure-induced skin damage. PMID:25582033

  18. NATURAL PRODUCTS FOR PEST MANAGEMENT

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The topic of natural products as pesticides is reviewed, with a discussion of the advantages and disadvantages of adopting a natural product-based strategy for pesticide discovery. Current and past natural product and natural product-based herbicides, insecticides, fungicides, molluscicides, rodent...

  19. Marine natural products.

    PubMed

    Blunt, John W; Copp, Brent R; Keyzers, Robert A; Munro, Murray H G; Prinsep, Michèle R

    2013-02-01

    This review covers the literature published in 2011 for marine natural products, with 870 citations (558 for the period January to December 2011) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1152 for 2011), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included. PMID:23263727

  20. Marine natural products.

    PubMed

    Blunt, John W; Copp, Brent R; Keyzers, Robert A; Munro, Murray H G; Prinsep, Michèle R

    2016-03-01

    This review covers the literature published in 2014 for marine natural products (MNPs), with 1116 citations (753 for the period January to December 2014) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1378 in 456 papers for 2014), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included. PMID:26837534

  1. Marine natural products.

    PubMed

    Blunt, John W; Copp, Brent R; Keyzers, Robert A; Munro, Murray H G; Prinsep, Michèle R

    2014-01-17

    This review covers the literature published in 2012 for marine natural products, with 1035 citations (673 for the period January to December 2012) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1241 for 2012), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included. PMID:24389707

  2. Marine natural products.

    PubMed

    Blunt, John W; Copp, Brent R; Keyzers, Robert A; Munro, Murray H G; Prinsep, Michèle R

    2015-02-01

    This review covers the literature published in 2013 for marine natural products (MNPs), with 982 citations (644 for the period January to December 2013) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1163 for 2013), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included. PMID:25620233

  3. Natural fatty acid synthase inhibitors as potent therapeutic agents for cancers: A review.

    PubMed

    Zhang, Jia-Sui; Lei, Jie-Ping; Wei, Guo-Qing; Chen, Hui; Ma, Chao-Ying; Jiang, He-Zhong

    2016-09-01

    Context Fatty acid synthase (FAS) is the only mammalian enzyme to catalyse the synthesis of fatty acid. The expression level of FAS is related to cancer progression, aggressiveness and metastasis. In recent years, research on natural FAS inhibitors with significant bioactivities and low side effects has increasingly become a new trend. Herein, we present recent research progress on natural fatty acid synthase inhibitors as potent therapeutic agents. Objective This paper is a mini overview of the typical natural FAS inhibitors and their possible mechanism of action in the past 10 years (2004-2014). Method The information was collected and compiled through major databases including Web of Science, PubMed, and CNKI. Results Many natural products induce cancer cells apoptosis by inhibiting FAS expression, with fewer side effects than synthetic inhibitors. Conclusion Natural FAS inhibitors are widely distributed in plants (especially in herbs and foods). Some natural products (mainly phenolics) possessing potent biological activities and stable structures are available as lead compounds to synthesise promising FAS inhibitors. PMID:26864638

  4. Natural products: Emulation illuminates biosynthesis

    NASA Astrophysics Data System (ADS)

    Mercer, Jaron A. M.; Burns, Noah Z.

    2015-11-01

    A concise synthesis of the fungal natural product epicolactone suggests that this highly stereochemically complex yet racemic natural product may come from a cascade reaction between two polyhydroxylated arenes.

  5. Pest management with natural products

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The 2012 Philadelphia ACS Symposium on Natural Products for Pest Management introduced recent discoveries and applications of natural products from insect, terrestrial plant, microbial, and synthetic sources for the management of insects, weeds, plant pathogenic microbes, and nematodes. The symposiu...

  6. Marizomib, a potent second generation proteasome inhibitor from natural origin.

    PubMed

    Ma, Long; Diao, Aipo

    2015-01-01

    The malignance of cancers reinforces the need to find potent antineoplastic agents. In the past decades, proteasome has been witnessed as a potential target to fulfil this purpose, as evidenced by the fact that the first-in-class proteasome inhibitor Bortezomib was marketed in 2003. Marizomib (Salinosporamide A, NPI-0052), as a marine natural product, promises to be of high efficacy against multiple myeloma (MM), relapsed/refractory MM and other types of solid tumours. Compared with Bortezomib, it arguably has fewer severe side effects. Marizomib has been termed as orphan drug against multiple myeloma by US Food and Drug Administration (FDA) in 2013 and by European Medicines Agency (EMA) in 2014. As one of the second generation proteasome inhibitors (PIs), Marizomib is expected to bring about a sustained and complete therapeutic to extend cancer patients' life span. In this article, we intended to briefly review the historical developments, mechanisms, pharmacology, biosynthesis and side effects of this agent, aiming to provide concise coverage for a broad readership. In the end, we proposed our perspective for its futuristic applications. PMID:25403165

  7. Natural cholinesterase inhibitors from Myristica cinnamomea King.

    PubMed

    Abdul Wahab, Siti Mariam; Sivasothy, Yasodha; Liew, Sook Yee; Litaudon, Marc; Mohamad, Jamaludin; Awang, Khalijah

    2016-08-01

    A new acylphenol, malabaricone E (1) together with the known malabaricones A-C (2-4), maingayones A and B (5 and 6) and maingayic acid B (7) were isolated from the ethyl acetate extract of the fruits of Myristica cinnamomea King. Their structures were determined by 1D and 2D NMR techniques and LCMS-IT-TOF analysis. Compounds 3 (1.84±0.19 and 1.76±0.21μM, respectively) and 4 (1.94±0.27 and 2.80±0.49μM, respectively) were identified as dual inhibitors, with almost equal acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibiting potentials. The Lineweaver-Burk plots of compounds 3 and 4 indicated that they were mixed-mode inhibitors. Based on the molecular docking studies, compounds 3 and 4 interacted with the peripheral anionic site (PAS), the catalytic triad and the oxyanion hole of the AChE. As for the BChE, while compound 3 interacted with the PAS, the catalytic triad and the oxyanion hole, compound 4 only interacted with the catalytic triad and the oxyanion hole. PMID:27236720

  8. Natural Products for Cancer Prevention

    PubMed Central

    Greenlee, Heather

    2013-01-01

    OBJECTIVES To review the clinical trial literature on the use and effects of natural products for cancer prevention. DATA SOURCES Clinical trials published in PubMed. CONCLUSION There is a growing body of literature on the use of natural products for cancer prevention. To date, few trials have demonstrated conclusive benefit. Current guidelines recommend against the use of natural products for cancer prevention. IMPLICATIONS FOR NURSING PRACTICE Clinicians should ask patients about their use of natural products and motivations for use. If patients are using natural products specifically for cancer prevention, they should be counseled on the current guidelines, as well as their options for other cancer prevention strategies. PMID:22281308

  9. Affinity Crystallography: A New Approach to Extracting High-Affinity Enzyme Inhibitors from Natural Extracts.

    PubMed

    Aguda, Adeleke H; Lavallee, Vincent; Cheng, Ping; Bott, Tina M; Meimetis, Labros G; Law, Simon; Nguyen, Nham T; Williams, David E; Kaleta, Jadwiga; Villanueva, Ivan; Davies, Julian; Andersen, Raymond J; Brayer, Gary D; Brömme, Dieter

    2016-08-26

    Natural products are an important source of novel drug scaffolds. The highly variable and unpredictable timelines associated with isolating novel compounds and elucidating their structures have led to the demise of exploring natural product extract libraries in drug discovery programs. Here we introduce affinity crystallography as a new methodology that significantly shortens the time of the hit to active structure cycle in bioactive natural product discovery research. This affinity crystallography approach is illustrated by using semipure fractions of an actinomycetes culture extract to isolate and identify a cathepsin K inhibitor and to compare the outcome with the traditional assay-guided purification/structural analysis approach. The traditional approach resulted in the identification of the known inhibitor antipain (1) and its new but lower potency dehydration product 2, while the affinity crystallography approach led to the identification of a new high-affinity inhibitor named lichostatinal (3). The structure and potency of lichostatinal (3) was verified by total synthesis and kinetic characterization. To the best of our knowledge, this is the first example of isolating and characterizing a potent enzyme inhibitor from a partially purified crude natural product extract using a protein crystallographic approach. PMID:27498895

  10. Supramolecular complexations of natural products.

    PubMed

    Schneider, Hans-Jörg; Agrawal, Pawan; Yatsimirsky, Anatoly K

    2013-08-21

    Complexations of natural products with synthetic receptors as well as the use of natural products as host compounds are reviewed, with an emphasis on possible practical uses or on biomedical significance. Applications such as separation, sensing, enzyme monitoring, and protection of natural drugs are first outlined. We then discuss examples of complexes with all important classes of natural compounds, such as amino acids, peptides, nucleosides/nucleotides, carbohydrates, catecholamines, flavonoids, terpenoids/steroids, alkaloids, antibiotics and toxins. PMID:23703643

  11. Pectin as an Extraordinary Natural Kinetic Hydrate Inhibitor

    NASA Astrophysics Data System (ADS)

    Xu, Shurui; Fan, Shuanshi; Fang, Songtian; Lang, Xuemei; Wang, Yanhong; Chen, Jun

    2016-03-01

    Pectin as a novel natural kinetic hydrate inhibitor, expected to be eco-friendly and sufficiently biodegradable, was studied in this paper. The novel crystal growth inhibition (CGI) and standard induction time methods were used to evaluate its effect as hydrate inhibitor. It could successfully inhibit methane hydrate formation at subcooling temperature up to 12.5 °C and dramatically slowed the hydrate crystal growth. The dosage of pectin decreased by 66% and effective time extended 10 times than typical kinetic inhibitor. Besides, its maximum growth rate was no more than 2.0%/h, which was far less than 5.5%/h of growth rate for PVCap at the same dosage. The most prominent feature was that it totally inhibited methane hydrate crystal rapid growth when hydrate crystalline occurred. Moreover, in terms of typical natural inhibitors, the inhibition activity of pectin increased 10.0-fold in induction time and 2.5-fold in subcooling temperature. The extraordinary inhibition activity is closely related to its hydrogen bonding interaction with water molecules and the hydrophilic structure. Finally, the biodegradability and economical efficiency of pectin were also taken into consideration. The results showed the biodegradability improved 75.0% and the cost reduced by more than 73.3% compared to typical commercial kinetic inhibitors.

  12. Pectin as an Extraordinary Natural Kinetic Hydrate Inhibitor.

    PubMed

    Xu, Shurui; Fan, Shuanshi; Fang, Songtian; Lang, Xuemei; Wang, Yanhong; Chen, Jun

    2016-01-01

    Pectin as a novel natural kinetic hydrate inhibitor, expected to be eco-friendly and sufficiently biodegradable, was studied in this paper. The novel crystal growth inhibition (CGI) and standard induction time methods were used to evaluate its effect as hydrate inhibitor. It could successfully inhibit methane hydrate formation at subcooling temperature up to 12.5 °C and dramatically slowed the hydrate crystal growth. The dosage of pectin decreased by 66% and effective time extended 10 times than typical kinetic inhibitor. Besides, its maximum growth rate was no more than 2.0%/h, which was far less than 5.5%/h of growth rate for PVCap at the same dosage. The most prominent feature was that it totally inhibited methane hydrate crystal rapid growth when hydrate crystalline occurred. Moreover, in terms of typical natural inhibitors, the inhibition activity of pectin increased 10.0-fold in induction time and 2.5-fold in subcooling temperature. The extraordinary inhibition activity is closely related to its hydrogen bonding interaction with water molecules and the hydrophilic structure. Finally, the biodegradability and economical efficiency of pectin were also taken into consideration. The results showed the biodegradability improved 75.0% and the cost reduced by more than 73.3% compared to typical commercial kinetic inhibitors. PMID:26996773

  13. Pectin as an Extraordinary Natural Kinetic Hydrate Inhibitor

    PubMed Central

    Xu, Shurui; Fan, Shuanshi; Fang, Songtian; Lang, Xuemei; Wang, Yanhong; Chen, Jun

    2016-01-01

    Pectin as a novel natural kinetic hydrate inhibitor, expected to be eco-friendly and sufficiently biodegradable, was studied in this paper. The novel crystal growth inhibition (CGI) and standard induction time methods were used to evaluate its effect as hydrate inhibitor. It could successfully inhibit methane hydrate formation at subcooling temperature up to 12.5 °C and dramatically slowed the hydrate crystal growth. The dosage of pectin decreased by 66% and effective time extended 10 times than typical kinetic inhibitor. Besides, its maximum growth rate was no more than 2.0%/h, which was far less than 5.5%/h of growth rate for PVCap at the same dosage. The most prominent feature was that it totally inhibited methane hydrate crystal rapid growth when hydrate crystalline occurred. Moreover, in terms of typical natural inhibitors, the inhibition activity of pectin increased 10.0-fold in induction time and 2.5-fold in subcooling temperature. The extraordinary inhibition activity is closely related to its hydrogen bonding interaction with water molecules and the hydrophilic structure. Finally, the biodegradability and economical efficiency of pectin were also taken into consideration. The results showed the biodegradability improved 75.0% and the cost reduced by more than 73.3% compared to typical commercial kinetic inhibitors. PMID:26996773

  14. Search method for inhibitors of Staphyloxanthin production by methicillin-resistant Staphylococcus aureus.

    PubMed

    Sakai, Kent; Koyama, Nobuhiro; Fukuda, Takashi; Mori, Yukiko; Onaka, Hiroyasu; Tomoda, Hiroshi

    2012-01-01

    Staphyloxanthin, a yellow pigment produced by methicillin-resistant Staphylococcus aureus (MRSA), is a virulent factor escaping from the host immune system. A new screening method for inhibitors of staphyloxanthin production by MRSA was established using paper disks. By this screening method, inhibitors of staphyloxanthin production were selected from the natural product library (ca. 300) and from actinomycete culture broths (ca. 1000). From the natural product library, four known inhibitors of lipid metabolism, cerulenin, dihydrobisvertinol, xanthohumol and zaragozic acid, were found to inhibit staphyloxanthin production; however, typical antibiotics used clinically, including vancomycin, had no effect on staphyloxanthin production. From actinomycete culture broths, two known anthraquinones, 6-deoxy-8-O-methylrabelomycin and tetrangomycin, were found to inhibit staphyloxanthin production by MRSA in the paper disk assay. These results suggested that this screening method is useful and effective to find compounds targeting staphyloxanthin production, leading to a new type of chemotherapeutics against MRSA infection. PMID:22223336

  15. Natural products and caries prevention.

    PubMed

    Cheng, Lei; Li, Jiyao; He, Libang; Zhou, Xuedong

    2015-01-01

    Dental caries is considered as the most common polymicrobial oral disease in the world. With the aim of developing alternative approaches to reduce or prevent the decay, numerous papers showed the potential anticaries activity of a number of natural products. The natural products with anticaries effects are selected from e.g. food, beverages, flowers or traditional herbs. Most of the effective components are proven to be polyphenol compounds. Many of the natural products are studied as antibacterial agents, while some of them are found to be effective in shifting the de-/remineralization balance. However, the mechanisms of the anticaries effects are still unclear for most of the natural products. In the future, more efforts need to be made to seek novel effective natural products via in vitro experiment, animal study and in situ investigations, as well as to enhance their anticaries effects with the help of novel technology like nanotechnology. PMID:25871417

  16. NSAID induction of interleukin 1/catabolin inhibitor production by osteoarthritic synovial tissue.

    PubMed

    Herman, J H; Sowder, W G; Hess, E V

    1991-02-01

    Select classes of nonsteroidal antiinflammatory drugs (NSAID), independent of their cyclooxygenase suppressing property, may potentially regulate pathophysiologic mechanisms operative in accelerated cartilage catabolism occurring in osteoarthritis (OA). Piroxicam has been shown to downregulate the expression of interleukin 1 (IL-1) associated chondrocyte enzyme inducing activity (catabolin) produced by OA synovium. In situ membrane synthesis of catabolin/IL-1 inhibitors functioning at various levels in thymocyte and catabolin bioassay systems is currently shown. The piroxicam effect appears due to a selective increase in production of a naturally occurring inhibitor(s) and/or induction of new inhibitor formation acting on chondrocytes at a post-IL-1 receptor level. PMID:2027111

  17. Natural Products as Molecular Messengers*

    PubMed Central

    Meinwald, Jerrold

    2011-01-01

    The chemistry of naturally-occurring compounds has long been pursued in the search for medicines, dyes, pesticides, flavors, and fragrances. In addition, the deeper aim of understanding life itself as a chemical phenomenon has motivated generations of scientists. One consequence of such studies has been the realization that natural products often serve central roles as biological signaling agents. We consider natural products from the viewpoint of the organisms that produce and/or respond to them, and suggest how a naturally-occurring compound may acquire its role in chemical communication. PMID:21190370

  18. Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs).

    PubMed

    Goettig, Peter; Magdolen, Viktor; Brandstetter, Hans

    2010-11-01

    Including the true tissue kallikrein KLK1, kallikrein-related peptidases (KLKs) represent a family of fifteen mammalian serine proteases. While the physiological roles of several KLKs have been at least partially elucidated, their activation and regulation remain largely unclear. This obscurity may be related to the fact that a given KLK fulfills many different tasks in diverse fetal and adult tissues, and consequently, the timescale of some of their physiological actions varies significantly. To date, a variety of endogenous inhibitors that target distinct KLKs have been identified. Among them are the attenuating Zn(2+) ions, active site-directed proteinaceous inhibitors, such as serpins and the Kazal-type inhibitors, or the huge, unspecific compartment forming α(2)-macroglobulin. Failure of these inhibitory systems can lead to certain pathophysiological conditions. One of the most prominent examples is the Netherton syndrome, which is caused by dysfunctional domains of the Kazal-type inhibitor LEKTI-1 which fail to appropriately regulate KLKs in the skin. Small synthetic inhibitory compounds and natural polypeptidic exogenous inhibitors have been widely employed to characterize the activity and substrate specificity of KLKs and to further investigate their structures and biophysical properties. Overall, this knowledge leads not only to a better understanding of the physiological tasks of KLKs, but is also a strong fundament for the synthesis of small compound drugs and engineered biomolecules for pharmaceutical approaches. In several types of cancer, KLKs have been found to be overexpressed, which makes them clinically relevant biomarkers for prognosis and monitoring. Thus, down regulation of excessive KLK activity in cancer and in skin diseases by small inhibitor compounds may represent attractive therapeutical approaches. PMID:20615447

  19. Targeting Mycobacterial Enzymes with Natural Products.

    PubMed

    Sieniawska, Elwira

    2015-10-22

    Tuberculosis (TB) is a recurring threat to contemporary civilization. It affects not only those within developing countries, but has also appeared again in places where it was once considered eradicated. TB co-infection in patients infected by HIV is, at the time of writing, the most common cause of death. In the field of searching for new antimycobacterial drug leads, compounds of natural origin still remain a promising source. The review is intended to gather information about natural products (metabolites of plants, fungi, bacteria, and marine sponges) that show activity against mycobacterial enzymes. Here, natural metabolites are presented as being inhibitors/activators of the mycobacterial enzymes involved in mycobacterial growth in vitro (ClpC1, ClpP, MurE ligase, mycothiol S-conjugate amidase, β-ketoacyl-ACP synthase, InhA) and in vivo, as regards the host cell (PtpB). Each enzyme is briefly described so as to generate an understanding of its role in mycobacterial growth and engender a perception of the mechanism of action of the studied natural compounds. Furthermore, after the introduction of the enzyme, its inhibitors are listed and exactly characterized. PMID:26441042

  20. Synthesis of Polycyclic Natural Products

    SciTech Connect

    Tuan Hoang Nguyen

    2003-05-31

    With the continuous advancements in molecular biology and modern medicine, organic synthesis has become vital to the support and extension of those discoveries. The isolations of new natural products allow for the understanding of their biological activities and therapeutic value. Organic synthesis is employed to aid in the determination of the relationship between structure and function of these natural products. The development of synthetic methodologies in the course of total syntheses is imperative for the expansion of this highly interdisciplinary field of science. In addition to the practical applications of total syntheses, the structural complexity of natural products represents a worthwhile challenge in itself. The pursuit of concise and efficient syntheses of complex molecules is both gratifying and enjoyable.

  1. Natural Products as Chemical Probes

    PubMed Central

    Carlson, Erin E.

    2010-01-01

    Natural products have evolved to encompass a broad spectrum of chemical and functional diversity. It is this diversity, along with their structural complexity, that enables nature’s small molecules to target a nearly limitless number of biological macromolecules and to often do so in a highly selective fashion. Because of these characteristics, natural products have seen great success as therapeutic agents. However, this vast pool of compounds holds much promise beyond the development of future drugs. These features also make them ideal tools for the study of biological systems. Recent examples of the use of natural products and their derivatives as chemical probes to explore biological phenomena and assemble biochemical pathways are presented here. PMID:20509672

  2. Natural Inhibitors of Snake Venom Metalloendopeptidases: History and Current Challenges.

    PubMed

    Bastos, Viviane A; Gomes-Neto, Francisco; Perales, Jonas; Neves-Ferreira, Ana Gisele C; Valente, Richard H

    2016-01-01

    The research on natural snake venom metalloendopeptidase inhibitors (SVMPIs) began in the 18th century with the pioneering work of Fontana on the resistance that vipers exhibited to their own venom. During the past 40 years, SVMPIs have been isolated mainly from the sera of resistant animals, and characterized to different extents. They are acidic oligomeric glycoproteins that remain biologically active over a wide range of pH and temperature values. Based on primary structure determination, mammalian plasmatic SVMPIs are classified as members of the immunoglobulin (Ig) supergene protein family, while the one isolated from muscle belongs to the ficolin/opsonin P35 family. On the other hand, SVMPIs from snake plasma have been placed in the cystatin superfamily. These natural antitoxins constitute the first line of defense against snake venoms, inhibiting the catalytic activities of snake venom metalloendopeptidases through the establishment of high-affinity, non-covalent interactions. This review presents a historical account of the field of natural resistance, summarizing its main discoveries and current challenges, which are mostly related to the limitations that preclude three-dimensional structural determinations of these inhibitors using "gold-standard" methods; perspectives on how to circumvent such limitations are presented. Potential applications of these SVMPIs in medicine are also highlighted. PMID:27571103

  3. Nature of N-nitrosodimethylamine demethylase and its inhibitors.

    PubMed

    Yoo, J S; Cheung, R J; Patten, C J; Wade, D; Yang, C S

    1987-07-01

    The present study was undertaken to examine the nature of the low Km (KmI) form of rat liver microsomal N-nitrosodimethylamine demethylase (NDMAd) and its inhibition by organic compounds which are commonly present in the assay mixture. Using radiometric and colorimetric assay methods with an NADPH-generating system consisting of 0.4 mM NADP, 10 mM glucose-6-phosphate, and glucose-6-phosphate dehydrogenase (0.4 units/ml), Km values of 40-50 microM were obtained. These Km values were lower than the values of 60-80 microM reported previously. This decrease was due to the elimination of inhibitors such as glycerol in the assay mixture. Glycerol was a competitive inhibitor, and this observation explained in part why purified P-450ac (acetone-inducible form of P-450), displayed a higher Km value in a reconstituted NDMAd system, which contained glycerol, than in microsomes. Semi-carbazide which had been used in many previous assays of NDMAd was also found to be a competitive inhibitor of this enzyme. Other inhibitors studied include the commonly used solvents dimethylsulfoxide, acetone, ethylene glycol, dimethylformamide, ethyl acetate, benzene, and hexane as well as thiol compounds dithiothreitol and mercaptoethanol. Although very low Km values (10-20 microM) for N-nitrosodimethylamine metabolism were reported in studies with perfused liver, liver slices, and isolated liver cells, we believe that the KmI form of liver NDMAd is responsible for the metabolism and activation of N-nitrosodimethylamine in the rat liver. PMID:3581075

  4. Natural Corrosion Inhibitors for Steel Reinforcement in Concrete — a Review

    NASA Astrophysics Data System (ADS)

    Raja, Pandian Bothi; Ghoreishiamiri, Seyedmojtaba; Ismail, Mohammad

    2015-04-01

    Reinforced concrete is one of the widely used construction materials for bridges, buildings, platforms and tunnels. Though reinforced concrete is capable of withstanding a large range of severe environments including marine, industrial and alpine conditions, there are still a large number of failures in concrete structures for many reasons. Either carbonation or chloride attack is the main culprit which is due to depassivation of reinforced steel and subsequently leads to rapid steel corrosion. Among many corrosion prevention measures, application of corrosion inhibitors play a vital role in metal protection. Numerous range of corrosion inhibitors were reported for concrete protection that were also used commercially in industries. This review summarizes the application of natural products as corrosion inhibitors for concrete protection and also scrutinizes various factors influencing its applicability.

  5. EIA's Natural Gas Production Data

    EIA Publications

    2009-01-01

    This special report examines the stages of natural gas processing from the wellhead to the pipeline network through which the raw product becomes ready for transportation and eventual consumption, and how this sequence is reflected in the data published by the Energy Information Administration (EIA).

  6. Natural Products from Mangrove Actinomycetes

    PubMed Central

    Xu, Dong-Bo; Ye, Wan-Wan; Han, Ying; Deng, Zi-Xin; Hong, Kui

    2014-01-01

    Mangroves are woody plants located in tropical and subtropical intertidal coastal regions. The mangrove ecosystem is becoming a hot spot for natural product discovery and bioactivity survey. Diverse mangrove actinomycetes as promising and productive sources are worth being explored and uncovered. At the time of writing, we report 73 novel compounds and 49 known compounds isolated from mangrove actinomycetes including alkaloids, benzene derivatives, cyclopentenone derivatives, dilactones, macrolides, 2-pyranones and sesquiterpenes. Attractive structures such as salinosporamides, xiamycins and novel indolocarbazoles are highlighted. Many exciting compounds have been proven as potential new antibiotics, antitumor and antiviral agents, anti-fibrotic agents and antioxidants. Furthermore, some of their biosynthetic pathways have also been revealed. This review is an attempt to consolidate and summarize the past and the latest studies on mangrove actinomycetes natural product discovery and to draw attention to their immense potential as novel and bioactive compounds for marine drugs discovery. PMID:24798926

  7. Discover natural compounds as potential phosphodiesterase-4B inhibitors via computational approaches.

    PubMed

    Li, Jing; Zhou, Nan; Liu, Wen; Li, Jianzong; Feng, Yu; Wang, Xiaoyun; Wu, Chuanfang; Bao, Jinku

    2016-05-01

    cAMP, intracellular cyclic adenosine monophosphate, is a ubiquitous second messenger that plays a key role in many physiological processes. PDE4B which can reduce the cAMP level by hydrolyzing cAMP to 5'-AMP has become a therapeutic target for the treatment of human diseases such as respiratory disorders, inflammation diseases, neurological and psychiatric disorders. However, the use of currently available PDE4B inhibitors is restricted due to serious side effects caused by targeting PDE4D. Hence, we are attempting to find out subfamily-selective PDE4B inhibitors from natural products, using computer-aided approaches such as virtual screening, docking, and molecular dynamics simulation. Finally, four potential PDE4B-selective inhibitors (ZINC67912770, ZINC67912780, ZINC72320169, and ZINC28882432) were found. Compared to the reference drug (roflumilast), they scored better during the virtual screening process. Binding free energy for them was -317.51, -239.44, -215.52, and -165.77 kJ/mol, better than -129.05 kJ/mol of roflumilast. The pharmacophore model of the four candidate inhibitors comprised six features, including one hydrogen bond donor, four hydrogen bond acceptors, and one aromatic ring feature. It is expected that our study will pave the way for the design of potent PDE4B-selective inhibitors of new drugs to treat a wide variety of diseases such as asthma, COPD, psoriasis, depression, etc. PMID:26159554

  8. Bacterial symbionts and natural products

    PubMed Central

    Crawford, Jason M.; Clardy, Jon

    2011-01-01

    The study of bacterial symbionts of eukaryotic hosts has become a powerful discovery engine for chemistry. This highlight looks at four case studies that exemplify the range of chemistry and biology involved in these symbioses: a bacterial symbiont of a fungus and a marine invertebrate that produce compounds with significant anticancer activity, and bacterial symbionts of insects and nematodes that produce compounds that regulate multilateral symbioses. In the last ten years, a series of shocking revelations – the molecular equivalents of a reality TV show’s uncovering the true parents of a well known individual or a deeply hidden family secret – altered the study of genetically encoded small molecules, natural products for short. These revelations all involved natural products produced by bacterial symbionts, and while details differed, two main plot lines emerged: parentage, in which the real producers of well known natural products with medical potential were not the organisms from which they were originally discovered, and hidden relationships, in which bacterially produced small molecules turned out to be the unsuspected regulators of complex interactions. For chemists, these studies led to new molecules, new biosynthetic pathways, and an understanding of the biological functions these molecules fulfill. PMID:21594283

  9. Antiplatelet properties of natural products.

    PubMed

    Vilahur, Gemma; Badimon, Lina

    2013-01-01

    Cardiovascular diseases (CVD) and its main underlying cause, atherothrombosis, are the major culprits of morbidity and mortality worldwide. Apart from the treatment of cardiovascular risk factors and the use of antithrombotic agents there is considerable interest in the role of natural food products and their bioactive components in the prevention and treatment of cardiovascular disorders. The consumption of healthy diets rich in functional foods, such as the Mediterranean diet, has shown to exert profound cardioprotective effects in the primary and secondary prevention of CVD. Moreover, accumulating data have attributed these beneficial effects, at least in part, to the modulation of key players in the pathogenesis of atherosclerosis, including amelioration in the lipid profile and vascular function and a decrease in oxidative stress and inflammation. Although with a much less clear picture, natural dietary compounds have also demonstrated to exert antiplatelet activities, further contributing to reduce the thrombotic risk. This article provides a brief overview of the atherothrombotic process to further provide an up-to-date review of the antiplatelet properties exerted by natural products and/or food-derived bioactive constituents - including ω-3 PUFA, olive oil, garlic and onions, tomatoes, mushrooms, polyphenol-rich beverages, and flavonol-rich cocoa - as well as to describe the mechanisms underlying these antiplatelet activities. PMID:23994642

  10. Natural products for cancer chemotherapy

    PubMed Central

    Demain, Arnold L.; Vaishnav, Preeti

    2011-01-01

    Summary For over 40 years, natural products have served us well in combating cancer. The main sources of these successful compounds are microbes and plants from the terrestrial and marine environments. The microbes serve as a major source of natural products with anti‐tumour activity. A number of these products were first discovered as antibiotics. Another major contribution comes from plant alkaloids, taxoids and podophyllotoxins. A vast array of biological metabolites can be obtained from the marine world, which can be used for effective cancer treatment. The search for novel drugs is still a priority goal for cancer therapy, due to the rapid development of resistance to chemotherapeutic drugs. In addition, the high toxicity usually associated with some cancer chemotherapy drugs and their undesirable side‐effects increase the demand for novel anti‐tumour drugs active against untreatable tumours, with fewer side‐effects and/or with greater therapeutic efficiency. This review points out those technologies needed to produce the anti‐tumour compounds of the future. PMID:21375717

  11. Antimalarial natural products: a review

    PubMed Central

    Mojab, Faraz

    2012-01-01

    Objective: Malaria is an infectious disease commonplace in tropical countries. For many years, major antimalarial drugs consisted of natural products, but since 1930s these drugs have been largely replaced with a series of synthetic drugs. This article tries to briefly indicate that some plants which previously were used to treat malaria, as a result of deficiencies of synthetic drugs, have revived into useful products once more. It also attempts to describe some tests which can be used to evaluate plant extracts for antimalarial activity. Materials and Methods: By referring to some recent literatures, data were collected about plants used for the treatment of malaria, evaluation of plant extracts for antimalarial activity, modes of action of natural antimalarial agents, and recent research on antimalarial plants in Iran and other countries. Results and Conclusion: There is an urgent need for the development of new treatments for malaria. Many countries have a vast precedence in the use of medicinal plants and the required knowledge spans many centuries. Although malaria is controlled in Iran, some researchers tend to study malaria and related subjects. In vitro biological tests for the detection of antimalarial activities in plant extracts are currently available. It is vital that the efficacy and safety of traditional medicines be validated and their active constituents be identified in order to establish reliable quality control measures. PMID:25050231

  12. Natural substances (acetogenins) from the family Annonaceae are powerful inhibitors of mitochondrial NADH dehydrogenase (Complex I).

    PubMed Central

    Degli Esposti, M; Ghelli, A; Ratta, M; Cortes, D; Estornell, E

    1994-01-01

    Natural products from the plants of the family Annonaceae, collectively called Annonaceous acetogenins, are very potent inhibitors of the NADH-ubiquinone reductase (Complex I) activity of mammalian mitochondria. The properties of five of such acetogenins are compared with those of rotenone and piericidin, classical potent inhibitors of Complex I. Rolliniastatin-1 and rolliniastatin-2 are more powerful than piericidin in terms of both their inhibitory constant and the protein-dependence of their titre in bovine submitochondrial particles. These acetogenins could be considered therefore the most potent inhibitors of mammalian Complex I. Squamocin and otivarin also have an inhibitory constant lower than that of piericidin, but display a larger protein-dependence of the titre. Squamocin and otivarin, contrary to the other acetogenins, behave qualitatively like rotenone. Rolliniastatin-2 shows unique properties as its interaction, although mutually exclusive to that of piericidin, appears to be mutually non-exclusive to that of rotenone. It is the first time that a potent inhibitor of Complex I is found not to overlap the active site of rotenone. PMID:8037664

  13. Natural compounds as corrosion inhibitors for highly cycled systems

    SciTech Connect

    Quraishi, M.A.; Farooqi, I.H.; Saini, P.A.

    1999-11-01

    Strict environmental legislations have led to the development of green inhibitors in recent years. In continuation of the authors` research work on development of green inhibitors, they have investigated the aqueous extracts of three plants namely: Azadirachta indica, Punica Granatum and Momordica charantia as corrosion inhibitors for mild steel in 3% NaCl using weight loss and electrochemical methods. All the investigated compounds exhibited excellent corrosion inhibition properties comparable to that of HEDP. Azadirachta showed better scale inhibition effect than HEDP.

  14. Enantiomeric Natural Products: Occurrence and Biogenesis**

    PubMed Central

    Finefield, Jennifer M.; Sherman, David H.; Kreitman, Martin; Williams, Robert M.

    2012-01-01

    In Nature, chiral natural products are usually produced in optically pure form; however, on occasion Nature is known to produce enantiomerically opposite metabolites. These enantiomeric natural products can arise in Nature from a single species, or from different genera and/or species. Extensive research has been carried out over the years in an attempt to understand the biogenesis of naturally occurring enantiomers, however, many fascinating puzzles and stereochemical anomalies still remain. PMID:22555867

  15. Natural products as sources for new pesticides

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Natural products as pesticides have been reviewed from several perspectives in the past; however, no review has examined the impact of natural product and natural product-based pesticides, as a function of new active ingredient registrations with the Environmental Protection Agency (EPA), on the U.S...

  16. Identification of Novel Human Dipeptidyl Peptidase-IV Inhibitors of Natural Origin (Part II): In Silico Prediction in Antidiabetic Extracts

    PubMed Central

    Guasch, Laura; Sala, Esther; Ojeda, María José; Valls, Cristina; Bladé, Cinta; Mulero, Miquel; Blay, Mayte; Ardévol, Anna; Garcia-Vallvé, Santiago; Pujadas, Gerard

    2012-01-01

    Background Natural extracts play an important role in traditional medicines for the treatment of diabetes mellitus and are also an essential resource for new drug discovery. Dipeptidyl peptidase IV (DPP-IV) inhibitors are potential candidates for the treatment of type 2 diabetes mellitus, and the effectiveness of certain antidiabetic extracts of natural origin could be, at least partially, explained by the inhibition of DPP-IV. Methodology/Principal Findings Using an initial set of 29,779 natural products that are annotated with their natural source and an experimentally validated virtual screening procedure previously developed in our lab (Guasch et al.; 2012) [1], we have predicted 12 potential DPP-IV inhibitors from 12 different plant extracts that are known to have antidiabetic activity. Seven of these molecules are identical or similar to molecules with described antidiabetic activity (although their role as DPP-IV inhibitors has not been suggested as an explanation for their bioactivity). Therefore, it is plausible that these 12 molecules could be responsible, at least in part, for the antidiabetic activity of these extracts through their inhibitory effect on DPP-IV. In addition, we also identified as potential DPP-IV inhibitors 6 molecules from 6 different plants with no described antidiabetic activity but that share the same genus as plants with known antidiabetic properties. Moreover, none of the 18 molecules that we predicted as DPP-IV inhibitors exhibits chemical similarity with a group of 2,342 known DPP-IV inhibitors. Conclusions/Significance Our study identified 18 potential DPP-IV inhibitors in 18 different plant extracts (12 of these plants have known antidiabetic properties, whereas, for the remaining 6, antidiabetic activity has been reported for other plant species from the same genus). Moreover, none of the 18 molecules exhibits chemical similarity with a large group of known DPP-IV inhibitors. PMID:23028712

  17. Misassigned natural products and their revised structures.

    PubMed

    Yoo, Hye-Dong; Nam, Sang-Jip; Chin, Young-Won; Kim, Min-Sun

    2016-02-01

    Natural products are a major pipeline for drug development and are responsible for more than 50 % of drugs on the market. NMR is a fundamental and powerful tool for the structure determination of natural products. It is essential to provide unambiguous chemical structure information on natural products in drug development research, including the structure-activity relationship, derivatization and pharmacokinetic/pharmacodynamic studies. Advancement of NMR instruments has made it possible to deal with nanomole-scale natural products for structure elucidation, but misinterpretation of NMR spectra still occurs. We review 21 natural products with revised chemical structures and the methods used for those revisions. PMID:26310208

  18. Natural products and anti-inflammatory activity.

    PubMed

    Yuan, Gaofeng; Wahlqvist, Mark L; He, Guoqing; Yang, Min; Li, Duo

    2006-01-01

    The aim of this review paper was to summarise some commonly available natural products and their anti-inflammatory activity. We have collected data from MEDLINE, Current Contents and scientific journals, which included 92 publications. There are numerous natural products detailed in this literature; however we have summarized a few of the most commonly available and potent ones. In this paper, the natural products with anti-inflammatory activity including curcumin, parthenolide, cucurbitacins, 1,8-cineole, pseudopterosins, lyprinol, bromelain, flavonoids, saponins, marine sponge natural products and Boswellia serrata gum resin were reviewed. Natural products play a significant role in human health in relation to the prevention and treatment of inflammatory conditions. Further studies are being conducted to investigate the mechanism of action, metabolism, safety and long term side effect of these natural products, as well as interactions between these natural products with food and drug components. PMID:16672197

  19. Search for Inhibitors of the Ubiquitin-Proteasome System from Natural Sources for Cancer Therapy.

    PubMed

    Tsukamoto, Sachiko

    2016-01-01

    Since the approval of the proteasome inhibitor, Velcade(®), by the Food and Drug Administration (FDA) for the treatment of relapsed multiple myeloma, inhibitors of the ubiquitin-proteasome system have been attracting increasing attention as promising drug leads for cancer therapy. While the development of drugs for diseases related to this proteolytic system has mainly been achieved by searching libraries of synthetic small molecules or chemical modifications to drug leads, limited searches have been conducted on natural sources. We have been searching natural sources for inhibitors that target this proteolytic system through in-house screening. Our recent studies on the search for natural inhibitors of the ubiquitin-proteasome system, particularly, inhibitors against the proteasome, E1 enzyme (Uba1), E2 enzyme (Ubc13-Uev1A heterodimer), and E3 enzyme (Hdm2), and also those against deubiquitinating enzyme (USP7), are reviewed here. PMID:26833439

  20. Grassypeptolides As Natural Inhibitors of Dipeptidyl Peptidase 8 and T-Cell Activation

    PubMed Central

    Kwan, Jason C.; Liu, Yanxia; Ratnayake, Ranjala; Hatano, Ryo; Kuribara, Akiko; Morimoto, Chiko; Ohnuma, Kei; Paul, Valerie J.; Ye, Tao

    2014-01-01

    Natural products made by marine cyanobacteria are often highly modified peptides and depsipeptides that have the potential to act as inhibitors for proteases. In the interest of finding novel protease inhibition activity and selectivity grassypeptolide A (1) was screened against a panel of proteases and found to selectively inhibit DPP8 over DPP4. Grassypeptolides were also found to inhibit IL-2 production and proliferation in activated T-cells, consistent with a putative role of DPP8 in the immune system. These effects were also observed in Jurkat cells, and DPP activity in Jurkat cell cytosol was shown to be inhibited by grassypeptolides. In silico docking suggests two possible binding modes of grassypeptolides – both at the active site of DPP8 and at one of the entrances to the internal cavity. Collectively these results suggest that grassypeptolides may be useful tool compounds in the study of DPP8 function. PMID:24591193

  1. Search for β-Secretase Inhibitors from Natural Spices.

    PubMed

    Matsumura, Shinichi; Murata, Kazuya; Yoshioka, Yuri; Matsuda, Hideaki

    2016-04-01

    The growing number of Alzheimer's disease (AD) patients prompted us to seek effective natural resources for the prevention of AD. We focused on the inhibition of β-secretase, which is known to catalyze the production of senile plaque. Sixteen spices used in Asian countries were selected for the screening. Among the extracts tested, hexane extracts obtained from turmeric, cardamom, long pepper, cinnamon, Sichuan pepper, betel, white turmeric and aromatic ginger showed potent inhibitory activities. Their active principles were identified as sesquiterpenoids, monoterpenoids, fatty acid derivatives and phenylpropanoids using GC-MS analyses. The chemical structures and IC50 values of the compounds are disclosed. The results suggest that long-term consumption'of aromatic compounds from spices could be effective in the prevention of AD. PMID:27396206

  2. Discovery and Rational Design of Natural-Product-Derived 2-Phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine Analogs as Novel and Potent Dipeptidyl Peptidase 4 (DPP-4) Inhibitors for the Treatment of Type 2 Diabetes.

    PubMed

    Li, Shiliang; Xu, Hongling; Cui, Shichao; Wu, Fangshu; Zhang, Youli; Su, Mingbo; Gong, Yinghui; Qiu, Shaobing; Jiao, Qian; Qin, Chun; Shan, Jiwei; Zhang, Ming; Wang, Jiawei; Yin, Qiao; Xu, Minghao; Liu, Xiaofeng; Wang, Rui; Zhu, Lili; Li, Jia; Xu, Yufang; Jiang, Hualiang; Zhao, Zhenjiang; Li, Jingya; Li, Honglin

    2016-07-28

    Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based scaffold hopping as well as electrostatic complementary methods. Those ingenious drug design strategies bring us approximate 7400-fold boost in potency. Compounds 22a and 24a are the most potent ones (IC50 ≈ 2.0 nM) with good pharmacokinetic profiles. Compound 22a demonstrated stable pharmacological effect. A 3 mg/kg oral dose provided >80% inhibition of DPP-4 activity within 24 h, which is comparable to the performance of the long-acting control omarigliptin. Moreover, the efficacy of 22a in improving the glucose tolerance is also comparable with omarigliptin. In this study, not only promising DPP-4 inhibitors as long acting antidiabetic that are clinically on demand are identified, but the target fish docking and medicinal chemistry strategies were successfully implemented. PMID:27396490

  3. Recent Advances in Natural Product Discovery

    PubMed Central

    Luo, Yunzi; Cobb, Ryan E.; Zhao, Huimin

    2014-01-01

    Natural products have been and continue to be the source and inspiration for a substantial fraction of human therapeutics. Although the pharmaceutical industry has largely turned its back on natural product discovery efforts, such efforts continue to flourish in academia with promising results. Natural products have traditionally been identified from a top-down perspective, but more recently genomics- and bioinformatics-guided bottom-up approaches have provided powerful alternative strategies. Here we review recent advances in natural product discovery from both angles, including diverse sampling and innovative culturing and screening approaches, as well as genomics-driven discovery and genetic manipulation techniques for both native and heterologous expression. PMID:25260043

  4. From a natural product lead to the identification of potent and selective benzofuran-3-yl-(indol-3-yl)maleimides as glycogen synthase kinase 3beta inhibitors that suppress proliferation and survival of pancreatic cancer cells.

    PubMed

    Gaisina, Irina N; Gallier, Franck; Ougolkov, Andrei V; Kim, Ki H; Kurome, Toru; Guo, Songpo; Holzle, Denise; Luchini, Doris N; Blond, Sylvie Y; Billadeau, Daniel D; Kozikowski, Alan P

    2009-04-01

    Recent studies have demonstrated that glycogen synthase kinase 3beta (GSK-3beta) is overexpressed in human colon and pancreatic carcinomas, contributing to cancer cell proliferation and survival. Here, we report the design, synthesis, and biological evaluation of benzofuran-3-yl-(indol-3-yl)maleimides, potent GSK-3beta inhibitors. Some of these compounds show picomolar inhibitory activity toward GSK-3beta and an enhanced selectivity against cyclin-dependent kinase 2 (CDK-2). Selected GSK-3beta inhibitors were tested in the pancreatic cancer cell lines MiaPaCa-2, BXPC-3, and HupT3. We determined that some of these compounds, namely compounds 5, 6, 11, 20, and 26, demonstrate antiproliferative activity against some or all of the pancreatic cancer cells at low micromolar to nanomolar concentrations. We found that the treatment of pancreatic cancer cells with GSK-3beta inhibitors 5 and 26 resulted in suppression of GSK-3beta activity and a distinct decrease of the X-linked inhibitor of apoptosis (XIAP) expression, leading to significant apoptosis. The present data suggest a possible role for GSK-3beta inhibitors in cancer therapy, in addition to their more prominent applications in CNS disorders. PMID:19338355

  5. Discovery of Novel Antiangiogenic Marine Natural Product Scaffolds.

    PubMed

    Ebrahim, Hassan Y; El Sayed, Khalid A

    2016-03-01

    Marine natural products (MNPs) are recognized for their structural complexity, diversity, and novelty. The vast majority of MNPs are pharmacologically relevant through their ability to modulate macromolecular targets underlying human diseases. Angiogenesis is a fundamental process in cancer progression and metastasis. Targeting angiogenesis through selective modulation of linked protein kinases is a valid strategy to discover novel effective tumor growth and metastasis inhibitors. An in-house marine natural products mini-library, which comprises diverse MNP entities, was submitted to the Lilly's Open Innovation Drug Discovery platform. Accepted structures were subjected to in vitro screening to discover mechanistically novel angiogenesis inhibitors. Active hits were subjected to additional angiogenesis-targeted kinase profiling. Some natural and semisynthetic MNPs, including multiple members of the macrolide latrunculins, the macrocyclic oxaquinolizidine alkaloid araguspongine C, and the sesquiterpene quinone puupehenone, showed promising results in primary and secondary angiogenesis screening modules. These hits inhibited vascular endothelial growth factor (VEGF)-mediated endothelial tube-like formation, with minimal cytotoxicity at relevant doses. Secondary kinase profiling identified six target protein kinases, all involved in angiogenesis signaling pathways. Molecular modeling and docking experiments aided the understanding of molecular binding interactions, identification of pharmacophoric epitopes, and deriving structure-activity relationships of active hits. Marine natural products are prolific resources for the discovery of chemically and mechanistically unique selective antiangiogenic scaffolds. PMID:26978377

  6. Discovery of Novel Antiangiogenic Marine Natural Product Scaffolds

    PubMed Central

    Ebrahim, Hassan Y.; El Sayed, Khalid A.

    2016-01-01

    Marine natural products (MNPs) are recognized for their structural complexity, diversity, and novelty. The vast majority of MNPs are pharmacologically relevant through their ability to modulate macromolecular targets underlying human diseases. Angiogenesis is a fundamental process in cancer progression and metastasis. Targeting angiogenesis through selective modulation of linked protein kinases is a valid strategy to discover novel effective tumor growth and metastasis inhibitors. An in-house marine natural products mini-library, which comprises diverse MNP entities, was submitted to the Lilly’s Open Innovation Drug Discovery platform. Accepted structures were subjected to in vitro screening to discover mechanistically novel angiogenesis inhibitors. Active hits were subjected to additional angiogenesis-targeted kinase profiling. Some natural and semisynthetic MNPs, including multiple members of the macrolide latrunculins, the macrocyclic oxaquinolizidine alkaloid araguspongine C, and the sesquiterpene quinone puupehenone, showed promising results in primary and secondary angiogenesis screening modules. These hits inhibited vascular endothelial growth factor (VEGF)-mediated endothelial tube-like formation, with minimal cytotoxicity at relevant doses. Secondary kinase profiling identified six target protein kinases, all involved in angiogenesis signaling pathways. Molecular modeling and docking experiments aided the understanding of molecular binding interactions, identification of pharmacophoric epitopes, and deriving structure-activity relationships of active hits. Marine natural products are prolific resources for the discovery of chemically and mechanistically unique selective antiangiogenic scaffolds. PMID:26978377

  7. Counting on natural products for drug design

    NASA Astrophysics Data System (ADS)

    Rodrigues, Tiago; Reker, Daniel; Schneider, Petra; Schneider, Gisbert

    2016-06-01

    Natural products and their molecular frameworks have a long tradition as valuable starting points for medicinal chemistry and drug discovery. Recently, there has been a revitalization of interest in the inclusion of these chemotypes in compound collections for screening and achieving selective target modulation. Here we discuss natural-product-inspired drug discovery with a focus on recent advances in the design of synthetically tractable small molecules that mimic nature's chemistry. We highlight the potential of innovative computational tools in processing structurally complex natural products to predict their macromolecular targets and attempt to forecast the role that natural-product-derived fragments and fragment-like natural products will play in next-generation drug discovery.

  8. Super Natural II--a database of natural products.

    PubMed

    Banerjee, Priyanka; Erehman, Jevgeni; Gohlke, Björn-Oliver; Wilhelm, Thomas; Preissner, Robert; Dunkel, Mathias

    2015-01-01

    Natural products play a significant role in drug discovery and development. Many topological pharmacophore patterns are common between natural products and commercial drugs. A better understanding of the specific physicochemical and structural features of natural products is important for corresponding drug development. Several encyclopedias of natural compounds have been composed, but the information remains scattered or not freely available. The first version of the Supernatural database containing ∼ 50,000 compounds was published in 2006 to face these challenges. Here we present a new, updated and expanded version of natural product database, Super Natural II (http://bioinformatics.charite.de/supernatural), comprising ∼ 326,000 molecules. It provides all corresponding 2D structures, the most important structural and physicochemical properties, the predicted toxicity class for ∼ 170,000 compounds and the vendor information for the vast majority of compounds. The new version allows a template-based search for similar compounds as well as a search for compound names, vendors, specific physical properties or any substructures. Super Natural II also provides information about the pathways associated with synthesis and degradation of the natural products, as well as their mechanism of action with respect to structurally similar drugs and their target proteins. PMID:25300487

  9. High throughput Screening to Identify Natural Human Monoamine Oxidase B Inhibitors

    PubMed Central

    Mazzio, E; Deiab, S; Park, K; Soliman, KFA

    2012-01-01

    Age-related increase in monoamine oxidase B (MAO-B) may contribute to CNS neurodegenerative diseases. Moreover, MAO-B inhibitors are used in the treatment of idiopathic Parkinson disease as preliminary monotherapy or adjunct therapy with L-dopa. To date, meager natural sources of MAO-B inhibitors have been identified, and the relative strength, potency and rank of many plants relative to standard drugs such as Selegiline (L-deprenyl, Eldepryl) are not known. In this work, we developed and utilized a high throughput enzyme microarray format to screen and evaluate 905 natural product extracts (0.025–.7 mg/ml) to inhibit human MAO-B derived from BTI-TN-5B1-4 cells infected with recombinant baculovirus. The protein sequence of purified enzyme was confirmed using 1D gel electrophoresis-matrix assisted laser desorption ionization-time-of-flight-tandem mass spectroscopy, and enzyme activity was confirmed by [1] substrate conversion (3-mM benzylamine) to H202 and [2] benzaldehyde. Of the 905 natural extracts tested, the lowest IC50s [<0.07 mg/ml] were obtained with extracts of Amur Corktree (Phellodendron amurense), Bakuchi Seed(Cyamopsis psoralioides), Licorice Root (Glycyrrhiza glabra/uralensis), Babchi (Psoralea corylifolia seed). The data also show, albeit to a lesser extent, inhibitory properties of herbs originating from the mint family (Lamiaceae) and Turmeric, Comfrey, Bringraj, Skullcap, Kava-kava, Wild Indigo, Gentian and Green Tea. In conclusion, the data reflect relative potency information by rank of commonly used herbs and plants that contain human MAO-B inhibitory properties in their natural form. PMID:22887993

  10. Functional chromatographic technique for natural product isolation†

    PubMed Central

    Lau, Eric C.; Mason, Damian J.; Eichhorst, Nicole; Engelder, Pearce; Mesa, Celestina; Kithsiri Wijeratne, E. M.; Gunaherath, G. M. Kamal B.; Leslie Gunatilaka, A. A.

    2015-01-01

    Natural product discovery arises through a unique interplay between chromatographic purification and biological assays. Currently, most techniques used for natural product purification deliver leads without a defined biological action. We now describe a technique, referred to herein as functional chromatography, that deploys biological affinity as the matrix for compound isolation. PMID:25588099

  11. Bioactive natural products from novel microbial sources.

    PubMed

    Challinor, Victoria L; Bode, Helge B

    2015-09-01

    Despite the importance of microbial natural products for human health, only a few bacterial genera have been mined for the new natural products needed to overcome the urgent threat of antibiotic resistance. This is surprising, given that genome sequencing projects have revealed that the capability to produce natural products is not a rare feature among bacteria. Even the bacteria occurring in the human microbiome produce potent antibiotics, and thus potentially are an untapped resource for novel compounds, potentially with new activities. This review highlights examples of bacteria that should be considered new sources of natural products, including anaerobes, pathogens, and symbionts of humans, insects, and nematodes. Exploitation of these producer strains, combined with advances in modern natural product research methodology, has the potential to open the way for a new golden age of microbial therapeutics. PMID:26509922

  12. Synthesis and comparison of the biological activity of monocyclic phosphonate, difluorophosphonate and phosphate analogs of the natural AChE inhibitor cyclophostin.

    PubMed

    Martin, Benjamin P; Vasilieva, Elena; Dupureur, Cynthia M; Spilling, Christopher D

    2015-12-15

    New monocyclic phosphate, phosphonate and difluorophosphonate analogs of the natural AChE inhibitor cyclophostin were synthesized and their activity toward human AChE examined. Surprisingly, the phosphate, phosphonate, and difluorophosphonate analogs all showed diminished activity when compared with the natural product. PMID:26585276

  13. Naturally occurring tyrosinase inhibitors: mechanism and applications in skin health, cosmetics and agriculture industries.

    PubMed

    Parvez, Shoukat; Kang, Moonkyu; Chung, Hwan-Suck; Bae, Hyunsu

    2007-09-01

    Tyrosinase is a copper-containing enzyme, which is widely distributed in microorganisms, animals and plants and is a key enzyme in melanin biosynthesis, involved in determining the color of mammalian skin and hair. In addition, unfavorable enzymatic browning of plant-derived foods by tyrosinase causes a decrease in nutritional quality and economic loss of food products. The inadequacy of current conventional methods to prevent tyrosinase action encourages researchers to seek new potent tyrosinase inhibitors for food and cosmetics. This article presents a study on the importance of tyrosinase, biochemical characteristics, type of inhibitions, activators from various natural sources with its clinical and industrial importance in recent prospects is discussed in this paper. PMID:17605157

  14. Natural Products for Pest Management

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Most organisms synthesize secondary products with biological activity that is useful in their defense. Defense can be against vertebrates, arthropods, mollusks, plants (both algal and higher plants), and microbes. Many of these compounds have been used from ancient times to the present as pharmace...

  15. Natural products: Hunting microbial metabolites

    NASA Astrophysics Data System (ADS)

    Schmidt, Eric W.

    2015-05-01

    Symbiotic bacteria synthesize many specialized small molecules; however, establishing the role these chemicals play in human health and disease has been difficult. Now, the chemical structure and mechanism of the Escherichia coli product colibactin provides insight into the link between this secondary metabolite and colorectal cancer.

  16. Targeting Nuclear Receptors with Marine Natural Products

    PubMed Central

    Yang, Chunyan; Li, Qianrong; Li, Yong

    2014-01-01

    Nuclear receptors (NRs) are important pharmaceutical targets because they are key regulators of many metabolic and inflammatory diseases, including diabetes, dyslipidemia, cirrhosis, and fibrosis. As ligands play a pivotal role in modulating nuclear receptor activity, the discovery of novel ligands for nuclear receptors represents an interesting and promising therapeutic approach. The search for novel NR agonists and antagonists with enhanced selectivities prompted the exploration of the extraordinary chemical diversity associated with natural products. Recent studies involving nuclear receptors have disclosed a number of natural products as nuclear receptor ligands, serving to re-emphasize the translational possibilities of natural products in drug discovery. In this review, the natural ligands of nuclear receptors will be described with an emphasis on their mechanisms of action and their therapeutic potentials, as well as on strategies to determine potential marine natural products as nuclear receptor modulators. PMID:24473166

  17. The possible presence of natural β-D-glucosidase inhibitors in jujube leaf extract.

    PubMed

    Jo, Youngje; Lim, Seokwon; Chang, Pahn-Shick; Choi, Young Jin

    2016-03-01

    Isoquercitrin is a phenolic compound well-known for having greater health benefits than quercitin, its aglycone derivative, and other related glycosides. However, isoquercitrin is rarely found in nature. Here, we optimized the conditions for the enzymatic transformation of isoquercitrin from rutin that was extracted from jujube leaf using the hesperidinase, enzyme complex containing β-D-glucosidase and α-L-rhamnosidase. The maximum productivity (2.57±0.16mg/mL) was experimentally found under the following conditions: 47.3°C, 52.16h, and pH 5.31, which agreed well with the predicted value (2.65mg/mL). However, the achievement of this maximum yield was due to the absence of β-D-glucosidase activity. Further investigations using a β-D-glucosidase assay and reaction measurements under various conditions revealed that the β-D-glucosidase activity was not blocked by denaturation or known inhibitory factors. Currently, there are no recognized β-D-glucosidase inhibitors present in the jujube leaf; however, our observations strongly suggest that an unidentified β-D-glucosidase inhibitor exists in jujube leaf extract. PMID:26471546

  18. Marine Natural Products as Models to Circumvent Multidrug Resistance.

    PubMed

    Long, Solida; Sousa, Emília; Kijjoa, Anake; Pinto, Madalena M M

    2016-01-01

    Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds. PMID:27399665

  19. New Synthetic Methods for Hypericum Natural Products

    SciTech Connect

    Insik Jeon

    2006-12-12

    Organic chemistry has served as a solid foundation for interdisciplinary research areas, such as molecular biology and medicinal chemistry. An understanding of the biological activities and structural elucidations of natural products can lead to the development of clinically valuable therapeutic options. The advancements of modern synthetic methodologies allow for more elaborate and concise natural product syntheses. The theme of this study centers on the synthesis of natural products with particularly challenging structures and interesting biological activities. The synthetic expertise developed here will be applicable to analog syntheses and to other research problems.

  20. Biodegradation potential of a modified natural product

    SciTech Connect

    Sajjad, W.

    1996-12-31

    Biodegradation potential of a modified natural product for treating petroleum contaminated soils was investigated along with some commercially available microbial cultures in three different scales from a laboratory to pilot to case studies. The modified natural product is lignocellulosic in nature and proprietary product of a company in Iowa. The production process of this product involves mechanical size reduction, blending/coating, and aerobic digestion of hay, corn cob residue, straw or crop residue in presence of poultry manure. The degradation kinetics of the petroleum products in the contaminated soils were measured both directly and indirectly. Residual petroleum products in different soils (treated and untreated) at various time periods were quantified by gas chromatographic (GC) analysis on extracted samples. The indirect assessment of the kinetics of biological activity involved the measurement of CO{sub 2} evolved from flasks (250 ml capacity) containing contaminated soil (about 50 ml) with various treatments. The results indicated that the biodegradation kinetics of petroleum products in the contaminated soils were significantly improved by treatment with this modified natural product. In most cases tested, this product performed significantly better than the available commercial bacterial cultures for biological removal of petroleum products from contaminated soils. This study also demonstrated the significance of temperature and moisture content in biodegradation kinetics.

  1. Natural antioxidants in meat and poultry products.

    PubMed

    Karre, Liz; Lopez, Keyla; Getty, Kelly J K

    2013-06-01

    In response to recent claims that synthetic antioxidants have the potential to cause toxicological effects and consumers' increased interest in purchasing natural products, the meat and poultry industry has been seeking sources of natural antioxidants. Due to their high phenolic compound content, fruits and other plant materials provide a good alternative to conventional antioxidants. Plum, grape seed extract, cranberry, pomegranate, bearberry, pine bark extract, rosemary, oregano, and other spices functions as antioxidants in meat and poultry products. Pomegranate, pine bark extract, cinnamon, and cloves have exhibited stronger antioxidant properties than some synthetic options. Plum products, grape seed extract, pine bark extract, rosemary, and some spices all have been shown to affect the color of finished meat or poultry products; however, in some products such as pork sausage or uncured meats, an increase in red color may be desired. When selecting a natural antioxidant, sensory and quality impact on the product should be considered to achieve desired traits. PMID:23501254

  2. Design of O-acetylserine sulfhydrylase inhibitors by mimicking Nature

    PubMed Central

    Salsi, Enea; Bayden, Alexander S.; Spyrakis, Francesca; Amadasi, Alessio; Campanini, Barbara; Bettati, Stefano; Dodatko, Tetyana; Cozzini, Pietro; Kellogg, Glen E.; Cook, Paul F.; Roderick, Steven L.; Mozzarelli, Andrea

    2009-01-01

    The inhibition of cysteine biosynthesis in prokaryotes and protozoa has been proposed to be relevant for the development of antibiotics. Haemophilus influenzae O-acetylserine sulfhydrylase (OASS), catalyzing L-cysteine formation, is inhibited by the insertion of the C-terminal pentapeptide (MNLNI) of serine acetyltransferase into the active site. 400 MNXXI pentapeptides were generated, docked into OASS active site using GOLD and scored with HINT. The terminal P5 Ile accounts for about 50% of the binding energy. Glu or Asp at position P4, and to a lesser extent, at position P3, also significantly contribute to the binding interaction. The predicted affinity of 14 selected pentapeptides correlated well with the experimentally determined dissociation constants. The X-ray structure of three high affinity pentapeptides-OASS complexes were compared with the docked poses. These results, combined with a GRID analysis of the active site, allowed us to define a pharmacophoric scaffold for the design of peptidomimetic inhibitors. PMID:19928859

  3. Tubulin-Interactive Natural Products as Anticancer Agents1

    PubMed Central

    Kingston, David G. I.

    2009-01-01

    This review provides an overview of the discovery, structures, and biological activities of anticancer natural products which act by inhibiting or promoting the assembly of tubulin to microtubules. The emphasis is on providing recent information on those compounds in clinical use or in advanced clinical trials. The vinca alkaloids, the combretastatins, NPI-2358, the halichondrin B analog eribulin, dolastatin 10, noscapine, hemiasterlin, and rhizoxin are discussed as tubulin polymerization inhibitors, while the taxanes and the epothilones are the major classes of tubulin polymerization promoters presented, with brief treatments of discodermolide, eleutherobin, and laulimalide. The challenges and future directions of tubulin-interactive natural products-based drug discovery programs are also discussed briefly. PMID:19125622

  4. Cancer wars: natural products strike back

    PubMed Central

    Basmadjian, Christine; Zhao, Qian; Bentouhami, Embarek; Djehal, Amel; Nebigil, Canan G.; Johnson, Roger A.; Serova, Maria; de Gramont, Armand; Faivre, Sandrine; Raymond, Eric; Désaubry, Laurent G.

    2014-01-01

    Natural products have historically been a mainstay source of anticancer drugs, but in the 90's they fell out of favor in pharmaceutical companies with the emergence of targeted therapies, which rely on antibodies or small synthetic molecules identified by high throughput screening. Although targeted therapies greatly improved the treatment of a few cancers, the benefit has remained disappointing for many solid tumors, which revitalized the interest in natural products. With the approval of rapamycin in 2007, 12 novel natural product derivatives have been brought to market. The present review describes the discovery and development of these new anticancer drugs and highlights the peculiarities of natural product and new trends in this exciting field of drug discovery. PMID:24822174

  5. Cancer wars: Natural products strike back

    NASA Astrophysics Data System (ADS)

    Basmadjian, Christine; Zhao, Qian; Djehal, Amel; Bentouhami, Embarek; Nebigil, Canan; Johnson, Roger; Serova, Maria; De Gramont, Armand; Faivre, Sandrine; Raymond, Eric; Désaubry, Laurent

    2014-05-01

    Natural products have historically been a mainstay source of anticancer drugs, but in the 90’s they fell out of favor in pharmaceutical companies with the emergence of targeted therapies, which rely on antibodies or small synthetic molecules identified by high throughput screening. Although targeted therapies greatly improved the treatment of a few cancers, the benefit has remained disappointing for many sol¬¬id tumors, which revitalized the interest in natural products. With the approval of rapamycin in 2007, twelve novel natural product derivatives have been brought to market. The present review describes the discovery and development of these new anticancer drugs and highlights the peculiarities of natural product and new trends in this exciting field of drug discovery.

  6. Engineering microbial hosts for production of bacterial natural products.

    PubMed

    Zhang, Mingzi M; Wang, Yajie; Ang, Ee Lui; Zhao, Huimin

    2016-08-27

    Covering up to end 2015Microbial fermentation provides an attractive alternative to chemical synthesis for the production of structurally complex natural products. In most cases, however, production titers are low and need to be improved for compound characterization and/or commercial production. Owing to advances in functional genomics and genetic engineering technologies, microbial hosts can be engineered to overproduce a desired natural product, greatly accelerating the traditionally time-consuming strain improvement process. This review covers recent developments and challenges in the engineering of native and heterologous microbial hosts for the production of bacterial natural products, focusing on the genetic tools and strategies for strain improvement. Special emphasis is placed on bioactive secondary metabolites from actinomycetes. The considerations for the choice of host systems will also be discussed in this review. PMID:27072804

  7. Amplification of Guthrie card DNA: effect of guanidine thiocyanate on binding of natural whole blood PCR inhibitors.

    PubMed

    Makowski, G S; Davis, E L; Hopfer, S M

    1997-01-01

    Amplification of DNA from whole blood collected on Guthrie card filter paper presents considerable technical obstacles due to the presence of natural PCR inhibitors (protein, heavy metals, heme, and heme degradation products) and low copy number of genomic material. For this purpose we evaluated guanidine thiocyanate-impregnated filter paper (GT-903), a DNA collection device designed specifically to bind PCR inhibitors and preserve DNA in an aqueous extractable form. Compared to standard 903, which retains DNA and elutes inhibitors during aqueous extraction, we found GT-903 retained 90% of protein, hemoglobin, and iron. SDS-PAGE analysis indicated that the majority of the protein released from standard 903 corresponded to albumin (70-) and globin (15-kDa); negligible levels of these proteins were eluted from GT-903. To evaluate PCR efficiency, we amplified the 491 bp region encoding the cystic fibrosis delta F508 mutation. Using comparable template, we found GT-903 amplification more efficient than standard 903 following qualitative (TBE-PAGE) and quantitative (anti-dsDNA EIA) determination. We conclude that GT-903 provides a good DNA collection device and addresses the complications associated with natural PCR inhibitors. PMID:9058242

  8. An introduction to natural products isolation.

    PubMed

    Sarker, Satyajit D; Nahar, Lutfun

    2012-01-01

    Natural products, well known for unique chemical diversity and bioactivity, have continued to offer templates for the development of novel scaffolds of drugs. With the remarkable developments in the areas of separation science, spectroscopic techniques, microplate-based ultrasensitive in vitro assays and high-throughput screening (HTS) technologies, natural products research has gained momentum in recent years. The pre-isolation analyses of crude extracts or fraction from different natural matrices, isolation, online detection and dereplication of natural products, studies on chemotaxonomy and biosynthesis, chemical finger-printing, quality control of herbal products, and metabolomic studies have now become much easier than ever before because of the availability of a number of modern sophisticated hyphenated techniques, e.g., GC-MS, LC-PDA, LC-MS, LC-FTIR, LC-NMR, LC-NMR-MS, and CE-MS. This introductory chapter presents a general overview of the processes involved in natural products research, starting from extraction and isolation to elucidation of the structures of purified natural products and their bioactivity. PMID:22367891

  9. How EIA Estimates Natural Gas Production

    EIA Publications

    2004-01-01

    The Energy Information Administration (EIA) publishes estimates monthly and annually of the production of natural gas in the United States. The estimates are based on data EIA collects from gas producing states and data collected by the U. S. Minerals Management Service (MMS) in the Department of Interior. The states and MMS collect this information from producers of natural gas for various reasons, most often for revenue purposes. Because the information is not sufficiently complete or timely for inclusion in EIA's Natural Gas Monthly (NGM), EIA has developed estimation methodologies to generate monthly production estimates that are described in this document.

  10. Inhibitors

    MedlinePlus

    ... Community Counts Blood Safety Inhibitors Articles & Key Findings Free Materials Videos Starting the Conversation Playing it Safe A Look at Hemophilia Joint Range of Motion My Story Links to Other Websites ...

  11. Naturally occurring products in cancer therapy

    PubMed Central

    Rajesh, E.; Sankari, Leena S.; Malathi, L.; Krupaa, Jayasri R.

    2015-01-01

    Natural products have been used for the treatment of various diseases and are becoming an important research area for drug discovery. These products, especially phytochemicals have been extensively studies and have exhibited anti-carcinogenic activities by interfering with the initiation, development and progression of cancer through the modulation of various mechanisms including cellular proliferation, differentiation, apoptosis, angiogenesis, and metastasis. This concept is gaining attention because it is a cost-effective alternative to cancer treatment. In this article, we have discussed some of the naturally occurring products used in cancer treatment. PMID:26015704

  12. Natural product discovery: past, present, and future.

    PubMed

    Katz, Leonard; Baltz, Richard H

    2016-03-01

    Microorganisms have provided abundant sources of natural products which have been developed as commercial products for human medicine, animal health, and plant crop protection. In the early years of natural product discovery from microorganisms (The Golden Age), new antibiotics were found with relative ease from low-throughput fermentation and whole cell screening methods. Later, molecular genetic and medicinal chemistry approaches were applied to modify and improve the activities of important chemical scaffolds, and more sophisticated screening methods were directed at target disease states. In the 1990s, the pharmaceutical industry moved to high-throughput screening of synthetic chemical libraries against many potential therapeutic targets, including new targets identified from the human genome sequencing project, largely to the exclusion of natural products, and discovery rates dropped dramatically. Nonetheless, natural products continued to provide key scaffolds for drug development. In the current millennium, it was discovered from genome sequencing that microbes with large genomes have the capacity to produce about ten times as many secondary metabolites as was previously recognized. Indeed, the most gifted actinomycetes have the capacity to produce around 30-50 secondary metabolites. With the precipitous drop in cost for genome sequencing, it is now feasible to sequence thousands of actinomycete genomes to identify the "biosynthetic dark matter" as sources for the discovery of new and novel secondary metabolites. Advances in bioinformatics, mass spectrometry, proteomics, transcriptomics, metabolomics and gene expression are driving the new field of microbial genome mining for applications in natural product discovery and development. PMID:26739136

  13. Cyclic Lipodepsipeptides Produced by Pseudomonas spp. Naturally Present in Raw Milk Induce Inhibitory Effects on Microbiological Inhibitor Assays for Antibiotic Residue Screening

    PubMed Central

    Reybroeck, Wim; De Vleeschouwer, Matthias; Marchand, Sophie; Sinnaeve, Davy; Heylen, Kim; De Block, Jan; Madder, Annemieke; Martins, José C.; Heyndrickx, Marc

    2014-01-01

    Two Pseudomonas strains, identified as closely related to Pseudomonas tolaasii, were isolated from milk of a farm with frequent false-positive Delvotest results for screening putative antibiotic residues in raw milk executed as part of the regulatory quality programme. Growth at 5 to 7°C of these isolates in milk resulted in high lipolysis and the production of bacterial inhibitors. The two main bacterial inhibitors have a molecular weight of 1168.7 and 1140.7 Da respectively, are heat-tolerant and inhibit Geobacillus stearothermophilus var. calidolactis, the test strain of most of the commercially available microbiological inhibitor tests for screening of antibiotic residues in milk. Furthermore, these bacterial inhibitors show antimicrobial activity against Staphylococcus aureus, Bacillus cereus and B. subtilis and also interfere negatively with yoghurt production. Following their isolation and purification with RP-HPLC, the inhibitors were identified by NMR analysis as cyclic lipodepsipeptides of the viscosin group. Our findings bring to light a new challenge for quality control in the dairy industry. By prolonging the refrigerated storage of raw milk, the keeping quality of milk is influenced by growth and metabolic activities of psychrotrophic bacteria such as pseudomonads. Besides an increased risk of possible spoilage of long shelf-life milk, the production at low temperature of natural bacterial inhibitors may also result in false-positive results for antibiotic residue screening tests based on microbial inhibitor assays thus leading to undue production loss. PMID:24853676

  14. Cyclic lipodepsipeptides produced by Pseudomonas spp. naturally present in raw milk induce inhibitory effects on microbiological inhibitor assays for antibiotic residue screening.

    PubMed

    Reybroeck, Wim; De Vleeschouwer, Matthias; Marchand, Sophie; Sinnaeve, Davy; Heylen, Kim; De Block, Jan; Madder, Annemieke; Martins, José C; Heyndrickx, Marc

    2014-01-01

    Two Pseudomonas strains, identified as closely related to Pseudomonas tolaasii, were isolated from milk of a farm with frequent false-positive Delvotest results for screening putative antibiotic residues in raw milk executed as part of the regulatory quality programme. Growth at 5 to 7°C of these isolates in milk resulted in high lipolysis and the production of bacterial inhibitors. The two main bacterial inhibitors have a molecular weight of 1168.7 and 1140.7 Da respectively, are heat-tolerant and inhibit Geobacillus stearothermophilus var. calidolactis, the test strain of most of the commercially available microbiological inhibitor tests for screening of antibiotic residues in milk. Furthermore, these bacterial inhibitors show antimicrobial activity against Staphylococcus aureus, Bacillus cereus and B. subtilis and also interfere negatively with yoghurt production. Following their isolation and purification with RP-HPLC, the inhibitors were identified by NMR analysis as cyclic lipodepsipeptides of the viscosin group. Our findings bring to light a new challenge for quality control in the dairy industry. By prolonging the refrigerated storage of raw milk, the keeping quality of milk is influenced by growth and metabolic activities of psychrotrophic bacteria such as pseudomonads. Besides an increased risk of possible spoilage of long shelf-life milk, the production at low temperature of natural bacterial inhibitors may also result in false-positive results for antibiotic residue screening tests based on microbial inhibitor assays thus leading to undue production loss. PMID:24853676

  15. Using Genomics for Natural Product Structure Elucidation.

    PubMed

    Tietz, Jonathan I; Mitchell, Douglas A

    2016-01-01

    Natural products (NPs) are the most historically bountiful source of chemical matter for drug development-especially for anti-infectives. With insights gleaned from genome mining, interest in natural product discovery has been reinvigorated. An essential stage in NP discovery is structural elucidation, which sheds light not only on the chemical composition of a molecule but also its novelty, properties, and derivatization potential. The history of structure elucidation is replete with techniquebased revolutions: combustion analysis, crystallography, UV, IR, MS, and NMR have each provided game-changing advances; the latest such advance is genomics. All natural products have a genetic basis, and the ability to obtain and interpret genomic information for structure elucidation is increasingly available at low cost to non-specialists. In this review, we describe the value of genomics as a structural elucidation technique, especially from the perspective of the natural product chemist approaching an unknown metabolite. Herein we first introduce the databases and programs of interest to the natural products chemist, with an emphasis on those currently most suited for general usability. We describe strategies for linking observed natural product-linked phenotypes to their corresponding gene clusters. We then discuss techniques for extracting structural information from genes, illustrated with numerous case examples. We also provide an analysis of the biases and limitations of the field with recommendations for future development. Our overview is not only aimed at biologically-oriented researchers already at ease with bioinformatic techniques, but also, in particular, at natural product, organic, and/or medicinal chemists not previously familiar with genomic techniques. PMID:26456468

  16. Mechanistic Advances in Plant Natural Product Enzymes

    PubMed Central

    Usera, Aimee R.; O’Connor, Sarah E.

    2009-01-01

    Summary of Recent Advances The biosynthetic pathways of plant natural products offer an abundance of knowledge to scientists in many fields. Synthetic chemists can be inspired by the synthetic strategies that nature uses to construct these compounds. Chemical and biological engineers are working to reprogram these biosynthetic pathways to more efficiently produce valuable products. Finally, biochemists and enzymologists are interested in the detailed mechanisms of the complex transformations involved in construction of these natural products. Study of biosynthetic enzymes and pathways therefore has a wide-ranging impact. In recent years, many plant biosynthetic pathways have been characterized, particularly the pathways that are responsible for alkaloid biosynthesis. Here we highlight recently studied alkaloid biosynthetic enzymes that catalyze production of numerous complex medicinal compounds, as well as the specifier proteins in glucosinosolate biosynthesis, whose structure and mechanism of action are just beginning to be unraveled. PMID:19632140

  17. Computational approaches to natural product discovery

    PubMed Central

    Medema, Marnix H.; Fischbach, Michael A.

    2016-01-01

    From the earliest Streptomyces genome sequences, the promise of natural product genome mining has been captivating: genomics and bioinformatics would transform compound discovery from an ad hoc pursuit to a high-throughput endeavor. Until recently, however, genome mining has advanced natural product discovery only modestly. Here, we argue that the development of algorithms to mine the continuously increasing amounts of (meta)genomic data will enable the promise of genome mining to be realized. We review computational strategies that have been developed to identify biosynthetic gene clusters in genome sequences and predict the chemical structures of their products. We then discuss networking strategies that can systematize large volumes of genetic and chemical data, and connect genomic information to metabolomic and phenotypic data. Finally, we provide a vision of what natural product discovery might look like in the future, specifically considering long-standing questions in microbial ecology regarding the roles of metabolites in interspecies interactions. PMID:26284671

  18. Natural and Synthetic Polymers as Inhibitors of Drug Efflux Pumps

    PubMed Central

    2007-01-01

    Inhibition of efflux pumps is an emerging approach in cancer therapy and drug delivery. Since it has been discovered that polymeric pharmaceutical excipients such as Tweens® or Pluronics® can inhibit efflux pumps, various other polymers have been investigated regarding their potential efflux pump inhibitory activity. Among them are polysaccharides, polyethylene glycols and derivatives, amphiphilic block copolymers, dendrimers and thiolated polymers. In the current review article, natural and synthetic polymers that are capable of inhibiting efflux pumps as well as their application in cancer therapy and drug delivery are discussed. PMID:17896100

  19. Synthetic Biological Approaches to Natural Product Biosynthesis

    PubMed Central

    Winter, Jaclyn M; Tang, Yi

    2012-01-01

    Small molecules produced in Nature continue to be an inspiration for the development of new therapeutic agents. These natural products possess exquisite chemical diversity, which gives rise to their wide range of biological activities. In their host organism, natural products are assembled and modified by dedicated biosynthetic pathways that Nature has meticulously developed. Often times, the complex structures or chemical modifications instated by these pathways are difficult to replicate using traditional synthetic methods. An alternative approach for creating or enhancing the structural variation of natural products is through combinatorial biosynthesis. By rationally reprogramming and manipulating the biosynthetic machinery responsible for their production, unnatural metabolites that were otherwise inaccessible can be obtained. Additionally, new chemical structures can be synthesized or derivatized by developing the enzymes that carry out these complicated chemical reactions into biocatalysts. In this review, we will discuss a variety of combinatorial biosynthetic strategies, their technical challenges, and highlight some recent (since 2007) examples of rationally designed unnatural metabolites, as well as platforms that have been established for the production and modification of clinically important pharmaceutical compounds. PMID:22221832

  20. Structural basis of sialidase in complex with geranylated flavonoids as potent natural inhibitors

    PubMed Central

    Lee, Youngjin; Ryu, Young Bae; Youn, Hyung-Seop; Cho, Jung Keun; Kim, Young Min; Park, Ji-Young; Lee, Woo Song; Park, Ki Hun; Eom, Soo Hyun

    2014-01-01

    Sialidase catalyzes the removal of a terminal sialic acid from glycoconjugates and plays a pivotal role in nutrition, cellular interactions and pathogenesis mediating various infectious diseases including cholera, influenza and sepsis. An array of antiviral sialidase agents have been developed and are commercially available, such as zanamivir and oseltamivir for treating influenza. However, the development of bacterial sialidase inhibitors has been much less successful. Here, natural polyphenolic geranylated flavonoids which show significant inhibitory effects against Cp-NanI, a sialidase from Clostridium perfringens, are reported. This bacterium causes various gastrointestinal diseases. The crystal structure of the Cp-NanI catalytic domain in complex with the best inhibitor, diplacone, is also presented. This structure explains how diplacone generates a stable enzyme–inhibitor complex. These results provide a structural framework for understanding the interaction between sialidase and natural flavonoids, which are promising scaffolds on which to discover new anti-sialidase agents. PMID:24816104

  1. Natural nitric oxide (NO) inhibitors from Chloranthus japonicus.

    PubMed

    Guo, Yan-Qiong; Zhao, Jing-Jun; Li, Zhen-Zhen; Tang, Gui-Hua; Zhao, Zhi-Min; Yin, Sheng

    2016-07-01

    Eight new lindenane sesquiterpenoid dimers, chlojapolides A-H (1-8), along with 11 known analogues were isolated from the whole plant of Chloranthus japonicus. Their structures including absolute configurations were elucidated by spectral and chemical methods. All the compounds were examined for their inhibitory effects on the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW 264.7 macrophages, and compounds 1, 11, 13, and 17 exhibited pronounced inhibition with IC50 values in the range of 6.91-15.75μM, being more active than the positive control, quercetin (IC50=15.90μM). PMID:27177824

  2. Psychoactive natural products: overview of recent developments.

    PubMed

    Ujváry, István

    2014-01-01

    Natural psychoactive substances have fascinated the curious mind of shamans, artists, scholars and laymen since antiquity. During the twentieth century, the chemical composition of the most important psychoactive drugs, that is opium, cannabis, coca and "magic mushrooms", has been fully elucidated. The mode of action of the principal ingredients has also been deciphered at the molecular level. In the past two decades, the use of herbal drugs, such as kava, kratom and Salvia divinorum, began to spread beyond their traditional geographical and cultural boundaries. The aim of the present paper is to briefly summarize recent findings on the psychopharmacology of the most prominent psychoactive natural products. Current knowledge on a few lesser-known drugs, including bufotenine, glaucine, kava, betel, pituri, lettuce opium and kanna is also reviewed. In addition, selected cases of alleged natural (or semi-natural) products are also mentioned. PMID:24695249

  3. Countercurrent Separation of Natural Products: An Update

    PubMed Central

    2015-01-01

    This work assesses the current instrumentation, method development, and applications in countercurrent chromatography (CCC) and centrifugal partition chromatography (CPC), collectively referred to as countercurrent separation (CCS). The article provides a critical review of the CCS literature from 2007 since our last review (J. Nat. Prod.2008, 71, 1489–1508), with a special emphasis on the applications of CCS in natural products research. The current state of CCS is reviewed in regard to three continuing topics (instrumentation, solvent system development, theory) and three new topics (optimization of parameters, workflow, bioactivity applications). The goals of this review are to deliver the necessary background with references for an up-to-date perspective of CCS, to point out its potential for the natural product scientist, and thereby to induce new applications in natural product chemistry, metabolome, and drug discovery research involving organisms from terrestrial and marine sources. PMID:26177360

  4. Supercritical fluid extraction in natural products analyses.

    PubMed

    Nahar, Lutfun; Sarker, Satyajit D

    2012-01-01

    Supercritical fluids (SCFs) are increasingly replacing the organic solvents, e.g., n-hexane, chloroform, dichloromethane, or methanol, that are conventionally used in industrial extraction, purification, and recrystallization operations because of regulatory and environmental pressures on hydrocarbon and ozone-depleting emissions. In natural products extraction and isolation, supercritical fluid extraction (SFE), especially employing supercritical CO(2), has become a popular choice. Sophisticated modern technologies allow precise regulation of changes in temperature and pressure, and thus manipulation of solvating property of the SCF, which helps the extraction of natural products of a wide range of polarities. This chapter deals mainly with the application of the SFE technology in the natural products extraction and isolation, and outlines various methodologies with specific examples. PMID:22367893

  5. Early state research on antifungal natural products.

    PubMed

    Negri, Melyssa; Salci, Tânia P; Shinobu-Mesquita, Cristiane S; Capoci, Isis R G; Svidzinski, Terezinha I E; Kioshima, Erika Seki

    2014-01-01

    Nosocomial infections caused by fungi have increased greatly in recent years, mainly due to the rising number of immunocompromised patients. However, the available antifungal therapeutic arsenal is limited, and the development of new drugs has been slow. Therefore, the search for alternative drugs with low resistance rates and fewer side effects remains a major challenge. Plants produce a variety of medicinal components that can inhibit pathogen growth. Studies of plant species have been conducted to evaluate the characteristics of natural drug products, including their sustainability, affordability, and antimicrobial activity. A considerable number of studies of medicinal plants and alternative compounds, such as secondary metabolites, phenolic compounds, essential oils and extracts, have been performed. Thus, this review discusses the history of the antifungal arsenal, surveys natural products with potential antifungal activity, discusses strategies to develop derivatives of natural products, and presents perspectives on the development of novel antifungal drug candidates. PMID:24609016

  6. Artificial neural network cascade identifies multi-P450 inhibitors in natural compounds

    PubMed Central

    Li, Zhangming; Li, Yan; Sun, Lu; Tang, Yun; Liu, Lanru

    2015-01-01

    Substantial evidence has shown that most exogenous substances are metabolized by multiple cytochrome P450 (P450) enzymes instead of by merely one P450 isoform. Thus, multi-P450 inhibition leads to greater drug-drug interaction risk than specific P450 inhibition. Herein, we innovatively established an artificial neural network cascade (NNC) model composed of 23 cascaded networks in a ladder-like framework to identify potential multi-P450 inhibitors among natural compounds by integrating 12 molecular descriptors into a P450 inhibition score (PIS). Experimental data reporting in vitro inhibition of five P450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) were obtained for 8,148 compounds from the Cytochrome P450 Inhibitors Database (CPID). The results indicate significant positive correlation between the PIS values and the number of inhibited P450 isoforms (Spearman’s ρ = 0.684, p < 0.0001). Thus, a higher PIS indicates a greater possibility for a chemical to inhibit the enzyme activity of at least three P450 isoforms. Ten-fold cross-validation of the NNC model suggested an accuracy of 78.7% for identifying whether a compound is a multi-P450 inhibitor or not. Using our NNC model, 22.2% of the approximately 160,000 natural compounds in TCM Database@Taiwan were identified as potential multi-P450 inhibitors. Furthermore, chemical similarity calculations suggested that the prevailing parent structures of natural multi-P450 inhibitors were alkaloids. Our findings show that dissection of chemical structure contributes to confident identification of natural multi-P450 inhibitors and provides a feasible method for virtually evaluating multi-P450 inhibition risk for a known structure. PMID:26719820

  7. Natural Product Anacardic Acid from Cashew Nut Shells Stimulates Neutrophil Extracellular Trap Production and Bactericidal Activity.

    PubMed

    Hollands, Andrew; Corriden, Ross; Gysler, Gabriela; Dahesh, Samira; Olson, Joshua; Raza Ali, Syed; Kunkel, Maya T; Lin, Ann E; Forli, Stefano; Newton, Alexandra C; Kumar, Geetha B; Nair, Bipin G; Perry, J Jefferson P; Nizet, Victor

    2016-07-01

    Emerging antibiotic resistance among pathogenic bacteria is an issue of great clinical importance, and new approaches to therapy are urgently needed. Anacardic acid, the primary active component of cashew nut shell extract, is a natural product used in the treatment of a variety of medical conditions, including infectious abscesses. Here, we investigate the effects of this natural product on the function of human neutrophils. We find that anacardic acid stimulates the production of reactive oxygen species and neutrophil extracellular traps, two mechanisms utilized by neutrophils to kill invading bacteria. Molecular modeling and pharmacological inhibitor studies suggest anacardic acid stimulation of neutrophils occurs in a PI3K-dependent manner through activation of surface-expressed G protein-coupled sphingosine-1-phosphate receptors. Neutrophil extracellular traps produced in response to anacardic acid are bactericidal and complement select direct antimicrobial activities of the compound. PMID:27226531

  8. Current natural products with antihypertensive activity.

    PubMed

    Bai, Ren-Ren; Wu, Xiao-Ming; Xu, Jin-Yi

    2015-10-01

    Natural products have been an important source of new drugs, which also played a dominant role in the discovery and research of new drugs for the treatment of hypertension. This review article reviews the recent progress in the research and development of natural lead compounds with antihypertensive activity, including alkaloids, diterpenes, coumarins, flavonoids, and peptides. We summarized their structures, sources, as well as the antihypertensive mechanisms. These information provides instructive reference for the following structural modifications and optimization. PMID:26481372

  9. Natural Product Sugar Biosynthesis and Enzymatic Glycodiversification**

    PubMed Central

    Thibodeaux, Christopher J.; Melançon, Charles E.; Liu, Hung-wen

    2009-01-01

    Many biologically active small molecule natural products produced by microorganisms derive their activities from sugar substituents. Changing the structures of these sugars can have a profound impact on the biological properties of the parent compounds. This realization has inspired attempts to derivatize the sugar moieties of these natural products through exploitation of the sugar biosynthetic machinery. This approach requires an understanding of the biosynthetic pathway of each target sugar and detailed mechanistic knowledge of the key enzymes. Scientists have begun to unravel the biosynthetic logic behind the assembly of many glycosylated natural products, and have found that a core set of enzyme activities is mixed and matched to synthesize the diverse sugar structures observed in nature. Remarkably, many of these sugar biosynthetic enzymes and glycosyltransferases also exhibit relaxed substrate specificity. The promiscuity of these enzymes has prompted efforts to modify the sugar structures and/or alter the glycosylation patterns of natural products via metabolic pathway engineering and/or enzymatic glycodiversification. In applied biomedical research, these studies will enable the development of new glycosylation tools and generate novel glycoforms of secondary metabolites with useful biological activity. PMID:19058170

  10. Antiviral Natural Products and Herbal Medicines

    PubMed Central

    Lin, Liang-Tzung; Hsu, Wen-Chan; Lin, Chun-Ching

    2014-01-01

    Viral infections play an important role in human diseases, and recent outbreaks in the advent of globalization and ease of travel have underscored their prevention as a critical issue in safeguarding public health. Despite the progress made in immunization and drug development, many viruses lack preventive vaccines and efficient antiviral therapies, which are often beset by the generation of viral escape mutants. Thus, identifying novel antiviral drugs is of critical importance and natural products are an excellent source for such discoveries. In this mini-review, we summarize the antiviral effects reported for several natural products and herbal medicines. PMID:24872930

  11. Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance.

    PubMed

    Gurden, Mark D; Westwood, Isaac M; Faisal, Amir; Naud, Sébastien; Cheung, Kwai-Ming J; McAndrew, Craig; Wood, Amy; Schmitt, Jessica; Boxall, Kathy; Mak, Grace; Workman, Paul; Burke, Rosemary; Hoelder, Swen; Blagg, Julian; Van Montfort, Rob L M; Linardopoulos, Spiros

    2015-08-15

    Acquired resistance to therapy is perhaps the greatest challenge to effective clinical management of cancer. With several inhibitors of the mitotic checkpoint kinase MPS1 in preclinical development, we sought to investigate how resistance against these inhibitors may arise so that mitigation or bypass strategies could be addressed as early as possible. Toward this end, we modeled acquired resistance to the MPS1 inhibitors AZ3146, NMS-P715, and CCT251455, identifying five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed how the MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. Notably, we show that these mutations occur in nontreated cancer cell lines and primary tumor specimens, and that they also preexist in normal lymphoblast and breast tissues. In a parallel piece of work, we also show that the EGFR p.T790M mutation, the most common mutation conferring resistance to the EGFR inhibitor gefitinib, also preexists in cancer cells and normal tissue. Our results therefore suggest that mutations conferring resistance to targeted therapy occur naturally in normal and malignant cells and these mutations do not arise as a result of the increased mutagenic plasticity of cancer cells. PMID:26202014

  12. Metabolic Engineering for the Production of Natural Products

    PubMed Central

    Pickens, Lauren B.; Tang, Yi; Chooi, Yit-Heng

    2014-01-01

    Natural products and natural product derived compounds play an important role in modern healthcare as frontline treatments for many diseases and as inspiration for chemically synthesized therapeutics. With advances in sequencing and recombinant DNA technology, many of the biosynthetic pathways responsible for the production of these chemically complex and pharmaceutically valuable compounds have been elucidated. With an ever expanding toolkit of biosynthetic components, metabolic engineering is an increasingly powerful method to improve natural product titers and generate novel compounds. Heterologous production platforms have enabled access to pathways from difficult to culture strains; systems biology and metabolic modeling tools have resulted in increasing predictive and analytic capabilities; advances in expression systems and regulation have enabled the fine-tuning of pathways for increased efficiency, and characterization of individual pathway components has facilitated the construction of hybrid pathways for the production of new compounds. These advances in the many aspects of metabolic engineering have not only yielded fascinating scientific discoveries but also make it an increasingly viable approach for the optimization of natural product biosynthesis. PMID:22432617

  13. An Update on Natural Products with Carbonic Anhydrase Inhibitory Activity.

    PubMed

    Karioti, Anastasia; Carta, Fabrizio; Supuran, Claudiu T

    2016-01-01

    Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological processes. They represent a typical example of enzyme convergent evolution, as six genetically unrelated families of such enzymes were described so far. It is more than 70 years that synthetic compounds, mainly sulfonamides, have been used in clinical practice as diuretics and systemic acting antiglaucoma drugs. Recent studies using natural product libraries and isolated constituents from natural sources (such as fungi and plants) have disclosed novel chemotypes possessing carbonic anhydrase inhibition activities. These natural sources offer new opportunities in the search for new and more effective carbonic anhydrase inhibitors, and may serve as new leads for the design and development of future drugs. This review will discuss the most recent advances in the search of naturally occurring products and their synthetic derivatives that inhibit the CAs and their mechanisms of action at molecular level. Plant extracts are not considered in the present review. PMID:26654592

  14. An automated Genomes-to-Natural Products platform (GNP) for the discovery of modular natural products

    PubMed Central

    Johnston, Chad W.; Skinnider, Michael A.; Wyatt, Morgan A.; Li, Xiang; Ranieri, Michael R. M.; Yang, Lian; Zechel, David L.; Ma, Bin; Magarvey, Nathan A.

    2015-01-01

    Bacterial natural products are a diverse and valuable group of small molecules, and genome sequencing indicates that the vast majority remain undiscovered. The prediction of natural product structures from biosynthetic assembly lines can facilitate their discovery, but highly automated, accurate, and integrated systems are required to mine the broad spectrum of sequenced bacterial genomes. Here we present a genome-guided natural products discovery tool to automatically predict, combinatorialize and identify polyketides and nonribosomal peptides from biosynthetic assembly lines using LC–MS/MS data of crude extracts in a high-throughput manner. We detail the directed identification and isolation of six genetically predicted polyketides and nonribosomal peptides using our Genome-to-Natural Products platform. This highly automated, user-friendly programme provides a means of realizing the potential of genetically encoded natural products. PMID:26412281

  15. New Methodology for Natural Gas Production Estimates

    EIA Publications

    2010-01-01

    A new methodology is implemented with the monthly natural gas production estimates from the EIA-914 survey this month. The estimates, to be released April 29, 2010, include revisions for all of 2009. The fundamental changes in the new process include the timeliness of the historical data used for estimation and the frequency of sample updates, both of which are improved.

  16. Chocolate: A Marvelous Natural Product of Chemistry

    ERIC Educational Resources Information Center

    Tannenbaum, Ginger

    2004-01-01

    The study of chocolate, a natural product, can be beneficial for the chemistry students as they ask frequently about the relevancy of their chemistry classes. The history of chocolate, its chemical and physical changes during processing, its composition, different crystalline forms, tempering and its viscosity are discussed.

  17. Marine Natural Products as Prototype Agrochemical Agents

    PubMed Central

    Peng, Jiangnan; Shen, Xiaoyu; El Sayed, Khalid A.; Dunbar, D. C Harles; Perry, Tony L.; Wilkins, Scott P.; Hamann, Mark T.; Bobzin, Steve; Huesing, Joseph; Camp, Robin; Prinsen, Mike; Krupa, Dan; Wideman, Margaret A.

    2016-01-01

    In the interest of identifying new leads that could serve as prototype agrochemical agents, 18 structurally diverse marine-derived compounds were examined for insecticidal, herbicidal, and fungicidal activities. Several new classes of compounds have been shown to be insecticidal, herbicidal, and fungicidal, which suggests that marine natural products represent an intriguing source for the discovery of new agrochemical agents. PMID:12670165

  18. Coal or natural gas for ecofuel production

    SciTech Connect

    Geertsema, A.

    1998-07-01

    The paper reviews the technology of the Fischer-Tropsch synthesis used in the Sasal plant in South Africa. It discusses environmental aspects and economics of new FT facilities for the production of diesel fuels. Several projects are briefly described which use this technology for natural gas conversion.

  19. Natural Products for Chemoprevention of Breast Cancer

    PubMed Central

    Ko, Eun-Yi; Moon, Aree

    2015-01-01

    Breast cancer is the primary cause of cancer death in women. Although current therapies have shown some promise against breast cancer, there is still no effective cure for the majority of patients in the advanced stages of breast cancer. Development of effective agents to slow, reduce, or reverse the incidence of breast cancer in high-risk women is necessary. Chemoprevention of breast cancer by natural products is advantageous, as these compounds have few side effects and low toxicity compared to synthetic compounds. In the present review, we summarize natural products which exert chemopreventive activities against breast cancer, such as curcumin, sauchinone, lycopene, denbinobin, genipin, capsaicin, and ursolic acid. This review examines the current knowledge about natural compounds and their mechanisms that underlie breast cancer chemopreventive activity both in vitro and in vivo. The present review may provide information on the use of these compounds for the prevention of breast cancer. PMID:26734584

  20. Natural products in modern life science.

    PubMed

    Bohlin, Lars; Göransson, Ulf; Alsmark, Cecilia; Wedén, Christina; Backlund, Anders

    2010-06-01

    With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure-activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific

  1. Natural products in modern life science

    PubMed Central

    Göransson, Ulf; Alsmark, Cecilia; Wedén, Christina; Backlund, Anders

    2010-01-01

    With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure–activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific

  2. [Inhibitors of microtubule polymerization- new natural compounds as potential anti-cancer drugs].

    PubMed

    Rogalska, Aneta; Miśkiewicz, Klaudia; Marczak, Agnieszka

    2015-01-01

    Inhibitors of microtubule polymerization are compounds which, by binding to the tubulin dimer, prevent the normal course of cell division and lead to cell death. They cause inhibition of mitosis, affect the cytoskeleton and disrupt the process of angiogenesis. Inhibitors of microtubule polymerization include natural substances, synthetic and semi-synthetic analogs. They contain a group of compounds having the ability to bind to the vinca alkaloid and colchicine domain of β-tubulin. Among them are vinca alkaloids, dolastatins and halichondrins, which connect to the vinca alkaloids domain, and combretastatins binding the colchicine site of protein. Tumor cells have greater capacity for cell proliferation and are also more susceptible to damage by microtubule inhibitors. Their action has been widely used in cancer therapy. PMID:25983296

  3. Intentional synthesis of corrosion inhibitors based on secondary products of sugar cane processing

    SciTech Connect

    Ledovskykh, V.M.

    1988-07-01

    Secondary products of sugar cane processing (mosto, wax, furfurol) were studied as starting raw materials for creating inhibitors for different purposes and temporary means of protecting metals from corrosion. In order to protect metals in different corrosive media the following inhibitors have been developed: an inhibitor for acid solutions (pickling metals, acid washing of the equipment) based on high-tonnage water-soluble waste mosto and combined synergistic inhibitors based on mixtures of it with cation- and anion-active surfactants, including nitrogen- and sulfur-containing substances obtained by intentional synthesis of another secondary product, furfurol; inhibitors for two-phase media (oil recovery and refining) of the carbonic acid amide and 2-alkylimidazoline classes from sugar cane wax; and inhibitors comprised of Li-, Na-, Ca-, and Al-plastic greases from sugar cane wax for atmospheric conditions.

  4. Structure-Based Design of Non-Natural Amino Acid Inhibitors of Amyloid Fibrillation

    PubMed Central

    Sievers, Stuart A.; Karanicolas, John; Chang, Howard W.; Zhao, Anni; Jiang, Lin; Zirafi, Onofrio; Stevens, Jason T.; Münch, Jan; Baker, David; Eisenberg, David

    2014-01-01

    Many globular and natively disordered proteins can convert into amyloid fibers. These fibers are associated with numerous pathologies1 as well as with normal cellular functions2,3, and frequently form during protein denaturation4,5. Inhibitors of pathological amyloid fibers could serve as leads for therapeutics, provided the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibers as templates, we have designed and characterized an all D-amino acid inhibitor of fibrillation of the tau protein found in Alzheimer’s disease, and a non-natural L-amino acid inhibitor of an amyloid fiber that enhances sexual transmission of HIV. Our results indicate that peptides from structure-based designs can disrupt the fibrillation of full-length proteins, including those like tau that lack fully ordered native structures. PMID:21677644

  5. Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation

    SciTech Connect

    Sievers, Stuart A.; Karanicolas, John; Chang, Howard W.; Zhao, Anni; Jiang, Lin; Zirafi, Onofrio; Stevens, Jason T.; Münch, Jan; Baker, David; Eisenberg, David

    2011-09-20

    Many globular and natively disordered proteins can convert into amyloid fibrils. These fibrils are associated with numerous pathologies as well as with normal cellular functions, and frequently form during protein denaturation. Inhibitors of pathological amyloid fibril formation could be useful in the development of therapeutics, provided that the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibrils as templates, we have designed and characterized an all-D-amino-acid inhibitor of the fibril formation of the tau protein associated with Alzheimer's disease, and a non-natural L-amino-acid inhibitor of an amyloid fibril that enhances sexual transmission of human immunodeficiency virus. Our results indicate that peptides from structure-based designs can disrupt the fibril formation of full-length proteins, including those, such as tau protein, that lack fully ordered native structures. Because the inhibiting peptides have been designed on structures of dual-{beta}-sheet 'steric zippers', the successful inhibition of amyloid fibril formation strengthens the hypothesis that amyloid spines contain steric zippers.

  6. Marine AChE inhibitors isolated from Geodia barretti: natural compounds and their synthetic analogs.

    PubMed

    Olsen, Elisabeth K; Hansen, Espen; W K Moodie, Lindon; Isaksson, Johan; Sepčić, Kristina; Cergolj, Marija; Svenson, Johan; Andersen, Jeanette H

    2016-02-01

    Barettin, 8,9-dihydrobarettin, bromoconicamin and a novel brominated marine indole were isolated from the boreal sponge Geodia barretti collected off the Norwegian coast. The compounds were evaluated as inhibitors of electric eel acetylcholinesterase. Barettin and 8,9-dihydrobarettin displayed significant inhibition of the enzyme, with inhibition constants (Ki) of 29 and 19 μM respectively towards acetylcholinesterase via a reversible noncompetitive mechanism. These activities are comparable to those of several other natural acetylcholinesterase inhibitors of marine origin. Bromoconicamin was less potent against acetylcholinesterase, and the novel compound was inactive. Based on the inhibitory activity, a library of 22 simplified synthetic analogs was designed and prepared to probe the role of the brominated indole, common to all the isolated compounds. From the structure-activity investigation it was shown that the brominated indole motif is not sufficient to generate a high acetylcholinesterase inhibitory activity, even when combined with natural cationic ligands for the acetylcholinesterase active site. The four natural compounds were also analysed for their butyrylcholinesterase inhibitory activity in addition and shown to display comparable activities. The study illustrates how both barettin and 8,9-dihydrobarettin display additional bioactivities which may help to explain their biological role in the producing organism. The findings also provide new insights into the structure-activity relationship of both natural and synthetic acetylcholinesterase inhibitors. PMID:26695619

  7. European Directive fragrances in natural products.

    PubMed

    Scheman, Andrew; Scheman, Nicole; Rakowski, Ella-Marie

    2014-01-01

    Information on the presence of European Directive fragrance (EUF) allergens in plants and foods is important for numerous reasons. If an individual is allergic to an EUF and is avoiding fragrance, it is possible that they may still be exposed to the allergen in a natural product. In addition, because many of these allergens are also found in foods, it is possible that ingestion of a food containing the allergen may induce systemic contact allergy. Finally, individuals with lip dermatitis may react to contact with foods that contain the allergen. In this article, we have used the data available to identify which plants and foods contain EUF. When available, concentrations of EUF in natural products are provided. The goal of this article is to narrow down the list of botanicals to avoid for specific EUF allergies. PMID:24603515

  8. Genome Mining for Ribosomally Synthesized Natural Products

    PubMed Central

    Velásquez, Juan E.; van der Donk, Wilfred

    2011-01-01

    In recent years, the number of known peptide natural products that are synthesized via the ribosomal pathway has rapidly grown. Taking advantage of sequence homology among genes encoding precursor peptides or biosynthetic proteins, in silico mining of genomes combined with molecular biology approaches has guided the discovery of a large number of new ribosomal natural products, including lantipeptides, cyanobactins, linear thiazole/oxazole-containing peptides, microviridins, lasso peptides, amatoxins, cyclotides, and conopeptides. In this review, we describe the strategies used for the identification of these ribosomally-synthesized and posttranslationally modified peptides (RiPPs) and the structures of newly identified compounds. The increasing number of chemical entities and their remarkable structural and functional diversity may lead to novel pharmaceutical applications. PMID:21095156

  9. Advanced biomaterials development from "natural products".

    PubMed

    Baier, R E

    1988-04-01

    Natural substances and structures can serve increasingly well as biomedical products, given recent advances in understanding of requirements for biocompatibility and of methods for their preservation and surface tailoring. A successful example is the derivation of limb salvaging vessels, used in arterial reconstructive surgery, from human umbilical cords. There are numerous opportunities for additional product development from the umbilical cords' main ingredient, Wharton's gel, ranging from biolubricants to wound-healing aids. Major problems yet to be overcome with natural starting materials are their propensity for calcification and eventual biodeterioration. Surface modification of biomaterials to exhibit desired degrees of interaction with contacting viable tissues promises the greatest beneficial results. General principles of bioadhesion have broad applicability, predicting material behavior in environments as diverse as blood, saliva, and seawater. PMID:3058928

  10. Natural Product Research in the Australian Marine Invertebrate Dicathais orbita

    PubMed Central

    Benkendorff, Kirsten

    2013-01-01

    The predatory marine gastropod Dicathais orbita has been the subject of a significant amount of biological and chemical research over the past five decades. Natural products research on D. orbita includes the isolation and identification of brominated indoles and choline esters as precursors of Tyrian purple, as well as the synthesis of structural analogues, bioactivity testing, biodistributional and biosynthetic studies. Here I also report on how well these compounds conform to Lipinski’s rule of five for druglikeness and their predicted receptor binding and enzyme inhibitor activity. The composition of mycosporine-like amino acids, fatty acids and sterols has also been described in the egg masses of D. orbita. The combination of bioactive compounds produced by D. orbita is of interest for further studies in chemical ecology, as well as for future nutraceutical development. Biological insights into the life history of this species, as well as ongoing research on the gene expression, microbial symbionts and biosynthetic capabilities, should facilitate sustainable production of the bioactive compounds. Knowledge of the phylogeny of D. orbita provides an excellent platform for novel research into the evolution of brominated secondary metabolites in marine molluscs. The range of polarities in the brominated indoles produced by D. orbita has also provided an effective model system used to develop a new method for biodistributional studies. The well characterized suite of chemical reactions that generate Tyrian purple, coupled with an in depth knowledge of the ecology, anatomy and genetics of D. orbita provide a good foundation for ongoing natural products research. PMID:23612370

  11. Accelerated solvent extraction for natural products isolation.

    PubMed

    Mottaleb, Mohammad A; Sarker, Satyajit D

    2012-01-01

    Accelerated solvent extraction (ASE(®)), first introduced in 1995, is an automated rapid extraction technique that utilizes common solvents at elevated temperature and pressure, and thereby increases the efficiency of extraction of organic compounds from solid and semisolid matrices. ASE(®) allows extractions for sample sizes 1-100 g in minutes, reduces solvent uses dramatically, and can be applied to a wide range of matrices, including natural products. PMID:22367894

  12. Standardization for natural product synthetic biology.

    PubMed

    Zhao, Huimin; Medema, Marnix H

    2016-08-27

    Standardization is one of the foundational features of modern-day engineering, and the use of standardized parts and processes is a key element that distinguishes bona fide synthetic biology from traditional genetic engineering. Here, we discuss the role of standardization in natural product synthetic biology, focusing on standardization of data on biosynthetic pathways and gene clusters, as well as the role of standardization in the process of biosynthetic gene cluster engineering. PMID:27313083

  13. Mass spectrometry in natural product chemistry.

    PubMed

    Clayton, E; Hill, H C; Reed, R I

    1966-01-01

    Some mass spectrometric techniques are described which seem applicable to investigating problems in natural product chemistry. One example is of a sample of 5 mcg of a compound being identified by comparison with an authentic sample of prostaglandin derivative. Compared were mass, ion content, and structure. In the prostaglandin/unknown substance comparison, high-resolution mass spectrometry resolved a quandary: apparent additional ions present in the unknown substance were shown to be an impurity. PMID:12262324

  14. Corrosion inhibitor testing and selection for exploration and production: A user's perspective

    SciTech Connect

    Kapusta, S.D.

    1999-06-01

    Inhibitor users need simple, reliable, and representative tests to select the best product from a number of candidates. This article describes a procedure that can help users test and select inhibitors for carbon dioxide/hydrogen sulfide (CO[sub 2]/H[sub 2]S) corrosion in oil and gas production, in a fast and cost-effective manner. The selection is based on two criteria: performance (effectiveness) against corrosion, and compatibility with other chemicals. The compatibility of the inhibitor with the injection and production systems must be confirmed.

  15. Natural and Heterologous Production of Bacteriocins

    NASA Astrophysics Data System (ADS)

    Cintas, Luis M.; Herranz, Carmen; Hernández, Pablo E.

    Bacteriocins are ribosomally synthesized antimicrobial peptides produced by bacteria, and their use as natural and nontoxic food preservatives has been the source of considerable interest for the research community. In addition, bacteriocins have been investigated for their potential use in human and veterinary applications and in the animal production field. In the native bacterial strain, most bacteriocins are synthesized as biologically inactive precursors, with N-terminal extensions, that are cleaved concomitantly during export of the bacteriocin by dedicated ABC transporters, or the general secretory pathway (GSP) or Sec-dependent pathway. However, a few bacteriocins are synthesized without an N-terminal extension, and others are circularized through a head-to-tail peptide bond, complicating the elucidation of their processing and transport across the cytoplasmic membrane. The high cost of synthetic bacteriocin synthesis and their low yields from many natural producers recommends the exploration of recombinant microbial systems for the heterologous production of bacteriocins. Other advantages of such systems include production of bacteriocins in safer hosts, increased bacteriocin production, control of bacteriocin gene expression, production of food ingredients with antimicrobial activity, construction of multibacteriocinogenic strains with a wider antagonistic spectrum, a better adaptation of the selected hosts to food environments, and providing antagonistic properties to lactic acid bacteria (LAB) used as starter, protective, or probiotic cultures. The recombinant production of bacteriocins mostly relies on the use of expression vectors that replicate in Gram-negative bacteria, Gram-positive bacteria, and yeasts, whereas the production of bacteriocins in heterologous LAB hosts may be essentially based on the expression of native biosynthetic genes, by exchanging or replacing leader peptides and/or dedicated processing and secretion systems (ABC transporters

  16. Identification of natural inhibitors of Entamoeba histolytica cysteine synthase from microbial secondary metabolites

    PubMed Central

    Mori, Mihoko; Jeelani, Ghulam; Masuda, Yui; Sakai, Kazunari; Tsukui, Kumiko; Waluyo, Danang; Tarwadi; Watanabe, Yoshio; Nonaka, Kenichi; Matsumoto, Atsuko; Ōmura, Satoshi; Nozaki, Tomoyoshi; Shiomi, Kazuro

    2015-01-01

    Amebiasis is a common worldwide diarrheal disease, caused by the protozoan parasite, Entamoeba histolytica. Metronidazole has been a drug of choice against amebiasis for decades despite its known side effects and low efficacy against asymptomatic cyst carriers. E. histolytica is also capable of surviving sub-therapeutic levels of metronidazole in vitro. Novel drugs with different mode of action are therefore urgently needed. The sulfur assimilatory de novo L-cysteine biosynthetic pathway is essential for various cellular activities, including the proliferation and anti-oxidative defense of E. histolytica. Since the pathway, consisting of two reactions catalyzed by serine acetyltransferase (SAT) and cysteine synthase (CS, O-acetylserine sulfhydrylase), does not exist in humans, it is a rational drug target against amebiasis. To discover inhibitors against the CS of E. histolytica (EhCS), the compounds of Kitasato Natural Products Library were screened against two recombinant CS isozymes: EhCS1 and EhCS3. Nine compounds inhibited EhCS1 and EhCS3 with IC50 values of 0.31–490 μM. Of those, seven compounds share a naphthoquinone moiety, indicating the structural importance of the moiety for binding to the active site of EhCS1 and EhCS3. We further screened >9,000 microbial broths for CS inhibition and purified two compounds, xanthofulvin and exophillic acid from fungal broths. Xanthofulvin inhibited EhCS1 and EhCS3. Exophillic acid showed high selectivity against EhCS1, but exhibited no inhibition against EhCS3. In vitro anti-amebic activity of the 11 EhCS inhibitors was also examined. Deacetylkinamycin C and nanaomycin A showed more potent amebicidal activity with IC50 values of 18 and 0.8 μM, respectively, in the cysteine deprived conditions. The differential sensitivity of trophozoites against deacetylkinamycin C in the presence or absence of L-cysteine in the medium and the IC50 values against EhCS suggest the amebicidal effect of deacetylkinamycin C is due to

  17. Synthetic and Natural Monoamine Oxidase Inhibitors as Potential Lead Compounds for Effective Therapeutics.

    PubMed

    Pathak, Ashish; Srivastava, Amit K; Singour, Pradeep K; Gouda, Panchanan

    2016-01-01

    Monoamine oxidases A and B (MAO-A and B) play a critical role in the metabolism of intracellular neurotransmitters of the central nervous system. For decades, MAO inhibitors have proven their clinical efficacy as potential drug targets for several neurological and neurodegenerative diseases. Use of first generation non selective MAO inhibitors as neuropsychiatric drugs elicited several side effects like hypertensive crisis and cheese reaction. Therefore their use is now limited due to non-selectivity towards MAO isoforms and inhibition of metabolizing enzymes like cytochrome P450. Development of selective and specific MAO inhibitors like moclobemide, toloxatone improves their efficacy as disease-modifying effects in monotherapy as well as adjunctive therapy. Recently a lot of research has been done to elucidate the pharmacological potential of medicinal plants and their isolated bioactive constituents having MAO inhibitory activity. Herbs containing MAO inhibitors are extensively used for the development of potent synthetic drugs and as safe and effective alternatives to the available synthetic drugs in the treatment of neurodegenerative diseases such as depression, Parkinson and Alzheimer's. In several diseases like Parkinson natural MAO inhibitors prevented the neuron denaturalization by their dual action via enhancing neurotransmission of dopamine as well as lowering the generation of free radicals and toxins. Currently development of selective MAO inhibitors is still under study to achieve more effective therapies by using Computer Aided Drug Designing, Ligand-based models and structure-activity hypothesis. These approaches also facilitate understanding the interaction of newly designed molecule with MAO enzymes and the rationalization of probable mechanisms of action. PMID:26104056

  18. Is There Consistency between the Binding Affinity and Inhibitory Potential of Natural Polyphenols as α-amylase Inhibitors?

    PubMed

    Xu, Wei; Shao, Rong; Xiao, Jianbo

    2016-07-26

    The inhibitory potential of natural polyphenols for α-amylases has attracted great interests among researchers. The structure-affinity properties of natural polyphenols binding to α-amylase and the structure-activity relationship of dietary polyphenols inhibiting α-amylase were deeply investigated. There is a lack of consistency between the structure-affinity relationship and the structure-activity relationship of natural polyphenols as α-amylase inhibitors. Is it consistent between the binding affinity and inhibitory potential of natural polyphenols as with α-amylase inhibitors? It was found that the consistency between the binding affinity and inhibitory potential of natural polyphenols as with α-amylase inhibitors is not equivocal. For example, there is no consistency between the binding affinity and the inhibitory potential of quercetin and its glycosides as α-amylase inhibitors. However, catechins with higher α-amylase inhibitory potential exhibited higher affinity with α-amylase. PMID:25748632

  19. Production of natural products through metabolic engineering of Saccharomyces cerevisiae.

    PubMed

    Krivoruchko, Anastasia; Nielsen, Jens

    2015-12-01

    Many high-value metabolites are produced in nature by organisms that are not ideal for large-scale production. Therefore, interest exists in expressing the biosynthetic pathways of these compounds in organisms that are more suitable for industrial production. Recent years have seen developments in both the discovery of various biosynthetic pathways, as well as development of metabolic engineering tools that allow reconstruction of complex pathways in microorganisms. In the present review we discuss recent advances in reconstruction of the biosynthetic pathways of various high-value products in the yeast Saccharomyces cerevisiae, a commonly used industrial microorganism. Key achievements in the production of different isoprenoids, aromatics and polyketides are presented and the metabolic engineering strategies underlying these accomplishments are discussed. PMID:25544013

  20. Neurotrophic Natural Products: Chemistry and Biology

    PubMed Central

    Xu, Jing; Lacoske, Michelle H.

    2014-01-01

    Neurodegenerative diseases and spinal cord injury affect approximately 50 million people worldwide, bringing the total healthcare cost to over 600 billion dollars per year. Nervous system growth factors, that is, neurotrophins, are a potential solution to these disorders, since they could promote nerve regeneration. An average of 500 publications per year attests to the significance of neurotrophins in biomedical sciences and underlines their potential for therapeutic applications. Nonetheless, the poor pharmacokinetic profile of neurotrophins severely restricts their clinical use. On the other hand, small molecules that modulate neurotrophic activity offer a promising therapeutic approach against neurological disorders. Nature has provided an impressive array of natural products that have potent neurotrophic activities. This Review highlights the current synthetic strategies toward these compounds and summarizes their ability to induce neuronal growth and rehabilitation. It is anticipated that neurotrophic natural products could be used not only as starting points in drug design but also as tools to study the next frontier in biomedical sciences: the brain activity map project. PMID:24353244

  1. Evaluation of Natural and Synthetic 1,4-naphthoquinones as Inhibitors of Monoamine Oxidase.

    PubMed

    Mostert, Samantha; Petzer, Anél; Petzer, Jacobus P

    2016-05-01

    Previous reports have documented that 1,4-naphthoquinones act as inhibitors of the monoamine oxidase (MAO) enzymes. In particular, fractionation of the extracts of cured tobacco leafs has led to the characterization of 2,3,6-trimethyl-1,4-naphthoquinone, a non-selective MAO inhibitor. To derive structure-activity relationships for MAO inhibition by the 1,4-naphthoquinone class of compounds, this study investigates the human MAO inhibitory activities of fourteen structurally diverse 1,4-naphthoquinones of natural and synthetic origin. Of these, 5,8-dihydroxy-1,4-naphthoquinone was found to be the most potent inhibitor with an IC50 value of 0.860 μm for the inhibition of MAO-B. A related compound, shikonin, inhibits both the MAO-A and MAO-B isoforms with IC50 values of 1.50 and 1.01 μm, respectively. It is further shown that MAO-A and MAO-B inhibition by these compounds is reversible by dialysis. In this respect, kinetic analysis suggests that the modes of MAO inhibition are competitive. This study contributes to the discovery of novel MAO inhibitors, which may be useful in the treatment for disorders such as Parkinson's disease, depressive illness, congestive heart failure and cancer. PMID:26684482

  2. The natural product cucurbitacin E inhibits depolymerization of actin filaments

    PubMed Central

    Sörensen, Pia M.; Iacob, Roxana E.; Fritzsche, Marco; Engen, John R.; Brieher, William M.; Charras, Guillaume; Eggert, Ulrike S.

    2012-01-01

    Although small molecule actin modulators have been widely used as research tools, only one cell permeable small molecule inhibitor of actin depolymerization (jasplakinolide) is commercially available. We report that the natural product cucurbitacin E inhibits actin depolymerization and show that its mechanism of action is different from jasplakinolide. In assays using pure fluorescently labeled actin, cucurbitacin E specifically affected depolymerization without affecting polymerization. It inhibited actin depolymerization at sub-stoichiometric concentrations up to 1:6 cucurbitacin:actin E. Cucurbitacin E specifically binds to filamentous actin (F-actin) forming a covalent bond at residue Cys257, but not to monomeric actin (G-actin). Based on its compatibility with phalloidin staining, we show that cucurbitacin E occupies a different binding site on actin filaments. Using loss of fluorescence after localized photoactivation, we found that cucurbitacin E inhibited actin depolymerization in live cells. Cucurbitacin E is a widely available plant-derived natural product, making it a useful tool to study actin dynamics in cells and actin-based processes such as cytokinesis. PMID:22724897

  3. Total Synthesis of Natural Products Using Hypervalent Iodine Reagents

    NASA Astrophysics Data System (ADS)

    Maertens, Gaetan; L'homme, Chloe; Canesi, Sylvain

    2014-12-01

    We present a review of natural product syntheses accomplished in our laboratory during the last five years. Each synthetic route features a phenol dearomatization promoted by an environmentally benign hypervalent iodine reagent. The dearomatizations demonstrate the “aromatic ring umpolung” concept, and involve stereoselective remodeling of the inert unsaturations of a phenol into a highly functionalized key intermediate that may contain a quaternary carbon center and a prochiral dienone system. Several new oxidative strategies were employed, including transpositions (1,3-alkyl shift and Prins-pinacol), a polycyclization, an ipso rearrangement, and direct nucleophilic additions at the phenol para position. Several alkaloids, heterocyclic compounds, and a polycyclic core have been achieved, including sceletenone (a serotonin reuptake inhibitor), acetylaspidoalbidine (an antitumor agent), fortucine (antiviral and antitumor), erysotramidine (curare-like effect), platensimycin (an antibiotic), and the main core of a kaurane diterpene (immunosuppressive agent and stimulator of apoptosis). These concise and in some cases enantioselective syntheses effectively demonstrate the importance of hypervalent iodine reagents in the total synthesis of bioactive natural products.

  4. Total synthesis of natural products using hypervalent iodine reagents

    PubMed Central

    Maertens, Gaëtan; L'Homme, Chloé; Canesi, Sylvain

    2014-01-01

    We present a review of natural product syntheses accomplished in our laboratory during the last 5 years. Each synthetic route features a phenol dearomatization promoted by an environmentally benign hypervalent iodine reagent. The dearomatizations demonstrate the “aromatic ring umpolung” concept, and involve stereoselective remodeling of the inert unsaturations of a phenol into a highly functionalized key intermediate that may contain a quaternary carbon center and a prochiral dienone system. Several new oxidative strategies were employed, including transpositions (1,3-alkyl shift and Prins-pinacol), a polycyclization, an ipso rearrangement, and direct nucleophilic additions at the phenol para position. Several alkaloids, heterocyclic compounds, and a polycyclic core have been achieved, including sceletenone (a serotonin reuptake inhibitor), acetylaspidoalbidine (an antitumor agent), fortucine (antiviral and antitumor), erysotramidine (curare-like effect), platensimycin (an antibiotic), and the main core of a kaurane diterpene (immunosuppressive agent and stimulator of apoptosis). These concise and in some cases enantioselective syntheses effectively demonstrate the importance of hypervalent iodine reagents in the total synthesis of bioactive natural products. PMID:25601909

  5. Microbial production of natural raspberry ketone.

    PubMed

    Beekwilder, Jules; van der Meer, Ingrid M; Sibbesen, Ole; Broekgaarden, Mans; Qvist, Ingmar; Mikkelsen, Joern D; Hall, Robert D

    2007-10-01

    Raspberry ketone is an important compound for the flavour industry. It is frequently used in products such as soft drinks, sweets, puddings and ice creams. The compound can be produced by organic synthesis. Demand for "natural" raspberry ketone is growing considerably. However, this product is extremely expensive. Consequently, there is a remaining desire to better understand how raspberry ketone is synthesized in vivo, and which genes and enzymes are involved. With this information we will then be in a better position to design alternative production strategies such as microbial fermentation. This article focuses on the identification and application of genes potentially linked to raspberry ketone synthesis. We have isolated candidate genes from both raspberry and other plants, and these have been introduced into bacterial and yeast expression systems. Conditions have been determined that result in significant levels of raspberry ketone, up to 5 mg/L. These results therefore lay a strong foundation for a potentially renewable source of "natural" flavour compounds making use of plant genes. PMID:17722151

  6. Phylogenetic Approaches to Natural Product Structure Prediction

    PubMed Central

    Ziemert, Nadine; Jensen, Paul R.

    2015-01-01

    Phylogenetics is the study of the evolutionary relatedness among groups of organisms. Molecular phylogenetics uses sequence data to infer these relationships for both organisms and the genes they maintain. With the large amount of publicly available sequence data, phylogenetic inference has become increasingly important in all fields of biology. In the case of natural product research, phylogenetic relationships are proving to be highly informative in terms of delineating the architecture and function of the genes involved in secondary metabolite biosynthesis. Polyketide synthases and nonribosomal peptide synthetases provide model examples in which individual domain phylogenies display different predictive capacities, resolving features ranging from substrate specificity to structural motifs associated with the final metabolic product. This chapter provides examples in which phylogeny has proven effective in terms of predicting functional or structural aspects of secondary metabolism. The basics of how to build a reliable phylogenetic tree are explained along with information about programs and tools that can be used for this purpose. Furthermore, it introduces the Natural Product Domain Seeker, a recently developed Web tool that employs phylogenetic logic to classify ketosynthase and condensation domains based on established enzyme architecture and biochemical function. PMID:23084938

  7. Scaffold Diversity Inspired by the Natural Product Evodiamine: Discovery of Highly Potent and Multitargeting Antitumor Agents.

    PubMed

    Wang, Shengzheng; Fang, Kun; Dong, Guoqiang; Chen, Shuqiang; Liu, Na; Miao, Zhenyuan; Yao, Jianzhong; Li, Jian; Zhang, Wannian; Sheng, Chunquan

    2015-08-27

    A critical question in natural product-based drug discovery is how to translate the product into drug-like molecules with optimal pharmacological properties. The generation of natural product-inspired scaffold diversity is an effective but challenging strategy to investigate the broader chemical space and identify promising drug leads. Extending our efforts to the natural product evodiamine, a diverse library containing 11 evodiamine-inspired novel scaffolds and their derivatives were designed and synthesized. Most of them showed good to excellent antitumor activity against various human cancer cell lines. In particular, 3-chloro-10-hydroxyl thio-evodiamine (66c) showed excellent in vitro and in vivo antitumor efficacy with good tolerability and low toxicity. Antitumor mechanism and target profiling studies indicate that compound 66c is the first-in-class triple topoisomerase I/topoisomerase II/tubulin inhibitor. Overall, this study provided an effective strategy for natural product-based drug discovery. PMID:26226379

  8. Prevention of microbial communities: novel approaches based natural products.

    PubMed

    Mogosanu, George D; Grumezescu, Alexandru M; Huang, Keng-Shiang; Bejenaru, Ludovic E; Bejenaru, Cornelia

    2015-01-01

    Firmly attached to different living or non-living, solid or fluid surfaces rich in nutrients and moisture, microbial biofilm is a matter of great interest due to its major importance for the healthcare community. Depending on common strategies such as mutual protection and hibernation (quiescent bacteria), the resistance, survival and virulence of microbial communities have large implications for human pathology, clinical environment and biomedical devices. The microbial biofilm is continuously changing, stimulating inflammation, increasing vascular permeability and preventing the action of macrophages. About 80% of human infections affecting the gastrointestinal, genitourinary and respiratory systems, oral mucosa and teeth, eyes, middle ear and skin are caused by biofilm-associated microorganisms. Therefore, the search for modern strategies is even more important as microbial biofilms resistant to conventional antibiotics, antiseptics and disinfectants are involved in the frequent treatment failures of some chronic inflammatory diseases and wounds. Natural products containing secondary metabolites, such as aromatic compounds, sulphurated derivatives, terpenoids (essential oils) and alkaloids as quorum-sensing inhibitors and biofilm disruptors, are promising alternatives for the prophylaxis and treatment of chronic infections. Surface modification of medical devices with non-polar functionalized nanoparticles stabilizes the natural compounds antibiofilm activity and inhibits microbial adhesion and biofilm formation and growth for a longer period of time. In this regard, an interdisciplinary approach is needed due to the large number of natural derivatives alone or in combination with biocompatible and biodegradable micro-/ nano-engineered materials. PMID:25594287

  9. Dithiolopyrrolone Natural Products: Isolation, Synthesis and Biosynthesis

    PubMed Central

    Qin, Zhiwei; Huang, Sheng; Yu, Yi; Deng, Hai

    2013-01-01

    Dithiolopyrrolones are a class of antibiotics that possess the unique pyrrolinonodithiole (4H-[1,2] dithiolo [4,3-b] pyrrol-5-one) skeleton linked to two variable acyl groups. To date, there are approximately 30 naturally occurring dithiolopyrrolone compounds, including holomycin, thiolutin, and aureothricin, and more recently thiomarinols, a unique class of hybrid marine bacterial natural products containing a dithiolopyrrolone framework linked by an amide bridge with an 8-hydroxyoctanoyl chain linked to a monic acid. Generally, dithiolopyrrolone antibiotics have broad-spectrum antibacterial activity against various microorganisms, including Gram-positive and Gram-negative bacteria, and even parasites. Holomycin appeared to be active against rifamycin-resistant bacteria and also inhibit the growth of the clinical pathogen methicillin-resistant Staphylococcus aureus N315. Its mode of action is believed to inhibit RNA synthesis although the exact mechanism has yet to be established in vitro. A recent work demonstrated that the fish pathogen Yersinia ruckeri employs an RNA methyltransferase for self-resistance during the holomycin production. Moreover, some dithiolopyrrolone derivatives have demonstrated promising antitumor activities. The biosynthetic gene clusters of holomycin have recently been identified in S. clavuligerus and characterized biochemically and genetically. The biosynthetic gene cluster of thiomarinol was also identified from the marine bacterium Pseudoalteromonas sp. SANK 73390, which was uniquely encoded by two independent pathways for pseudomonic acid and pyrrothine in a novel plasmid. The aim of this review is to give an overview about the isolations, characterizations, synthesis, biosynthesis, bioactivities and mode of action of this unique family of dithiolopyrrolone natural products, focusing on the period from 1940s until now. PMID:24141227

  10. A natural substrate-based fluorescence assay for inhibitor screening on diacylglycerol lipase α

    PubMed Central

    van der Wel, Tom; Janssen, Freek J.; Baggelaar, Marc P.; Deng, Hui; den Dulk, Hans; Overkleeft, Herman S.; van der Stelt, Mario

    2015-01-01

    The endocannabinoid 2-arachidonoylglycerol (2-AG) is predominantly biosynthesized by sn-1-diacylglycerol lipase α (DAGL-α) in the CNS. Selective inhibitors of DAGL-α will provide valuable insights in the role of 2-AG in endocannabinoid signaling processes and are potential therapeutics for the treatment of obesity and neurodegenerative diseases. Here, we describe the development of a natural substrate-based fluorescence assay for DAGL-α, using a coupled enzyme approach. The continuous setup of our assay allows monitoring of DAGL-α activity in real-time and in a 96-well plate format. This constitutes a major improvement to the currently available radiometric and LC/MS-based methods, which can be executed only in low-throughput formats. In addition, our assay circumvents the use of radioactive material. We demonstrate that our assay can be used to screen inhibitors of DAGL-α activity, using 1-stearoyl-2-arachidonoyl-sn-glycerol as the physiologically relevant natural substrate of DAGL-α. Furthermore, our method can be employed to measure DAGL activity and inhibition in the mouse brain membrane proteome. Consequently, our assay should serve as a valuable tool for rapid hit validation and lead optimization of DAGL-α inhibitors. PMID:25684760

  11. Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains.

    PubMed

    Rezaei Araghi, Raheleh; Ryan, Jeremy A; Letai, Anthony; Keating, Amy E

    2016-05-20

    Alpha helices form a critical part of the binding interface for many protein-protein interactions, and chemically stabilized synthetic helical peptides can be effective inhibitors of such helix-mediated complexes. In particular, hydrocarbon stapling of peptides to generate constrained helices can improve binding affinity and other peptide properties, but determining the best stapled peptide variant often requires laborious trial and error. Here, we describe the rapid discovery and optimization of a stapled-helix peptide that binds to Mcl-1, an antiapoptotic protein that is overexpressed in many chemoresistant cancers. To accelerate discovery, we developed a peptide library synthesis and screening scheme capable of identifying subtle affinity differences among Mcl-1-binding stapled peptides. We used our method to sample combinations of non-natural amino-acid substitutions that we introduced into Mcl-1 inhibitors in the context of a fixed helix-stabilizing hydrocarbon staple that increased peptide helical content and reduced proteolysis. Peptides discovered in our screen contained surprising substitutions at sites that are conserved in natural binding partners. Library-identified peptide M3d is the most potent molecule yet tested for selectively triggering mitochondrial permeabilization in Mcl-1 dependent cell lines. Our library approach for optimizing helical peptide inhibitors can be readily applied to the study of other biomedically important targets. PMID:26854535

  12. P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review

    PubMed Central

    Abdallah, Hossam M.; Al-Abd, Ahmed M.; El-Dine, Riham Salah; El-Halawany, Ali M.

    2014-01-01

    Resistance of solid tumors to treatment is significantly attributed to pharmacokinetic reasons at both cellular and multi-cellular levels. Anticancer agent must be bio-available at the site of action in a cytotoxic concentration to exert its proposed activity. P-glycoprotein (P-gp) is a member of the ATP-dependent membrane transport proteins; it is known to pump substrates out of cells in ATP-dependent mechanism. The over-expression of P-gp in tumor cells reduces the intracellular drug concentrations, which decreases the cytotoxicity of a broad spectrum of antitumor drugs. Accordingly, P-gp inhibitors/blockers are potential enhancer for the cellular bioavailability of several clinically important anticancer drugs such as, anthracyclines, taxanes, vinca alkaloids, and podophyllotoxins. Besides several chemically synthesized P-gp inhibitors/blockers, some naturally occurring compounds and plant extracts were reported for their modulation of multidrug resistance; however, this review will focus only on major classes of naturally occurring inhibitors viz., flavonoids, coumarins, terpenoids, alkaloids and saponins. PMID:25685543

  13. P-glycoprotein inhibitors of natural origin as potential tumor chemo-sensitizers: A review.

    PubMed

    Abdallah, Hossam M; Al-Abd, Ahmed M; El-Dine, Riham Salah; El-Halawany, Ali M

    2015-01-01

    Resistance of solid tumors to treatment is significantly attributed to pharmacokinetic reasons at both cellular and multi-cellular levels. Anticancer agent must be bio-available at the site of action in a cytotoxic concentration to exert its proposed activity. P-glycoprotein (P-gp) is a member of the ATP-dependent membrane transport proteins; it is known to pump substrates out of cells in ATP-dependent mechanism. The over-expression of P-gp in tumor cells reduces the intracellular drug concentrations, which decreases the cytotoxicity of a broad spectrum of antitumor drugs. Accordingly, P-gp inhibitors/blockers are potential enhancer for the cellular bioavailability of several clinically important anticancer drugs such as, anthracyclines, taxanes, vinca alkaloids, and podophyllotoxins. Besides several chemically synthesized P-gp inhibitors/blockers, some naturally occurring compounds and plant extracts were reported for their modulation of multidrug resistance; however, this review will focus only on major classes of naturally occurring inhibitors viz., flavonoids, coumarins, terpenoids, alkaloids and saponins. PMID:25685543

  14. [The interactions between natural products and OATP1B1].

    PubMed

    Shi, Mei-zhi; Liu, Yu; Bian, Jia-lin; Jin, Meng; Gui, Chun-shan

    2015-07-01

    Organic anion transporting polypeptide 1B1 (OATP1B1) is an important liver-specific uptake transporter, which mediates transport of numerous endogenous substances and drugs from blood into hepatocytes. To identify and investigate potential modulators of OATP1B1 from natural products, the effect of 21 frequently used natural compounds and extracts on OATP1B1-mediated fluorescein methotrexate transport was studied by using Chinese hamster ovary cells stably expressing OATP1B1 (CHO-OATP1B1) in 96-well plates. This method could be used for the screening of large compound libraries. Our studies showed that some flavonoids (e.g., quercetin, quercitrin, rutin, chrysanthemum flavonoids and mulberrin) and triterpenoids (e.g., glycyrrhetinic acid and glycyrrhizic acid) were inhibitors of OATP1B1 with IC50 values less than 16 µmol · L(-1). The IC50 value of glycyrrhetinic acid on OATP1B1 was comparable to its blood concentration in clinics, indicating an OATPlB1-mediated drug-drug interaction could occur. Structure-activity relationship analysis showed that flavonoids had much higher inhibitory activity than their glycosides. Furthermore, the type and length of saccharides had a significant effect on their activity. In addition, we used OATP1B1 substrates fluvastatin and rosuvastatin as probe drugs to investigate the substrate-dependent effect of several natural compounds on the function of OATP1B1 in vitro. Our results demonstrated that the effect of these natural products on the function of OATPlB1 was substrate-dependent. In summary, this study would be conducive to predicting and avoiding potential OATP1B1-mediated drug-drug and drug-food interactions and thus provide the experimental basis and guidance for rational drug use. PMID:26552146

  15. Natural products from microbes associated with insects

    PubMed Central

    Guo, Huijuan; Rischer, Maja; Poulsen, Michael

    2016-01-01

    Summary Here we review discoveries of secondary metabolites from microbes associated with insects. We mainly focus on natural products, where the ecological role has been at least partially elucidated, and/or the pharmaceutical properties evaluated, and on compounds with unique structural features. We demonstrate that the exploration of specific microbial–host interactions, in combination with multidisciplinary dereplication processes, has emerged as a successful strategy to identify novel chemical entities and to shed light on the ecology and evolution of defensive associations. PMID:26977191

  16. Natural products from microbes associated with insects.

    PubMed

    Beemelmanns, Christine; Guo, Huijuan; Rischer, Maja; Poulsen, Michael

    2016-01-01

    Here we review discoveries of secondary metabolites from microbes associated with insects. We mainly focus on natural products, where the ecological role has been at least partially elucidated, and/or the pharmaceutical properties evaluated, and on compounds with unique structural features. We demonstrate that the exploration of specific microbial-host interactions, in combination with multidisciplinary dereplication processes, has emerged as a successful strategy to identify novel chemical entities and to shed light on the ecology and evolution of defensive associations. PMID:26977191

  17. The chemistry of isoindole natural products

    PubMed Central

    Speck, Klaus

    2013-01-01

    Summary This review highlights the chemical and biological aspects of natural products containing an oxidized or reduced isoindole skeleton. This motif is found in its intact or modified form in indolocarbazoles, macrocyclic polyketides (cytochalasan alkaloids), the aporhoeadane alkaloids, meroterpenoids from Stachybotrys species and anthraquinone-type alkaloids. Concerning their biological activity, molecular structure and synthesis, we have limited this review to the most inspiring examples. Within different congeners, we have selected a few members and discussed the synthetic routes in more detail. The putative biosynthetic pathways of the presented isoindole alkaloids are described as well. PMID:24204418

  18. Multimodular biocatalysts for natural product assembly

    NASA Astrophysics Data System (ADS)

    Schwarzer, Dirk; Marahiel, Mohamed A.

    2001-03-01

    Nonribosomal peptides and polyketides represent a large class of natural products that show an extreme structural diversity and broad pharmacological relevance. They are synthesized from simple building blocks such as amino or carboxy acids and malonate derivatives on multimodular enzymes called nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), respectively. Although utilizing different substrates, NRPSs and PKSs show striking similarities in the modular architecture of their catalytic domains and product assembly-line mechanism. Among these compounds are well known antibiotics (penicillin, vancomycin and erythromycin) as well as potent immunosuppressive agents (cyclosporin, rapamycin and FK 506). This review focuses on the modular organization of NRPSs, PKSs and mixed NRPS/PKS systems and how modules and domains that build up the biosynthetic templates can be exploited for the rational design of recombinant enzymes capable of synthesizing novel compounds.

  19. Fungal natural products in research and development.

    PubMed

    Schueffler, Anja; Anke, Timm

    2014-10-01

    To date approximately 100 000 fungal species are known although far more than one million are expected. The variety of species and the diversity of their habitats, some of them less exploited, allow the conclusion that fungi continue to be a rich source of new metabolites. Besides the conventional fungal isolates, an increasing interest in endophytic and in marine-derived fungi has been noticed. In addition new screening strategies based on innovative chemical, biological, and genetic approaches have led to novel fungal metabolites in recent years. The present review focuses on new fungal natural products published from 2009 to 2013 highlighting the originality of the structures and their biological potential. Furthermore synthetic products based on fungal metabolites as well as new developments in the uses or the biological activity of known compounds or new derivatives are discussed. PMID:25122538

  20. Synthetic biology of fungal natural products

    PubMed Central

    Mattern, Derek J.; Valiante, Vito; Unkles, Shiela E.; Brakhage, Axel A.

    2015-01-01

    Synthetic biology is an ever-expanding field in science, also encompassing the research area of fungal natural product (NP) discovery and production. Until now, different aspects of synthetic biology have been covered in fungal NP studies from the manipulation of different regulatory elements and heterologous expression of biosynthetic pathways to the engineering of different multidomain biosynthetic enzymes such as polyketide synthases or non-ribosomal peptide synthetases. The following review will cover some of the exemplary studies of synthetic biology in filamentous fungi showing the capacity of these eukaryotes to be used as model organisms in the field. From the vast array of different NPs produced to the ease for genetic manipulation, filamentous fungi have proven to be an invaluable source for the further development of synthetic biology tools. PMID:26284053

  1. Plant cell culture strategies for the production of natural products

    PubMed Central

    Ochoa-Villarreal, Marisol; Howat, Susan; Hong, SunMi; Jang, Mi Ok; Jin, Young-Woo; Lee, Eun-Kyong; Loake, Gary J.

    2016-01-01

    Plants have evolved a vast chemical cornucopia to support their sessile lifestyles. Man has exploited this natural resource since Neolithic times and currently plant-derived chemicals are exploited for a myriad of applications. However, plant sources of most high-value natural products (NPs) are not domesticated and therefore their production cannot be undertaken on an agricultural scale. Further, these plant species are often slow growing, their populations limiting, the concentration of the target molecule highly variable and routinely present at extremely low concentrations. Plant cell and organ culture constitutes a sustainable, controllable and environmentally friendly tool for the industrial production of plant NPs. Further, advances in cell line selection, biotransformation, product secretion, cell permeabilisation, extraction and scale-up, among others, are driving increases in plant NP yields. However, there remain significant obstacles to the commercial synthesis of high-value chemicals from these sources. The relatively recent isolation, culturing and characterisation of cambial meristematic cells (CMCs), provides an emerging platform to circumvent many of these potential difficulties. [BMB Reports 2016; 49(3): 149-158] PMID:26698871

  2. Natural cysteine protease inhibitors in protozoa: Fifteen years of the chagasin family.

    PubMed

    Costa, Tatiana F R; Lima, Ana Paula C A

    2016-03-01

    Chagasin-type inhibitors comprise natural inhibitors of papain-like cysteine proteases that are distributed among Protist, Bacteria and Archaea. Chagasin was identified in the pathogenic protozoa Trypanosoma cruzi as an approximately 11 kDa protein that is a tight-binding and highly thermostable inhibitor of papain, cysteine cathepsins and endogenous parasite cysteine proteases. It displays an Imunoglobulin-like fold with three exposed loops to one side of the molecule, where amino acid residues present in conserved motifs at the tips of each loop contact target proteases. Differently from cystatins, the loop 2 of chagasin enters the active-site cleft, making direct contact with the catalytic residues, while loops 4 and 6 embrace the enzyme from the sides. Orthologues of chagasin are named Inhibitors of Cysteine Peptidases (ICP), and share conserved overall tri-dimensional structure and mode of binding to proteases. ICPs are tentatively distributed in three families: in family I42 are grouped chagasin-type inhibitors that share conserved residues at the exposed loops; family I71 contains Plasmodium ICPs, which are large proteins having a chagasin-like domain at the C-terminus, with lower similarity to chagasin in the conserved motif at loop 2; family I81 contains Toxoplasma ICP. Recombinant ICPs tested so far can inactivate protozoa cathepsin-like proteases and their mammalian counterparts. Studies on their biological roles were carried out in a few species, mainly using transgenic protozoa, and the conclusions vary. However, in all cases, alterations in the levels of expression of chagasin/ICPs led to substantial changes in one or more steps of parasite biology, with higher incidence in influencing their interaction with the hosts. We will cover most of the findings on chagasin/ICP structural and functional properties and overview the current knowledge on their roles in protozoa. PMID:26546840

  3. Natural AChE Inhibitors from Plants and their Contribution to Alzheimer’s Disease Therapy

    PubMed Central

    Murray, Ana Paula; Faraoni, María Belén; Castro, María Julia; Alza, Natalia Paola; Cavallaro, Valeria

    2013-01-01

    As acetylcholinesterase (AChE) inhibitors are an important therapeutic strategy in Alzheimer’s disease, efforts are being made in search of new molecules with anti-AChE activity. The fact that naturally-occurring compounds from plants are considered to be a potential source of new inhibitors has led to the discovery of an important number of secondary metabolites and plant extracts with the ability of inhibiting the enzyme AChE, which, according to the cholinergic hypothesis, increases the levels of the neurotransmitter acetylcholine in the brain, thus improving cholinergic functions in patients with Alzheimer’s disease and alleviating the symptoms of this neurological disorder. This review summarizes a total of 128 studies which correspond to the most relevant research work published during 2006-2012 (1st semester) on plant-derived compounds, plant extracts and essential oils found to elicit AChE inhibition. PMID:24381530

  4. Natural Products: Insights into Leishmaniasis Inflammatory Response

    PubMed Central

    Rodrigues, Igor A.; Mazotto, Ana Maria; Cardoso, Verônica; Alves, Renan L.; Amaral, Ana Claudia F.; Silva, Jefferson Rocha de Andrade; Pinheiro, Anderson S.; Vermelho, Alane B.

    2015-01-01

    Leishmaniasis is a vector-borne disease that affects several populations worldwide, against which there are no vaccines available and the chemotherapy is highly toxic. Depending on the species causing the infection, the disease is characterized by commitment of tissues, including the skin, mucous membranes, and internal organs. Despite the relevance of host inflammatory mediators on parasite burden control, Leishmania and host immune cells interaction may generate an exacerbated proinflammatory response that plays an important role in the development of leishmaniasis clinical manifestations. Plant-derived natural products have been recognized as bioactive agents with several properties, including anti-protozoal and anti-inflammatory activities. The present review focuses on the antileishmanial activity of plant-derived natural products that are able to modulate the inflammatory response in vitro and in vivo. The capability of crude extracts and some isolated substances in promoting an anti-inflammatory response during Leishmania infection may be used as part of an effective strategy to fight the disease. PMID:26538837

  5. Amorfrutins are potent antidiabetic dietary natural products.

    PubMed

    Weidner, Christopher; de Groot, Jens C; Prasad, Aman; Freiwald, Anja; Quedenau, Claudia; Kliem, Magdalena; Witzke, Annabell; Kodelja, Vitam; Han, Chung-Ting; Giegold, Sascha; Baumann, Matthias; Klebl, Bert; Siems, Karsten; Müller-Kuhrt, Lutz; Schürmann, Annette; Schüler, Rita; Pfeiffer, Andreas F H; Schroeder, Frank C; Büssow, Konrad; Sauer, Sascha

    2012-05-01

    Given worldwide increases in the incidence of obesity and type 2 diabetes, new strategies for preventing and treating metabolic diseases are needed. The nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma) plays a central role in lipid and glucose metabolism; however, current PPARγ-targeting drugs are characterized by undesirable side effects. Natural products from edible biomaterial provide a structurally diverse resource to alleviate complex disorders via tailored nutritional intervention. We identified a family of natural products, the amorfrutins, from edible parts of two legumes, Glycyrrhiza foetida and Amorpha fruticosa, as structurally new and powerful antidiabetics with unprecedented effects for a dietary molecule. Amorfrutins bind to and activate PPARγ, which results in selective gene expression and physiological profiles markedly different from activation by current synthetic PPARγ drugs. In diet-induced obese and db/db mice, amorfrutin treatment strongly improves insulin resistance and other metabolic and inflammatory parameters without concomitant increase of fat storage or other unwanted side effects such as hepatoxicity. These results show that selective PPARγ-activation by diet-derived ligands may constitute a promising approach to combat metabolic disease. PMID:22509006

  6. Natural product synthesis at the interface of chemistry and biology

    PubMed Central

    2014-01-01

    Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences. PMID:25043880

  7. CXCL14 is a natural inhibitor of the CXCL12-CXCR4 signaling axis.

    PubMed

    Tanegashima, Kosuke; Suzuki, Kenji; Nakayama, Yuki; Tsuji, Kohei; Shigenaga, Akira; Otaka, Akira; Hara, Takahiko

    2013-06-19

    Activation of the CXCL12-CXCR4 pathway is crucial for the migration of hematopoietic stem cells, various immune cells, and malignant tumor cells. Here, we show that another CXC chemokine, CXCL14, specifically binds to CXCR4 with high affinity and inhibits the CXCL12-mediated chemotaxis of human leukemia-derived cell lines and CD34(+) hematopoietic progenitor cells. Thus, CXCL14 functions as a natural inhibitor of CXCL12. Our observations suggest that CXCL14 represents, along with CXCR7, molecules that co-evolved with the CXCL12-CXCR4 axis to modulate important physiological processes in development, stem cell maintenance, and immune responses. PMID:23669361

  8. Towards the elusive structure of kotalanol, a naturally occurring glucosidase inhibitor.

    PubMed

    Mohan, Sankar; Pinto, B Mario

    2010-04-01

    This Highlight describes the detailed approach used to determine the absolute stereochemistry of the stereogenic centers in the acyclic side chain of kotalanol, a naturally occurring glucosidase inhibitor isolated from the plant Salacia reticulata. The plant extract itself is used in Ayurvedic medicine for the treatment of Type 2 diabetes. We highlight the syntheses of proposed candidates based on structure-activity relationships, the total synthesis of kotalanol, and crystallographic studies of kotalanol and its de-O-sulfonated derivative complexed with recombinant human maltase glucoamylase (MGA), a critical intestinal glucosidase involved in the breakdown of glucose oligomers into glucose. PMID:20336233

  9. α-glucosidase inhibitors from plants: A natural approach to treat diabetes

    PubMed Central

    Kumar, Sunil; Narwal, Smita; Kumar, Vipin; Prakash, Om

    2011-01-01

    Diabetes is a common metabolic disease characterized by abnormally high plasma glucose levels, leading to major complications, such as diabetic neuropathy, retinopathy, and cardiovascular diseases. One of the effective managements of diabetes mellitus, in particular, non–insulin-dependent diabetes mellitus (NIDDM) to decrease postprandial hyperglycemia, is to retard the absorption of glucose by inhibition of carbohydrate hydrolyzing enzymes, such as α-glucosidase and α-amylase, in the digestive organs. α-Glucosidase is the key enzyme catalyzing the final step in the digestive process of carbohydrates. Hence, α-glucosidase inhibitors can retard the liberation of d-glucose from dietary complex carbohydrates and delay glucose absorption, resulting in reduced postprandial plasma glucose levels and suppression of postprandial hyperglycemia. In recent years, many efforts have been made to identify effective α-glucosidase inhibitors from natural sources in order to develop a physiologic functional food or lead compounds for use against diabetes. Many α-glucosidase inhibitors that are phytoconstituents, such as flavonoids, alkaloids, terpenoids,anthocyanins, glycosides, phenolic compounds, and so on, have been isolated from plants. In the present review, we focus on the constituents isolated from different plants having α-glucosidase inhibitory potency along with IC50 values. PMID:22096315

  10. In Silico Discovery of Potential VEGFR-2 Inhibitors from Natural Derivatives for Anti-Angiogenesis Therapy

    PubMed Central

    Li, Jing; Zhou, Nan; Luo, Kun; Zhang, Wei; Li, Xinru; Wu, Chuanfang; Bao, Jinku

    2014-01-01

    Angiogenesis is the growth of new capillaries from existing blood vessels that supply oxygen and nutrients and provide gateways for immune surveillance. Abnormal vessel growth in term of excessive angiogenesis is a hallmark of cancer, inflammatory and eye diseases. VEGFR-2 (vascular endothelial growth factor receptor 2) dominating the process of angiogenesis has led to approval of therapeutic inhibitors and is becoming a promising target for anti-angiogenic drugs. Notwithstanding these successes, the clinical use of current VEGFR-2 blockers is more challenging than anticipated. Taking axitinib as a reference drug, in our study we found three potent VEGFR-2 inhibitors (ZINC08254217, ZINC08254138, and ZINC03838680) from natural derivatives. Each of the three inhibitors acquired a better grid score than axitinib (−62.11) when docked to VEGFR-2. Molecular dynamics simulations demonstrated that ZINC08254217– and ZINC08254138–VEGFR-2 complexes were more stable than axitinib. Similar to bind free energy for axitinib (−54.68 kcal/mol), such for ZINC03838680, ZINC08254217, and ZINC08254138 was −49.37, −43.32, and −32.73 kcal/mol respectively. These results suggested these three compounds could be candidate drugs against angiogenesis, with comparable VEGFR-2 binding affinity of axitinib. Hence findings in our study are able to provide valuable information on discovery of effective anti-angiogenesis therapy. PMID:25216334

  11. Historical variation of structural novelty in a natural product library.

    PubMed

    Kong, De-Xin; Guo, Ming-Yue; Xiao, Zhi-Hong; Chen, Ling-Ling; Zhang, Hong-Yu

    2011-11-01

    To evaluate the potential of natural products as novel structure suppliers, a historical analysis was performed on the structural novelty of a natural product library, viz., the Chapman & Hall/CRC Dictionary of Natural Products. The results show that although the unexplored natural product universe is still ample, it is more and more difficult to find novel agents from nature, with the discovery probability of novel structures and scaffolds being lower than 50% in the near future, which mainly results from the intrinsic redundancy of natural products and, thus, is unlikely to be reversed merely through technical progresses. PMID:22083910

  12. Enzyme inhibitors to increase poly-3-hydroxybutyrate production by transgenic tobacco.

    PubMed

    Suzuki, Yoshikatsu; Kurano, Minoru; Arai, Yuko; Nakashita, Hideo; Doi, Yoshiharu; Usami, Ron; Horikoshi, Kohki; Yamaguchi, Isamu

    2002-12-01

    Chemical regulation of secondary-metabolite synthesis was investigated through the improvement of poly-3-hydroxybutyrate (PHB) production in transgenic tobacco plants by the use of enzyme inhibitors. Two tobacco lines, BC3 and rCAB8, that produce PHB in both the cytosol and plastids were used. An acetyl-CoA carboxylase inhibitor, D-(+)-Quizalofop-ethyl, increased PHB accumulation in both lines 2-fold. The accumulation rate of plastidial PHB in the rCAB8 line was 2.5-fold higher than that of cytosolic PHB in the BC3 line. A specific inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, mevastatin, also increased PHB accumulation but only in the BC3 line. These results indicated that chemical regulation of the native metabolic flows by the specific enzyme inhibitors increased secondary-metabolite production in the transgenic tobacco plants we used. PMID:12596845

  13. Discovering Natural Product Modulators to Overcome Multidrug Resistance in Cancer Chemotherapy

    PubMed Central

    Wu, Chung-Pu; Ohnuma, Shinobu; Ambudkar, Suresh V.

    2012-01-01

    Multidrug resistance caused by the overexpression of ABC drug transporters is a major obstacle in clinical cancer chemotherapy. For several years, it appeared that direct inhibition of ABC transporters would be the cheapest and most efficient way to combat this problem. Unfortunately, progress in finding a potent, selective inhibitor to modulate ABC transporters and restore drug sensitivity in multidrug-resistant cancer cells has been slow and challenging. Candidate drugs should ideally be selective, potent and relatively non-toxic. Many researchers in recent years have turned their attention to utilizing natural products as the building blocks for the development of the next generation of inhibitors, especially after the disappointing results obtained from inhibitors of the first three generations at the clinical trial stage. The first step is to discover natural substances (distinct from the first three generation inhibitors) that are potent, selective and relatively non-toxic in order to be used clinically. Here, we present a brief overview of the prospect of using natural products to modulate the function of ABC drug transporters clinically and their impact on human physiology and pharmacology. PMID:21118092

  14. Natural product derived immune-regulatory agents.

    PubMed

    Talmadge, James E

    2016-08-01

    We can now declare that the clinical goal of immune intervention as a therapeutic strategy for neoplastic, infectious, autoimmune and inflammatory diseases, has been achieved and in many instances obtained regulatory approval. Although, interest in and optimism for this approach has fluctuated, in the last 20years, immunotherapy has progressed from trials with crude microbial mixtures and extracts to the sophisticated use of pure cultured bacterial, synthetized active moieties identified from crude extracts, analogues therefrom and agonists and antagonists identified during screening resulting in reproducible pharmacologically active compounds with multiple mechanisms of action. Our current understanding of the mechanism of action for immunoregulatory agents contributes to the future discovery of improved strategies to use these and future immunotherapies. In this review we have identified and discussed, those drugs that have been approved and or are in clinical development as immunoregulatory agents, emphasizing those derived from or associated with natural product. PMID:26968760

  15. Natural products: a safest approach for obesity.

    PubMed

    Vasudeva, Neeru; Yadav, Neerja; Sharma, Surendra Kumar

    2012-06-01

    Obesity is recognized as a social problem, associated with serious health risks and increased mortality. Numerous trials have been conducted to find and develop new anti-obesity drugs through herbal sources to minimize adverse reactions associated with the present anti-obesity drugs. The use of natural products as medicine has been documented for hundreds of years in various traditional systems of medicines throughout the world. This review focuses on the medicinal plants such as Achyranthus aspera, Camellia sinensis, Emblica officinalis, Garcinia cambogia, Terminalia arjuna, etc., being used traditionally in Ayurvedic, Unani, Siddha and Chinese, etc., systems of medicine. The review also highlights recent reported phytochemicals such as escins, perennisosides, dioscin, gracillin, etc., and the various extracts of the plants like Nelumbo nucifera, Panax japonicas, Cichorium intybus, Cyperus rotundus, Paeonia suffruticosa, etc., which have been successfully identified for the treatment of obesity. PMID:22821661

  16. Novel Chemical Space Exploration via Natural Products

    PubMed Central

    Rosén, Josefin; Gottfries, Johan; Muresan, Sorel; Backlund, Anders; Oprea, Tudor I.

    2009-01-01

    Natural products (NPs) are a rich source of novel compound classes and new drugs. In the present study we have used the chemical space navigation tool ChemGPS-NP to evaluate the chemical space occupancy by NPs and bioactive medicinal chemistry compounds from the database WOMBAT. The two sets differ notable in coverage of chemical space, and tangible lead-like NPs were found to cover regions of chemical space that lack representation in WOMBAT. Property based similarity calculations were performed to identify NP neighbours of approved drugs. Several of the NPs revealed by this method, were confirmed to exhibit the same activity as their drug neighbours. The identification of leads from a NP starting point may prove a useful strategy for drug discovery, in the search for novel leads with unique properties. PMID:19265440

  17. Spectroscopic Characterization of a Natural Product: Anethole

    NASA Astrophysics Data System (ADS)

    Barber, Victoria P.; Newby, Josh J.

    2013-06-01

    Anethole [(E)-1-methoxy-4-(1-propenyl)benzene] is a natural product molecule that is commonly recognized as the flavor component of anise, fennel, and licorice. Early jet-cooled spectroscopy of anethole showed the existence of two possible conformations, but did not address details of the vibronic structure. Here, we report the jet-cooled, laser-induced fluorescence and single vibronic level fluorescence spectra of anethole. Analysis of the spectra confirms the existence of two rotamers in the expansion that differ by the relative orientation of the methoxy and propenyl groups. The observed vibronic activity is similar to that of styrene and indicates planar symmetry of both rotamers. Vibrational assignments of anethole are assisted by density functional theory calculations and the results are compared with the analogous motions in styrene. V. H. Grassian, E. R. Bernstein, H. V. Secor and J. I. Seeman J. Phys. Chem. {93, 3470 (1989).

  18. CO Methanation for Synthetic Natural Gas Production.

    PubMed

    Kambolis, Anastasios; Schildhauer, Tilman J; Kröcher, Oliver

    2015-01-01

    Energy from woody biomass could supplement renewable energy production towards the replacement of fossil fuels. A multi-stage process involving gasification of wood and then catalytic transformation of the producer gas to synthetic natural gas (SNG) represents progress in this direction. SNG can be transported and distributed through the existing pipeline grid, which is advantageous from an economical point of view. Therefore, CO methanation is attracting a great deal of attention and much research effort is focusing on the understanding of the process steps and its further development. This short review summarizes recent efforts at Paul Scherrer Institute on the understanding of the reaction mechanism, the catalyst deactivation, and the development of catalytic materials with benign properties for CO methanation. PMID:26598405

  19. Natural Products as a Foundation for Drug Discovery

    PubMed Central

    Beutler, John A.

    2009-01-01

    Natural products have contributed to the development of many drugs for diverse indications. While most U.S. pharmaceutical companies have reduced or eliminated their in-house natural product groups, new paradigms and new enterprises have evolved to carry on a role for natural products in the pharmaceutical industry. Many of the reasons for the decline in popularity of natural products are being addressed by the development of new techniques for screening and production. This overview aims to inform pharmacologists of current strategies and techniques that make natural products a viable strategic choice for inclusion in drug discovery programs. PMID:20161632

  20. Natural furocoumarins as inducers and inhibitors of cytochrome P450 1A1 in rat hepatocytes.

    PubMed

    Baumgart, Annette; Schmidt, Melanie; Schmitz, Hans-Joachim; Schrenk, Dieter

    2005-02-15

    Furocoumarins are natural plant constituents present in medicinal plants and in a variety of foods such as grapefruit juice. They are phototoxic and act as potent inhibitors of drug metabolism. We have investigated the interaction of four furocoumarins angelicin, bergamottin, isopimpinellin, and 8-methoxypsoralen with the expression and activity of aryl hydrocarbon receptor (AhR)-regulated CYP1A1 in rat hepatocytes in primary culture, both in the presence and absence of light. In intact hepatocytes pretreated with 2,3,7,8-tetrachlorodibenzo-p-dioxin and in microsomes isolated thereof, all furocoumarins tested acted as potent inhibitors of CYP1A1 activity bergamottin being the most potent inhibitor in microsomes with an IC(50) of 10 nM in the presence and 60 nM in the absence of light. 8-Methoxypsoralen and angelicin led to a significant induction of CYP1A1 mRNA in hepatocytes, while all furocoumarins except bergamottin increased xenobiotic-responsive element-driven reporter gene expression in transfected H4IIE rat hepatoma cells when light was excluded. Furthermore, all furocoumarins tested induced the expression of endogenous, immunoreactive CYP1A1 protein, primarily in the dark. In conclusion, our results demonstrate that individual furocoumarins present in food and medicinal plants can interfere with AhR-regulated CYP1A1 expression and activity in at least three major ways, i.e., (i) act as highly potent inhibitors of the catalytic activity of CYP1A1 both in the presence and absence of light, (ii) induce CYP1A1 gene expression in the absence of light via activation of the AhR, and (iii) induce CYP1A1 gene expression without activation of the AhR. PMID:15670584

  1. Discovery of a novel HIV-1 integrase inhibitor from natural compounds through structure based virtual screening and cell imaging.

    PubMed

    Gu, Wan-Gang; Zhang, Xuan; Ip, Denis Tsz-Ming; Yang, Liu-Meng; Zheng, Yong-Tang; Wan, David Chi-Cheong

    2014-09-17

    The interaction between HIV-1 integrase and LEDGF/P75 has been validated as a target for anti-HIV drug development. Based on the crystal structure of integrase in complex with LEDGF/P75, a library containing 80 thousand natural compounds was filtered with virtual screening. 11 hits were selected for cell based assays. One compound, 3-(1,3-benzothiazol-2-yl)-8-{[bis(2-hydroxyethyl)amino]methyl}-7-hydroxy-2H-chromen-2-one (D719) inhibited integrase nuclear translocation in cell imaging. The binding mode of D719 was analyzed with molecular simulation. The anti-HIV activity of D719 was assayed by measuring the p24 antigen production in acute infection. The structure characteristics of D719 may provide valuable information for integrase inhibitor design. PMID:25128456

  2. Urokinase and type I plasminogen activator inhibitor production by normal human hepatocytes: modulation by inflammatory agents.

    PubMed

    Busso, N; Nicodeme, E; Chesne, C; Guillouzo, A; Belin, D; Hyafil, F

    1994-07-01

    We examined the effects of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha and transforming growth factor-beta) on the plasminogen activator system (urokinase, tissue-type plasminogen activator, type 1 plasminogen activator inhibitor) in primary cultures of human hepatocytes. We show that interleukin-1 beta and tumor necrosis factor-alpha increase urokinase-type plasminogen activator production, reinforcing the concept that increased urokinase production is associated with inflammatory processes. By contrast, the same agents (i.e., interleukin-1 beta and tumor necrosis factor-alpha) do not stimulate plasminogen activator inhibitor type 1 production. This latter observation rules out hepatocytes as a major cellular source of plasmatic plasminogen activator inhibitor type 1 during acute-phase-related responses. Among the inflammatory agents used, transforming growth factor-beta was found to be the most effective modulator of both urokinase-type plasminogen activator and plasminogen activator inhibitor type 1, inducing severalfold increases of activity of urokinase-type plasminogen activator, antigen and the corresponding mRNA and increasing plasminogen activator inhibitor type 1 antigen and mRNA levels. Urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 modulation by transforming growth factor-beta may play a critical role in hepatic pathophysiology. PMID:8020888

  3. Chocolate: A Marvelous Natural Product of Chemistry

    NASA Astrophysics Data System (ADS)

    Tannenbaum, Ginger

    2004-08-01

    Chocolate is a natural product as ubiquitous as television. Of course, it is eaten, but it is also found in air fresheners, marking pens, flavoring in a multitude of products including soda pop, and as an aroma in "chocolate-dyed" T-shirts. However, most of us are completely unaware of the complex chemical reactions that take place to produce chocolate and the necessary technology that has evolved to produce chocolate and all its byproducts. Processing results in a mixture of many components, an interesting contrast to most of the simple, one-step reactions introduced at the high school level. This article is a survey of chocolate from tree to table. After a brief introduction to the history of chocolate and how and where it is grown, the manufacturing process is examined, and the chemistry is explored. A bit of the jargon used in the industry is mentioned. Cocoa butter is a significant ingredient in chocolate, and an investigation of it introduces triglycerides, fatty acids, polymorphic behavior, and molecular packing of the fats in chocolate and how they affect the tempering process. There is a brief discussion of chocolate's non-Newtonian behavior and the resulting challenges presented in the manufacturing process. See Featured Molecules Featured on the Cover

  4. Use of natural health products in children

    PubMed Central

    Pike, Andrea; Etchegary, Holly; Godwin, Marshall; McCrate, Farah; Crellin, John; Mathews, Maria; Law, Rebecca; Newhook, Leigh Anne; Kinden, Jody

    2013-01-01

    Abstract Objective To gain a more thorough understanding of why parents choose to give their children natural health products (NHPs), parents’ sources of information about NHPs, and the extent of disclosure and conversation with family doctors about the use of NHPs. Design Qualitative study. Setting Newfoundland and Labrador. Participants Parents of children who were using NHPs (N = 20). Methods Individual, semistructured interviews were carried out with parents to obtain a better understanding of the reasoning behind the use of NHPs. Key themes emerging from the qualitative data were identified according to a number of criteria, including relevance to the research objectives, frequency with which a theme was mentioned, relative importance of the themes based on the amount of text taken up to address an issue, and emphasis (eg, emphatic or emotional speech). Main findings The types of NHPs used by parents participating in this study varied, except for the use of multivitamins. In addition, use of the products themselves was variable and inconsistent. Parents reported few concerns about the use of NHPs. The most commonly reported source of information about NHPs was family and friends. Most participants had not spoken to their family doctors about the use of NHPs. Conclusion Participants considered NHPs to be “natural” and seemed to equate this assessment with safety. This might explain why these parents sought advice and information from family and friends rather than from their family doctors and often failed to disclose the use of NHPs to their children’s family doctors. PMID:23946044

  5. Influence of natural zeolite and nitrification inhibitor on organics degradation and nitrogen transformation during sludge composting.

    PubMed

    Zhang, Junya; Sui, Qianwen; Li, Kun; Chen, Meixue; Tong, Juan; Qi, Lu; Wei, Yuansong

    2016-01-01

    Sludge composting is one of the most widely used treatments for sewage sludge resource utilization. Natural zeolite and nitrification inhibitor (NI) are widely used during composting and land application for nitrogen conservation, respectively. Three composting reactors (A--the control, B--natural zeolite addition, and C--3,4-dimethylpyrazole phosphate (DMPP) addition) were established to investigate the influence of NI and natural zeolite addition on organics degradation and nitrogen transformation during sludge composting conducted at the lab scale. The results showed that, in comparison with the control, natural zeolite addition accelerated organics degradation and the maturity of sludge compost was higher, while the DMPP addition slowed down the degradation of organic matters. Meanwhile, the nitrogen transformation functional genes including those responses for nitrification (amoA and nxrA) and denitrification (narG, nirS, nirK, and nosZ) were quantified through quantitative PCR (qPCR) to investigate the effects of natural zeolites and DMPP addition on nitrogen transformation. Although no significant difference in the abundance of nitrogen transformation functional genes was observed between treatments, addition of both natural zeolite and DMPP increases the final total nitrogen content by 48.6% and 23.1%, respectively. The ability of natural zeolite for nitrogen conservation was due to the absorption of NH3 by compost, and nitrogen conservation by DMPP was achieved by the source reduction of denitrification. Besides, it was assumed that the addition of natural zeolite and DMPP may affect the activity of these genes instead of the abundance. PMID:26358216

  6. A Historical Overview of Natural Products in Drug Discovery

    PubMed Central

    Dias, Daniel A.; Urban, Sylvia; Roessner, Ute

    2012-01-01

    Historically, natural products have been used since ancient times and in folklore for the treatment of many diseases and illnesses. Classical natural product chemistry methodologies enabled a vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. Many of these natural products have gone on to become current drug candidates. This brief review aims to highlight historically significant bioactive marine and terrestrial natural products, their use in folklore and dereplication techniques to rapidly facilitate their discovery. Furthermore a discussion of how natural product chemistry has resulted in the identification of many drug candidates; the application of advanced hyphenated spectroscopic techniques to aid in their discovery, the future of natural product chemistry and finally adopting metabolomic profiling and dereplication approaches for the comprehensive study of natural product extracts will be discussed. PMID:24957513

  7. Marine Natural Products as Novel Antioxidant Prototypes

    PubMed Central

    Takamatsu, Satoshi; Hodges, Tyler W.; Rajbhandari, Ira; Gerwick, William H.; Hamann, Mark T.; Nagle, Dale G.

    2016-01-01

    Pure natural products isolated from marine sponges, algae, and cyanobacteria were examined for antioxidant activity using a 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) solution-based chemical assay and a 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) cellular-based assay. The DCFH system detects only antioxidants that penetrate cellular membranes. Potent antioxidants were identified and the results from each system compared. The algal metabolites cymopol (1), avrainvilleol (3), and fragilamide (4), and the invertebrate constituent puupehenone (5) showed strong antioxidant activity in both systems. Several compounds were active in the DPPH assay but significantly less active in the DCFH system. The green algal metabolite 7-hydroxycymopol (2) was isolated from Cymopolia barbata and its structure determined. Compound 2 was significantly less active in the DCFH system than cymopol (1). The sponge metabolites (1S)-(+)-curcuphenol (6), aaptamine (7), isoaaptamine (8), and curcudiol (9) and the cyanobacterial pigment scytonemin (10) showed strong antioxidant activity in the DPPH assay, but were relatively inactive in the DCFH system. Thus, cellular uptake dramatically affects the potential significance of antioxidants discovered using only the DPPH assay. The apparent “proantioxidants” hormothamnione A diacetate (11) and Laurencia monomer diacetate (12) require metabolic activation for antioxidant activity. Significant advantages are achieved using both a solution- and cellular-based assay to discover new antioxidants. PMID:12762791

  8. Natural Products That Target Cancer Stem Cells.

    PubMed

    Moselhy, Jim; Srinivasan, Sowmyalakshmi; Ankem, Murali K; Damodaran, Chendil

    2015-11-01

    The cancer stem cell model suggests that tumor initiation is governed by a small subset of distinct cells with stem-like character termed cancer stem cells (CSCs). CSCs possess properties of self-renewal and intrinsic survival mechanisms that contribute to resistance of tumors to most chemotherapeutic drugs. The failure to eradicate CSCs during the course of therapy is postulated to be the driving force for tumor recurrence and metastasis. Recent studies have focused on understanding the unique phenotypic properties of CSCs from various tumor types, as well as the signaling pathways that underlie self-renewal and drug resistance. Natural products (NPs) such as those derived from botanicals and food sources may modulate vital signaling pathways involved in the maintenance of CSC phenotype. The Wingless/Integrated (WNT), Hedgehog, Notch and PI3K/AKT/mTOR pathways have all been associated with quiescence and self-renewal of CSCs, as well as execution of CSC function including differentiation, multidrug resistance and metastasis. Recent studies evaluating NPs against CSC support the epidemiological evidence linking plant-based diets with reduced malignancy rates. This review covers the key aspects of NPs as modulators of CSC fate. PMID:26503998

  9. Structure and Function of Macroalgal Natural Products.

    PubMed

    Young, Ryan M; Schoenrock, Kathryn M; von Salm, Jacqueline L; Amsler, Charles D; Baker, Bill J

    2015-01-01

    Since the initial discovery of marine phyco-derived secondary metabolites in the 1950s there has been a rapid increase in the description of new algal natural products. These metabolites have multiple ecological roles as well as commercial value as potential drugs or lead compounds. With the emergence of resistance to our current arsenal of drugs as well as the development of new chemotherapies for currently untreatable diseases, new compounds must be sourced. As outlined in this chapter algae produce a diverse range of chemicals many of which have potential for the treatment of human afflictions.In this chapter we outline the classes of metabolites produced by this chemically rich group of organisms as well as their respective ecological roles in the environment. Algae are found in nearly every environment on earth, with many of these organisms possessing the ability to shape the ecosystem they inhabit. With current challenges to climate stability, understanding how these important organisms interact with their environment as well as one another might afford better insight into how they respond to a changing climate. PMID:26108497

  10. Natural products and the aging process.

    PubMed

    Ergin, Volkan; Bali, Elif Burcu; Hariry, Reza Ebrahimi; Karasu, Cimen

    2013-12-01

    Abstract Literature surveys show that the most of the research that have been conducted on the effect of herbal remedies on many tissue pathologies, including metabolic disturbances, cardiovascular decline, neurodegeneration, cataract, diabetic retinopathy and skin inflammation, all lead to an accelerated aging process. The increased carbonylation of proteins (carbonyl stress) disturbing their function has been indicated as an underlying mechanism of cellular senescence and age-related diseases. Because it is also linked to the carbonyl stress, aging chronic disease and inflammation plays an important role in understanding the clinical implications of cellular stress response and relevant markers. Greater knowledge of the molecular and cellular mechanisms involved in several pathologies associated with aging would provide a better understanding to help us to develop suitable strategies, use specific targets to mitigate the effect of human aging, prevent particularly chronic degenerative diseases and improve quality of life. However, research is lacking on the herbal compounds affecting cellular aging signaling as well as studies regarding the action mechanism(s) of natural products in prevention of the age-related disease. This review provides leads for identifying new medicinal agents or potential phytochemical drugs from plant sources for the prevention or delaying cellular aging processes and the treatment of some disorders related with accelerated body aging. PMID:25436747

  11. The impact of enzyme engineering upon natural product glycodiversification

    PubMed Central

    Williams, Gavin J; Gantt, Richard W; Thorson, Jon S

    2015-01-01

    Glycodiversification of natural products is an effective strategy for small molecule drug development. Recently, improved methods for chemo-enzymatic synthesis of glycosyl donors has spurred the characterization of natural product glycosyltransferases (GTs), revealing that the substrate specificity of many naturally occurring GTs as too stringent for use in glycodiversification. Protein engineering of natural product GTs has emerged as an attractive approach to overcome this limitation. This review highlights recent progress in the engineering/evolution of enzymes relevant to natural product glycodiversification with a particular focus upon GTs. PMID:18678278

  12. Development of potent inhibitors of pyocyanin production in Pseudomonas aeruginosa

    PubMed Central

    Miller, Laura C.; O’Loughlin, Colleen T.; Zhang, Zinan; Siryaporn, Albert; Silpe, Justin E.; Bassler, Bonnie L.; Semmelhack, Martin F.

    2015-01-01

    The development of new approaches for the treatment of antimicrobial-resistant infections is an urgent public health priority. The Pseudomonas aeruginosa pathogen, in particular, is a leading source of infection in hospital settings, with few available treatment options. In the context of an effort to develop antivirulence strategies to combat bacterial infection, we identified a series of highly effective small molecules that inhibit the production of pyocyanin, a redox-active virulence factor produced by P. aeruginosa. Interestingly, these new antagonists appear to suppress P. aeruginosa virulence factor production through a pathway that is independent of LasR and RhlR. PMID:25597392

  13. Monoterpenoid inhibitors of NO production from Paeonia suffruticosa.

    PubMed

    Ding, Liqin; Jiang, Zhihu; Liu, Yue; Chen, Lixia; Zhao, Qian; Yao, Xinsheng; Zhao, Feng; Qiu, Feng

    2012-12-01

    Three pairs of monoterpene glycosides (1-6), of which compounds 1, 3, and 4 as new compounds, together with one new monoterpene (7) were obtained from the ethanol extract of Paeonia suffruticosa Andrews. Their structures were determined on the basis of chemical methods and spectral data. On this basis, the spectral characteristics of three pairs of monoterpene glycosides were also discussed. The inhibitory effects of isolated compounds on nitric oxide (NO) production in lipopolysaccharide-activated macrophages were evaluated, and NO production was suppressed significantly by compounds 4-7. PMID:23051963

  14. Machine Learning Estimates of Natural Product Conformational Energies

    PubMed Central

    Rupp, Matthias; Bauer, Matthias R.; Wilcken, Rainer; Lange, Andreas; Reutlinger, Michael; Boeckler, Frank M.; Schneider, Gisbert

    2014-01-01

    Machine learning has been used for estimation of potential energy surfaces to speed up molecular dynamics simulations of small systems. We demonstrate that this approach is feasible for significantly larger, structurally complex molecules, taking the natural product Archazolid A, a potent inhibitor of vacuolar-type ATPase, from the myxobacterium Archangium gephyra as an example. Our model estimates energies of new conformations by exploiting information from previous calculations via Gaussian process regression. Predictive variance is used to assess whether a conformation is in the interpolation region, allowing a controlled trade-off between prediction accuracy and computational speed-up. For energies of relaxed conformations at the density functional level of theory (implicit solvent, DFT/BLYP-disp3/def2-TZVP), mean absolute errors of less than 1 kcal/mol were achieved. The study demonstrates that predictive machine learning models can be developed for structurally complex, pharmaceutically relevant compounds, potentially enabling considerable speed-ups in simulations of larger molecular structures. PMID:24453952

  15. STRATEGIES FOR THE USE OF NATURAL PRODUCTS FOR WEED MANAGEMENT

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Natural products have not been utilized as extensively for weed management as they have been for insect and plant pathogen management, but there are several notable successes such as glufosinate and the natural product-derived triketone herbicides. The two fundamental approaches to the use of natur...

  16. The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase

    PubMed Central

    Redon, Sophie; Reichenbach, Patrick; Lingner, Joachim

    2010-01-01

    Telomeres, the physical ends of eukaryotes chromosomes are transcribed into telomeric repeat containing RNA (TERRA), a large non-coding RNA of unknown function, which forms an integral part of telomeric heterochromatin. TERRA molecules resemble in sequence the telomeric DNA substrate as they contain 5′-UUAGGG-3′ repeats near their 3′-end which are complementary to the template sequence of telomerase RNA. Here we demonstrate that endogenous TERRA is bound to human telomerase in cell extracts. Using in vitro reconstituted telomerase and synthetic TERRA molecules we demonstrate that the 5′-UUAGGG-3′ repeats of TERRA base pair with the RNA template of the telomerase RNA moiety (TR). In addition TERRA contacts the telomerase reverse transcriptase (TERT) protein subunit independently of hTR. In vitro studies further demonstrate that TERRA is not used as a telomerase substrate. Instead, TERRA acts as a potent competitive inhibitor for telomeric DNA in addition to exerting an uncompetitive mode of inhibition. Our data identify TERRA as a telomerase ligand and natural direct inhibitor of human telomerase. Telomerase regulation by the telomere substrate may be mediated via its transcription. PMID:20460456

  17. Analogs of natural aminoacyl-tRNA synthetase inhibitors clear malaria in vivo.

    PubMed

    Novoa, Eva Maria; Camacho, Noelia; Tor, Anna; Wilkinson, Barrie; Moss, Steven; Marín-García, Patricia; Azcárate, Isabel G; Bautista, José M; Mirando, Adam C; Francklyn, Christopher S; Varon, Sònia; Royo, Miriam; Cortés, Alfred; Ribas de Pouplana, Lluís

    2014-12-23

    Malaria remains a major global health problem. Emerging resistance to existing antimalarial drugs drives the search for new antimalarials, and protein translation is a promising pathway to target. Here we explore the potential of the aminoacyl-tRNA synthetase (ARS) family as a source of antimalarial drug targets. First, a battery of known and novel ARS inhibitors was tested against Plasmodium falciparum cultures, and their activities were compared. Borrelidin, a natural inhibitor of threonyl-tRNA synthetase (ThrRS), stands out for its potent antimalarial effect. However, it also inhibits human ThrRS and is highly toxic to human cells. To circumvent this problem, we tested a library of bioengineered and semisynthetic borrelidin analogs for their antimalarial activity and toxicity. We found that some analogs effectively lose their toxicity against human cells while retaining a potent antiparasitic activity both in vitro and in vivo and cleared malaria from Plasmodium yoelii-infected mice, resulting in 100% mice survival rates. Our work identifies borrelidin analogs as potent, selective, and unexplored scaffolds that efficiently clear malaria both in vitro and in vivo. PMID:25489076

  18. Molecular interaction of human brain acetylcholinesterase with a natural inhibitor huperzine-B: an enzoinformatics approach.

    PubMed

    Alam, Aftab; Shaikh, Sibhghatulla; Ahmad, Syed S; Ansari, Mohammad A; Shakil, Shahnawaz; Rizvi, Syed M D; Shakil, Shazi; Imran, Mohammad; Haneef, Mohammad; Abuzenadah, Adel M; Kamal, Mohammad A

    2014-04-01

    The present study emphasizes the molecular interactions between human brain acetylcholinesterase (AChE) and the natural ligand Huperzine-B and its comparison to 'AChE-Tolserine interactions'. Docking between Huperzine-B and AChE was performed using 'Autodock4.2'. Hydrophobic interactions and hydrogen bonds both play an equally important role in the correct positioning of Huperzine-B within the 'catalytic site' of AChE to permit docking. However, docking of Tolserine to AChE is largely dominated by hydrophobic interactions. Such information may aid in the design of versatile AChE-inhibitors, and is expected to aid in safe clinical use of Huperzine-B. Scope still remains in the determination of the three-dimensional structure of AChE-Huperzine-B complex by X-ray crystallography to validate the described data. Furthermore, this study confirms that Huperzine-B is a more efficient inhibitor of human brain AChE compared to tolserine with reference to Ki and ΔG values. PMID:24059299

  19. Computational Study on New Natural Compound Inhibitors of Pyruvate Dehydrogenase Kinases

    PubMed Central

    Zhou, Xiaoli; Yu, Shanshan; Su, Jing; Sun, Liankun

    2016-01-01

    Pyruvate dehydrogenase kinases (PDKs) are key enzymes in glucose metabolism, negatively regulating pyruvate dehyrogenase complex (PDC) activity through phosphorylation. Inhibiting PDKs could upregulate PDC activity and drive cells into more aerobic metabolism. Therefore, PDKs are potential targets for metabolism related diseases, such as cancers and diabetes. In this study, a series of computer-aided virtual screening techniques were utilized to discover potential inhibitors of PDKs. Structure-based screening using Libdock was carried out following by ADME (adsorption, distribution, metabolism, excretion) and toxicity prediction. Molecular docking was used to analyze the binding mechanism between these compounds and PDKs. Molecular dynamic simulation was utilized to confirm the stability of potential compound binding. From the computational results, two novel natural coumarins compounds (ZINC12296427 and ZINC12389251) from the ZINC database were found binding to PDKs with favorable interaction energy and predicted to be non-toxic. Our study provide valuable information of PDK-coumarins binding mechanisms in PDK inhibitor-based drug discovery. PMID:26959013

  20. Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy.

    PubMed

    Dyle, Michael C; Ebert, Scott M; Cook, Daniel P; Kunkel, Steven D; Fox, Daniel K; Bongers, Kale S; Bullard, Steven A; Dierdorff, Jason M; Adams, Christopher M

    2014-05-23

    Skeletal muscle atrophy is a common and debilitating condition that lacks an effective therapy. To address this problem, we used a systems-based discovery strategy to search for a small molecule whose mRNA expression signature negatively correlates to mRNA expression signatures of human skeletal muscle atrophy. This strategy identified a natural small molecule from tomato plants, tomatidine. Using cultured skeletal myotubes from both humans and mice, we found that tomatidine stimulated mTORC1 signaling and anabolism, leading to accumulation of protein and mitochondria, and ultimately, cell growth. Furthermore, in mice, tomatidine increased skeletal muscle mTORC1 signaling, reduced skeletal muscle atrophy, enhanced recovery from skeletal muscle atrophy, stimulated skeletal muscle hypertrophy, and increased strength and exercise capacity. Collectively, these results identify tomatidine as a novel small molecule inhibitor of muscle atrophy. Tomatidine may have utility as a therapeutic agent or lead compound for skeletal muscle atrophy. PMID:24719321

  1. Exploration of natural enzyme inhibitors with hypoglycemic potentials amongst Eucalyptus Spp. by in vitro assays

    PubMed Central

    Dey, Baishakhi; Mitra, Analava; Katakam, Prakash; Singla, Rajeev K

    2014-01-01

    AIM: To investigate the presence and potency of natural enzyme inhibitors with hypoglycemic potentials amongst Eucalyptus Spp. by in vitro assays. METHODS: The leaf extracts of the three different Eucalyptus species [E. globulus (EG), E. citriodora (EC), E. camaldulensis (ECA)] were subjected to in vitro assay procedures to explore the prevalence of natural enzyme inhibitors (NEIs) after preliminary qualitative and quantitative phytochemical evaluations, to study their inhibitory actions against the enzymes like α-amylase, α-glucosidase, aldose reductase, angiotensin converting enzyme and dipeptidyl peptidase 4 playing pathogenic roles in type 2 diabetes. The antioxidant potential and total antioxidant capacity of the species were also evaluated. RESULTS: Major bioactive compounds like polyphenols (341.75 ± 3.63 to 496.85 ± 3.98) and flavonoids (4.89 ± 0.01 to 7.15 ± 0.02) were found in appreciable quantity in three species. Based on the IC50 values of the extracts under investigation, in all assays the effectivity was in the order of EG > ECA > EC. The results of the ferric reducing antioxidant power assay showed that the reducing ability of the species was also in the order of EG > ECA > EC. A strong correlation (R2 = 0.81-0.99) was found between the phenolic contents and the inhibitory potentials of the extracts against the targeted enzymes. CONCLUSION: These results show immense hypoglycemic potentiality of the Eucalyptus Spp. and a remarkable source of NEIs for a future phytotherapeutic approach in Type 2 diabetes. PMID:24748933

  2. Screening alpha-glucosidase and alpha-amylase inhibitors from natural compounds by molecular docking in silico.

    PubMed

    Jhong, Chien-Hung; Riyaphan, Jirawat; Lin, Shih-Hung; Chia, Yi-Chen; Weng, Ching-Feng

    2015-01-01

    The alpha-glucosidase inhibitor is a common oral anti-diabetic drug used for controlling carbohydrates normally converted into simple sugars and absorbed by the intestines. However, some adverse clinical effects have been observed. The present study seeks an alternative drug that can regulate the hyperglycemia by down-regulating alpha-glucosidase and alpha-amylase activity by molecular docking approach to screen the hyperglycemia antagonist against alpha-glucosidase and alpha-amylase activities from the 47 natural compounds. The docking data showed that Curcumin, 16-hydroxy-cleroda-3,13-dine-16,15-olide (16-H), Docosanol, Tetracosanol, Antroquinonol, Berberine, Catechin, Quercetin, Actinodaphnine, and Rutin from 47 natural compounds had binding ability towards alpha-amylase and alpha-glucosidase as well. Curcumin had a better biding ability of alpha-amylase than the other natural compounds. Analyzed alpha-glucosidase activity reveals natural compound inhibitors (below 0.5 mM) are Curcumin, Actinodaphnine, 16-H, Quercetin, Berberine, and Catechin when compared to the commercial drug Acarbose (3 mM). A natural compound with alpha-amylase inhibitors (below 0.5 mM) includes Curcumin, Berberine, Docosanol, 16-H, Actinodaphnine/Tetracosanol, Catechin, and Quercetin when compared to Acarbose (1 mM). When taken together, the implication is that molecular docking is a fast and effective way to screen alpha-glucosidase and alpha-amylase inhibitors as lead compounds of natural sources isolated from medicinal plants. PMID:26154585

  3. The FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer’s disease amyloid-β peptides

    PubMed Central

    Lei, Xiling; Yu, Jing; Niu, Qi; Liu, Jianhua; Fraering, Patrick C.; Wu, Fang

    2015-01-01

    Known γ-secretase inhibitors or modulators display an undesirable pharmacokinetic profile and toxicity and have therefore not been successful in clinical trials for Alzheimer’s disease (AD). So far, no compounds from natural products have been identified as direct inhibitors of γ-secretase. To search for bioactive molecules that can reduce the amount of amyloid-beta peptides (Aβ) and that have better pharmacokinetics and an improved safety profile, we completed a screen of ~400 natural products by using cell-based and cell-free γ-secretase activity assays. We identified dihydroergocristine (DHEC), a component of an FDA- (Food and Drug Administration)-approved drug, to be a direct inhibitor of γ-secretase. Micromolar concentrations of DHEC substantially reduced Aβ levels in different cell types, including a cell line derived from an AD patient. Structure-activity relationship studies implied that the key moiety for inhibiting γ-secretase is the cyclized tripeptide moiety of DHEC. A Surface Plasmon Resonance assay showed that DHEC binds directly to γ-secretase and Nicastrin, with equilibrium dissociation constants (Kd) of 25.7 nM and 9.8 μM, respectively. This study offers DHEC not only as a new chemical moiety for selectively modulating the activity of γ-secretase but also a candidate for drug repositioning in Alzheimer’s disease. PMID:26567970

  4. The FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer's disease amyloid-β peptides.

    PubMed

    Lei, Xiling; Yu, Jing; Niu, Qi; Liu, Jianhua; Fraering, Patrick C; Wu, Fang

    2015-01-01

    Known γ-secretase inhibitors or modulators display an undesirable pharmacokinetic profile and toxicity and have therefore not been successful in clinical trials for Alzheimer's disease (AD). So far, no compounds from natural products have been identified as direct inhibitors of γ-secretase. To search for bioactive molecules that can reduce the amount of amyloid-beta peptides (Aβ) and that have better pharmacokinetics and an improved safety profile, we completed a screen of ~400 natural products by using cell-based and cell-free γ-secretase activity assays. We identified dihydroergocristine (DHEC), a component of an FDA- (Food and Drug Administration)-approved drug, to be a direct inhibitor of γ-secretase. Micromolar concentrations of DHEC substantially reduced Aβ levels in different cell types, including a cell line derived from an AD patient. Structure-activity relationship studies implied that the key moiety for inhibiting γ-secretase is the cyclized tripeptide moiety of DHEC. A Surface Plasmon Resonance assay showed that DHEC binds directly to γ-secretase and Nicastrin, with equilibrium dissociation constants (Kd) of 25.7 nM and 9.8 μM, respectively. This study offers DHEC not only as a new chemical moiety for selectively modulating the activity of γ-secretase but also a candidate for drug repositioning in Alzheimer's disease. PMID:26567970

  5. AGROCHEMICAL DISCOVERY: FINDING NEW FUNGICIDES FROM NATURAL PRODUCTS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The continuing development of fungicide resistance in plant and human pathogens necessitates the discovery and development of new fungicides. Discovery and evaluation of natural product fungicides is largely dependent upon the availability of miniaturized antifungal bioassays. Essentials for natur...

  6. Developing a drug-like natural product library.

    PubMed

    Quinn, Ronald J; Carroll, Anthony R; Pham, Ngoc B; Baron, Paul; Palframan, Meredith E; Suraweera, Lekha; Pierens, Gregory K; Muresan, Sorel

    2008-03-01

    Addressing drug-like/lead-like properties of biologically active small molecules early in a lead generation program is the current paradigm within the drug discovery community. Lipinski's "rule of five" has become the most commonly used tool to assess the relationship between structures and drug-like properties. Sixty percent of the 126 140 unique compounds in The Dictionary of Natural Products had no violations of Lipinski's "rule of five". We have isolated 814 natural products based on their expected drug-like/lead-like properties to generate a natural product library (NPL) in which 85% of the isolated compounds had no Lipinski violations. The library demonstrates the feasibility of obtaining natural products known for rich chemical diversity with the required physicochemical properties for drug discovery. The knowledge generated in creation of the library of structurally characterized pure natural products may provide opportunities to front-load lead-like property space in natural product drug discovery programs. PMID:18257534

  7. Culture conditions supporting inhibitor tolerance and rapid production of ethanol by P. stipitis NRRL Y-7124

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To expand the biomass to fuel ethanol industry, process strategies are needed to foster the production and utilization of microorganisms which can survive and ferment hexose and pentose sugars while exposed to inhibitors (such as ethanol, furfural, and hydroxymethylfurfural (HMF)). Furfural and HMF...

  8. Production of horsegram (Dolichos biflorus) Bowman-Birk inhibitor by an intein mediated protein purification system.

    PubMed

    Kumar, Vinod; Gowda, Lalitha R

    2013-05-01

    The seeds of the legume horsegram (Dolichos biflorus), a protein rich pulse (bean), contain multiple forms of Bowman-Birk inhibitors (protease inhibitors). The major inhibitor HGI-III contains seven interweaving disulfides and is extremely stable to high temperatures. A soluble HGI-III (rHGI) with the native N-terminus was produced using a pTWIN IMPACT™ purification system. Yield of rHGI was improved by introducing a trypsin sepharose affinity chromatography step resulting in ∼670 fold purification. The biochemical characteristics of rHGI point to its close similarity to seed HGI-III not only in its structure but also in its inhibitory characteristics toward bovine trypsin and chymotrypsin. The expression and purification strategy presented here promises to produce BBIs in their natural form for pharmacological and therapeutic use. PMID:23422783

  9. Marine Natural Products: A Way to New Drugs

    PubMed Central

    2009-01-01

    The investigation of marine natural products (low molecular weight bioregulators) is a rapidly developing scientific field at the intersection of biology and chemistry. Investigations aimed at detecting, identifying, and understanding the structure of marine natural products have led to the discovery of 20,000 new substances, including those characterized by an extremely high physiological activity. Some results and prospects of works aimed at creating new drugs on the basis of marine natural products are discussed herein. PMID:22649599

  10. p38 mitogen-activated protein kinase inhibitor reduces neurocan production in cultured spinal cord astrocytes.

    PubMed

    Yamaoka, Gotaro; Morino, Tadao; Morizane, Kei; Horiuchi, Hideki; Miura, Hiromasa; Ogata, Tadanori

    2012-06-20

    Chondroitin sulfate proteoglycans are formed in scar tissue after a spinal cord injury and inhibit axon regrowth. The production of neurocan, one of these chondroitin sulfate proteoglycans, in cultured spinal cord astrocytes increased after the addition of epidermal growth factor (EGF) in a dose-dependent manner (2-200 ng/ml). In astrocytes stimulated by 20 ng/ml of EGF, neurocan production was inhibited after the addition of the p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580: 3-10 μM) in a dose-dependent manner. These results suggest that the activation of p38 MAPK is one of the mechanisms of neurocan production in EGF-stimulated astrocytes. The p38 MAPK inhibitor may reduce neurocan production and accelerate axonal regrowth after a spinal cord injury. PMID:22525836