Influenza neuraminidase: a druggable target for natural products.

PubMed

Grienke, Ulrike; Schmidtke, Michaela; von Grafenstein, Susanne; Kirchmair, Johannes; Liedl, Klaus R; Rollinger, Judith M

2012-01-01

The imminent threat of influenza pandemics and repeatedly reported emergence of new drug-resistant influenza virus strains demonstrate the urgent need for developing innovative and effective antiviral agents for prevention and treatment. At present, influenza neuraminidase (NA), a key enzyme in viral replication, spread, and pathogenesis, is considered to be one of the most promising targets for combating influenza. Despite the substantial medical potential of NA inhibitors (NAIs), only three of these drugs are currently on the market (zanamivir, oseltamivir, and peramivir). Moreover, sudden changes in NAI susceptibility revealed the urgent need in the discovery/identification of novel inhibitors. Nature offers an abundance of biosynthesized compounds comprising chemical scaffolds of high diversity, which present an infinite pool of chemical entities for target-oriented drug discovery in the battle against this highly contagious pathogen. This review illuminates the increasing research efforts of the past decade (2000-2011), focusing on the structure, function and druggability of influenza NA, as well as its inhibition by natural products. Following a critical discussion of publications describing some 150 secondary plant metabolites tested for their inhibitory potential against influenza NA, the impact of three different strategies to identify and develop novel NAIs is presented: (i) bioactivity screening of herbal extracts, (ii) exploitation of empirical knowledge, and (iii) computational approaches. This work addresses the latest developments in theoretical and experimental research on properties of NA that are and will be driving anti-influenza drug development now and in the near future.

In silico polypharmacology of natural products.

PubMed

Fang, Jiansong; Liu, Chuang; Wang, Qi; Lin, Ping; Cheng, Feixiong

2017-04-27

Natural products with polypharmacological profiles have demonstrated promise as novel therapeutics for various complex diseases, including cancer. Currently, many gaps exist in our knowledge of which compounds interact with which targets, and experimentally testing all possible interactions is infeasible. Recent advances and developments of systems pharmacology and computational (in silico) approaches provide powerful tools for exploring the polypharmacological profiles of natural products. In this review, we introduce recent progresses and advances of computational tools and systems pharmacology approaches for identifying drug targets of natural products by focusing on the development of targeted cancer therapy. We survey the polypharmacological and systems immunology profiles of five representative natural products that are being considered as cancer therapies. We summarize various chemoinformatics, bioinformatics and systems biology resources for reconstructing drug-target networks of natural products. We then review currently available computational approaches and tools for prediction of drug-target interactions by focusing on five domains: target-based, ligand-based, chemogenomics-based, network-based and omics-based systems biology approaches. In addition, we describe a practical example of the application of systems pharmacology approaches by integrating the polypharmacology of natural products and large-scale cancer genomics data for the development of precision oncology under the systems biology framework. Finally, we highlight the promise of cancer immunotherapies and combination therapies that target tumor ecosystems (e.g. clones or 'selfish' sub-clones) via exploiting the immunological and inflammatory 'side' effects of natural products in the cancer post-genomics era. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Multiplexed Thiol Reactivity Profiling for Target Discovery of Electrophilic Natural Products.

PubMed

Tian, Caiping; Sun, Rui; Liu, Keke; Fu, Ling; Liu, Xiaoyu; Zhou, Wanqi; Yang, Yong; Yang, Jing

2017-11-16

Electrophilic groups, such as Michael acceptors, expoxides, are common motifs in natural products (NPs). Electrophilic NPs can act through covalent modification of cysteinyl thiols on functional proteins, and exhibit potent cytotoxicity and anti-inflammatory/cancer activities. Here we describe a new chemoproteomic strategy, termed multiplexed thiol reactivity profiling (MTRP), and its use in target discovery of electrophilic NPs. We demonstrate the utility of MTRP by identifying cellular targets of gambogic acid, an electrophilic NP that is currently under evaluation in clinical trials as anticancer agent. Moreover, MTRP enables simultaneous comparison of seven structurally diversified α,β-unsaturated γ-lactones, which provides insights into the relative proteomic reactivity and target preference of diverse structural scaffolds coupled to a common electrophilic motif and reveals various potential druggable targets with liganded cysteines. We anticipate that this new method for thiol reactivity profiling in a multiplexed manner will find broad application in redox biology and drug discovery. Copyright © 2017 Elsevier Ltd. All rights reserved.

Marine natural products for multi-targeted cancer treatment: A future insight.

PubMed

Kumar, Maushmi S; Adki, Kaveri M

2018-05-30

Cancer is world's second largest alarming disease, which involves abnormal cell growth and have potential to spread to other parts of the body. Most of the available anticancer drugs are designed to act on specific targets by altering the activity of involved transporters and genes. As cancer cells exhibit complex cellular machinery, the regeneration of cancer tissues and chemo resistance towards the therapy has been the main obstacle in cancer treatment. This fact encourages the researchers to explore the multitargeted use of existing medicines to overcome the shortcomings of chemotherapy for alternative and safer treatment strategies. Recent developments in genomics-proteomics and an understanding of the molecular pharmacology of cancer have also challenged researchers to come up with target-based drugs. The literature supports the evidence of natural compounds exhibiting antioxidant, antimitotic, anti-inflammatory, antibiotic as well as anticancer activity. In this review, we have selected marine sponges as a prolific source of bioactive compounds which can be explored for their possible use in cancer and have tried to link their role in cancer pathway. To prove this, we revisited the literature for the selection of cancer genes for the multitargeted use of existing drugs and natural products. We used Cytoscape network analysis and Search tool for retrieval of interacting genes/ proteins (STRING) to study the possible interactions to show the links between the antioxidants, antibiotics, anti-inflammatory and antimitotic agents and their targets for their possible use in cancer. We included total 78 pathways, their genes and natural compounds from the above four pharmacological classes used in cancer treatment for multitargeted approach. Based on the Cytoscape network analysis results, we shortlist 22 genes based on their average shortest path length connecting one node to all other nodes in a network. These selected genes are CDKN2A, FH, VHL, STK11, SUFU, RB1

Quantitative and Systems Pharmacology 3. Network-Based Identification of New Targets for Natural Products Enables Potential Uses in Aging-Associated Disorders.

PubMed

Fang, Jiansong; Gao, Li; Ma, Huili; Wu, Qihui; Wu, Tian; Wu, Jun; Wang, Qi; Cheng, Feixiong

2017-01-01

Aging that refers the accumulation of genetic and physiology changes in cells and tissues over a lifetime has been shown a high risk of developing various complex diseases, such as neurodegenerative disease, cardiovascular disease and cancer. Over the past several decades, natural products have been demonstrated as anti-aging interveners via extending lifespan and preventing aging-associated disorders. In this study, we developed an integrated systems pharmacology infrastructure to uncover new indications for aging-associated disorders by natural products. Specifically, we incorporated 411 high-quality aging-associated human genes or human-orthologous genes from mus musculus (MM), saccharomyces cerevisiae (SC), c aenorhabditis elegans (CE), and drosophila melanogaster (DM). We constructed a global drug-target network of natural products by integrating both experimental and computationally predicted drug-target interactions (DTI). We further built the statistical network models for identification of new anti-aging indications of natural products through integration of the curated aging-associated genes and drug-target network of natural products. High accuracy was achieved on the network models. We showcased several network-predicted anti-aging indications of four typical natural products (caffeic acid, metformin, myricetin, and resveratrol) with new mechanism-of-actions. In summary, this study offers a powerful systems pharmacology infrastructure to identify natural products for treatment of aging-associated disorders.

Quantitative and Systems Pharmacology 3. Network-Based Identification of New Targets for Natural Products Enables Potential Uses in Aging-Associated Disorders

PubMed Central

Fang, Jiansong; Gao, Li; Ma, Huili; Wu, Qihui; Wu, Tian; Wu, Jun; Wang, Qi; Cheng, Feixiong

2017-01-01

Aging that refers the accumulation of genetic and physiology changes in cells and tissues over a lifetime has been shown a high risk of developing various complex diseases, such as neurodegenerative disease, cardiovascular disease and cancer. Over the past several decades, natural products have been demonstrated as anti-aging interveners via extending lifespan and preventing aging-associated disorders. In this study, we developed an integrated systems pharmacology infrastructure to uncover new indications for aging-associated disorders by natural products. Specifically, we incorporated 411 high-quality aging-associated human genes or human-orthologous genes from mus musculus (MM), saccharomyces cerevisiae (SC), caenorhabditis elegans (CE), and drosophila melanogaster (DM). We constructed a global drug-target network of natural products by integrating both experimental and computationally predicted drug-target interactions (DTI). We further built the statistical network models for identification of new anti-aging indications of natural products through integration of the curated aging-associated genes and drug-target network of natural products. High accuracy was achieved on the network models. We showcased several network-predicted anti-aging indications of four typical natural products (caffeic acid, metformin, myricetin, and resveratrol) with new mechanism-of-actions. In summary, this study offers a powerful systems pharmacology infrastructure to identify natural products for treatment of aging-associated disorders. PMID:29093681

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

Application of Combination High-Throughput Phenotypic Screening and Target Identification Methods for the Discovery of Natural Product-Based Combination Drugs.

PubMed

Isgut, Monica; Rao, Mukkavilli; Yang, Chunhua; Subrahmanyam, Vangala; Rida, Padmashree C G; Aneja, Ritu

2018-03-01

Modern drug discovery efforts have had mediocre success rates with increasing developmental costs, and this has encouraged pharmaceutical scientists to seek innovative approaches. Recently with the rise of the fields of systems biology and metabolomics, network pharmacology (NP) has begun to emerge as a new paradigm in drug discovery, with a focus on multiple targets and drug combinations for treating disease. Studies on the benefits of drug combinations lay the groundwork for a renewed focus on natural products in drug discovery. Natural products consist of a multitude of constituents that can act on a variety of targets in the body to induce pharmacodynamic responses that may together culminate in an additive or synergistic therapeutic effect. Although natural products cannot be patented, they can be used as starting points in the discovery of potent combination therapeutics. The optimal mix of bioactive ingredients in natural products can be determined via phenotypic screening. The targets and molecular mechanisms of action of these active ingredients can then be determined using chemical proteomics, and by implementing a reverse pharmacokinetics approach. This review article provides evidence supporting the potential benefits of natural product-based combination drugs, and summarizes drug discovery methods that can be applied to this class of drugs. © 2017 Wiley Periodicals, Inc.

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.

Emerging potential of natural products for targeting mucins for therapy against inflammation and cancer.

PubMed

Macha, Muzafar A; Krishn, Shiv Ram; Jahan, Rahat; Banerjee, Kasturi; Batra, Surinder K; Jain, Maneesh

2015-03-01

Deregulated mucin expression is a hallmark of several inflammatory and malignant pathologies. Emerging evidence suggests that, apart from biomarkers, these deregulated mucins are functional contributors to the pathogenesis in inflammation and cancer. Both overexpression and downregulation of mucins in various organ systems is associated with pathobiology of inflammation and cancer. Restoration of mucin homeostasis has become an important goal for therapy and management of such disorders has fueled the quest for selective mucomodulators. With improved understanding of mucin regulation and mechanistic insights into their pathobiological roles, there is optimism to find selective non-toxic agents capable of modulating mucin expression and function. Recently, natural compounds derived from dietary sources have drawn attention due to their anti-inflammatory and anti-oxidant properties and low toxicity. Considerable efforts have been directed towards evaluating dietary natural products as chemopreventive and therapeutic agents; identification, characterization and synthesis of their active compounds; and improving their delivery and bioavailability. We describe the current understanding of mucin regulation, rationale for targeting mucins with natural products and discuss some natural products that modulate mucin expression and functions. We further discuss the approaches and parameters that should guide future research to identify and evaluate selective natural mucomodulators for therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Emerging Potential of Natural Products for Targeting Mucins for Therapy Against Inflammation and Cancer

PubMed Central

Macha, Muzafar A.; Krishn, Shiv Ram; Jahan, Rahat; Banerjee, Kasturi; Batra, Surinder K.; Jain, Maneesh

2015-01-01

Deregulated mucin expression is a hallmark of several inflammatory and malignant pathologies. Emerging evidence suggests that, apart from biomarkers, these deregulated mucins are functional contributors to pathogenesis in inflammation and cancer. Both overexpression and downregulation of mucins in various organ systems is associated with pathobiology of inflammation and cancer. Restoration of mucin homeostasis has become an important goal for therapy and management of such disorders and has fueled the quest for selective mucomodulators. With improved understanding of mucin regulation and mechanistic insights into their pathobiological roles, there is optimism to find selective non-toxic agents capable of modulating mucin expression and function. Recently, natural compounds derived from dietary sources have drawn attention due to their anti-inflammatory and anti-oxidant properties and low toxicity. Considerable efforts have been directed towards evaluating dietary natural products as chemopreventive and therapeutic agents; identification, characterization and synthesis of their active compounds; and improving their delivery and bioavailability. We describe the current understanding of mucin regulation, rationale for targeting mucins with natural products and discuss some natural products that modulate mucin expression and functions. We further discuss the approaches and parameters that should guide future research to identify and evaluate selective natural mucomodulators for therapy. PMID:25624117

Biological Targets and Mechanisms of Action of Natural Products from Marine Cyanobacteria

PubMed Central

Salvador-Reyes, Lilibeth A.

2015-01-01

Marine cyanobacteria are an ancient group of organisms and prolific producers of bioactive secondary metabolites. These compounds are presumably optimized by evolution over billions of years to exert high affinity for their intended biological target in the ecologically relevant organism but likely also possess activity in different biological contexts such as human cells. Screening of marine cyanobacterial extracts for bioactive natural products has largely focused on cancer cell viability; however, diversification of the screening platform led to the characterization of many new bioactive compounds. Targets of compounds have oftentimes been elusive if the compounds were discovered through phenotypic assays. Over the past few years, technology has advanced to determine mechanism of action (MOA) and targets through reverse chemical genetic and proteomic approaches, which has been applied to certain cyanobacterial compounds and will be discussed in this review. Some cyanobacterial molecules are the most-potent-in-class inhibitors and therefore may become valuable tools for chemical biology to probe protein function but also be templates for novel drugs, assuming in vitro potency translates into cellular and in vivo activity. Our review will focus on compounds for which the direct targets have been deciphered or which were found to target a novel pathway, and link them to disease states where target modulation may be beneficial. PMID:25571978

Cyclotron production of {sup 61}Cu using natural Zn and enriched {sup 64}Zn targets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Asad, A. H.; Smith, S. V.; Chan, S.

2012-12-19

Copper-61 ({sup 61}Cu) shares with {sup 64}Cu certain advantages for PET diagnostic imaging, but has a shorter half-life (3.4hr vs. 12.7hr) and a greater probability of positron production per disintegration (61% vs. 17.9%). One important application is for in vivo imaging of hypoxic tissue. In this study {sup 61}Cu was produced using the {sup 64}Zn(p,{alpha}){sup 61}Cu reaction on natural Zn or enriched {sup 64}Zn targets. The enriched {sup 64}Zn (99.82%) was electroplated onto high purity gold or silver foils or onto thin Al discs. A typical target bombardment used 30{mu}A; at 11.7, 14.5 or 17.6MeV over 30-60min. The {sup 61}Cumore » (radiochemical purity of >95%) was separated using a combination of cation and anion exchange columns. The {sup 64}Zn target material was recovered after each run, for re-use. In a direct comparison with enriched {sup 64}Zn-target results, {sup 61}Cu production using the cheaper {sup nat}Zn target proved to be an effective alternative.« less

Chemoprevention in gastrointestinal physiology and disease. Targeting the progression of cancer with natural products: a focus on gastrointestinal cancer.

PubMed

Khoogar, Roxane; Kim, Byung-Chang; Morris, Jay; Wargovich, Michael J

2016-05-01

The last decade has witnessed remarkable progress in the utilization of natural products for the prevention and treatment of human cancer. Many agents now in the pipeline for clinical trial testing have evolved from our understanding of how human nutritional patterns account for widespread differences in cancer risk. In this review, we have focused on many of these promising agents arguing that they may provide a new strategy for cancer control: natural products once thought to be only preventive in their mode of action now are being explored for efficacy in tandem with cancer therapeutics. Natural products may reduce off-target toxicity of therapeutics while making cancers more amenable to therapy. On the horizon is the use of certain natural products, in their own right, as mitigants of late-stage cancer, a new frontier for small-molecule natural product drug discovery. Copyright © 2016 the American Physiological Society.

Cancer Prevention with Promising Natural Products: Mechanisms of Action and Molecular Targets

PubMed Central

Pratheeshkumar, Poyil; Sreekala, Chakkenchath; Zhang, Zhuo; Budhraja, Amit; Ding, Songze; Son, Young-Ok; Wang, Xin; Hitron, Andrew; Hyun-Jung, Kim; Wang, Lei; Lee, Jeong-Chae; Shi, Xianglin

2016-01-01

Cancer is the second leading cause of death worldwide. There is greater need for more effective and less toxic therapeutic and preventive strategies. Natural products are becoming an important research area for novel and bioactive molecules for drug discovery. Phytochemicals and dietary compounds have been used for the treatment of cancer throughout history due to their safety, low toxicity, and general availability. Many active phytochemicals are in human clinical trials. Studies have indicated that daily consumption of dietary phytochemicals have cancer protective effects against carcinogens. They can inhibit, delay, or reverse carcinogenesis by inducing detoxifying and antioxidant enzymes systems, regulating inflammatory and proliferative signaling pathways, and inducing cell cycle arrest and apoptosis. Epidemiological studies have also revealed that high dietary intakes of fruits and vegetables reduce the risk of cancer. This review discusses potential natural cancer preventive compounds, their molecular targets, and their mechanisms of actions. PMID:22583402

Natural products inhibiting the ubiquitin-proteasome proteolytic pathway, a target for drug development.

PubMed

Tsukamoto, Sachiko; Yokosawa, Hideyoshi

2006-01-01

The ubiquitin-proteasome proteolytic pathway plays a major role in selective protein degradation and regulates various cellular events including cell cycle progression, transcription, DNA repair, signal transduction, and immune response. Ubiquitin, a highly conserved small protein in eukaryotes, attaches to a target protein prior to degradation. The polyubiquitin chain tagged to the target protein is recognized by the 26S proteasome, a high-molecular-mass protease subunit complex, and the protein portion is degraded by the 26S proteasome. The potential of specific proteasome inhibitors, which act as anti-cancer agents, is now under intensive investigation, and bortezomib (PS-341), a proteasome inhibitor, has been recently approved by FDA for multiple myeloma treatment. Since ubiquitination of proteins requires the sequential action of three enzymes, ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3), and polyubiquitination is a prerequisite for proteasome-mediated protein degradation, inhibitors of E1, E2, and E3 are reasonably thought to be drug candidates for treatment of diseases related to ubiquitination. Recently, various compounds inhibiting the ubiquitin-proteasome pathway have been isolated from natural resources. We also succeeded in isolating inhibitors against the proteasome and E1 enzyme from marine natural resources. In this review, we summarize the structures and biological activities of natural products that inhibit the ubiquitin-proteasome proteolytic pathway.

Development of Water Target for Radioisotope Production

NASA Astrophysics Data System (ADS)

Tripp, Nathan

2011-10-01

Ongoing studies of plant physiology at TUNL require a supply of nitrogen-13 for use as a radiotracer. Production of nitrogen-13 using a water target and a proton beam follows the nuclear reaction 16-O(p,a)13-N. Unfortunately the irradiation of trace amounts of oxygen-18 within a natural water target produces fluorine-18 by the reaction 18-O(p, n)18-F. The presence of this second radioisotope reduces the efficacy of nitrogen-13 as a radiotracer. Designing a natural water target for nitrogen-13 production at TUNL required the design of several new systems to address the problems inherent in nitrogen-13 production. A heat exchanger cools the target water after irradiation within the target cell. The resulting improved thermal regulation of the target water prevents the system from overheating and minimizes the effect of the cavitations occurring within the target. Alumina pellets within a scrubbing unit remove the fluorine-18 contamination from the irradiated water. The modular design of the water target apparatus makes the system highly adaptable, allowing for easy reuse and adaptation of the different components into future projects. The newly designed and constructed water target should meet the current and future needs of TUNL researchers in the production of nitrogen-13. This TUNL REU project was funded in part by a grant from the National Science Foundation (NSF) NSF-PHY-08-51813.

Simultaneous structure-activity studies and arming of natural products by C-H amination reveal cellular targets of eupalmerin acetate.

PubMed

Li, Jing; Cisar, Justin S; Zhou, Cong-Ying; Vera, Brunilda; Williams, Howard; Rodríguez, Abimael D; Cravatt, Benjamin F; Romo, Daniel

2013-06-01

Natural products have a venerable history of, and enduring potential for the discovery of useful biological activity. To fully exploit this, the development of chemical methodology that can functionalize unique sites within these complex structures is highly desirable. Here, we describe the use of rhodium(II)-catalysed C-H amination reactions developed by Du Bois to carry out simultaneous structure-activity relationship studies and arming (alkynylation) of natural products at 'unfunctionalized' positions. Allylic and benzylic C-H bonds in the natural products undergo amination while olefins undergo aziridination, and tertiary amine-containing natural products are converted to amidines by a C-H amination-oxidation sequence or to hydrazine sulfamate zwitterions by an unusual N-amination. The alkynylated derivatives are ready for conversion into cellular probes that can be used for mechanism-of-action studies. Chemo- and site-selectivity was studied with a diverse library of natural products. For one of these-the marine-derived anticancer diterpene, eupalmerin acetate-quantitative proteome profiling led to the identification of several protein targets in HL-60 cells, suggesting a polypharmacological mode of action.

Simultaneous structure-activity studies and arming of natural products by C-H amination reveal cellular targets of eupalmerin acetate

NASA Astrophysics Data System (ADS)

Li, Jing; Cisar, Justin S.; Zhou, Cong-Ying; Vera, Brunilda; Williams, Howard; Rodríguez, Abimael D.; Cravatt, Benjamin F.; Romo, Daniel

2013-06-01

Natural products have a venerable history of, and enduring potential for the discovery of useful biological activity. To fully exploit this, the development of chemical methodology that can functionalize unique sites within these complex structures is highly desirable. Here, we describe the use of rhodium(II)-catalysed C-H amination reactions developed by Du Bois to carry out simultaneous structure-activity relationship studies and arming (alkynylation) of natural products at ‘unfunctionalized’ positions. Allylic and benzylic C-H bonds in the natural products undergo amination while olefins undergo aziridination, and tertiary amine-containing natural products are converted to amidines by a C-H amination-oxidation sequence or to hydrazine sulfamate zwitterions by an unusual N-amination. The alkynylated derivatives are ready for conversion into cellular probes that can be used for mechanism-of-action studies. Chemo- and site-selectivity was studied with a diverse library of natural products. For one of these—the marine-derived anticancer diterpene, eupalmerin acetate—quantitative proteome profiling led to the identification of several protein targets in HL-60 cells, suggesting a polypharmacological mode of action.

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.

Bioactive Oligosaccharide Natural Products

PubMed Central

McCranie, Emilianne K.; Bachmann, Brian O.

2016-01-01

Oligosaccharide natural products target a wide spectrum of biological processes including disruption of cell wall biosynthesis, interference of bacterial translation, and inhibition of human α-amylase. Correspondingly, oligosaccharides possess potential for development as treatments of such diverse diseases as bacterial infections and type II diabetes. Despite their potent and selective activities and potential clinical relevance, isolated bioactive secondary metabolic oligosaccharides are less prevalent than other classes of natural products and their biosynthesis has received comparatively less attention. This review highlights the unique modes of action and biosynthesis of four classes of bioactive oligosaccharides: the orthosomycins, moenomycins, saccharomicins, and acarviostatins. PMID:24883430

Natural products from marine organisms with neuroprotective activity in the experimental models of Alzheimer's disease, Parkinson's disease and ischemic brain stroke: their molecular targets and action mechanisms.

PubMed

Choi, Dong-Young; Choi, Hyukjae

2015-02-01

Continuous increases in the incidence of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and brain stroke demand the urgent development of therapeutics. Marine organisms are well-known producers of natural products with diverse structures and pharmacological activities. Therefore, researchers have endeavored to identify marine natural products with neuroprotective effects. In this regard, this review summarizes therapeutic targets for AD, PD, and ischemic brain stroke and marine natural products with pharmacological activities on the targets according to taxonomies of marine organisms. Furthermore, several marine natural products on the clinical trials for the treatment of neurological disorders are discussed.

Deorphaning the Macromolecular Targets of the Natural Anticancer Compound Doliculide.

PubMed

Schneider, Gisbert; Reker, Daniel; Chen, Tao; Hauenstein, Kurt; Schneider, Petra; Altmann, Karl-Heinz

2016-09-26

The cyclodepsipeptide doliculide is a marine natural product with strong actin-polymerizing and anticancer activities. Evidence for doliculide acting as a potent and subtype-selective antagonist of prostanoid E receptor 3 (EP3) is presented. Computational target prediction suggested that this membrane receptor is a likely macromolecular target and enabled immediate in vitro validation. This proof-of-concept study demonstrates the in silico deorphanization of phenotypic screening hits as a viable concept for future natural-product-inspired chemical biology and drug discovery efforts. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

NCI Program for Natural Product Discovery: A Publicly-Accessible Library of Natural Product Fractions for High-Throughput Screening.

PubMed

Thornburg, Christopher C; Britt, John R; Evans, Jason R; Akee, Rhone K; Whitt, James A; Trinh, Spencer K; Harris, Matthew J; Thompson, Jerell R; Ewing, Teresa L; Shipley, Suzanne M; Grothaus, Paul G; Newman, David J; Schneider, Joel P; Grkovic, Tanja; O'Keefe, Barry R

2018-06-13

The US National Cancer Institute's (NCI) Natural Product Repository is one of the world's largest, most diverse collections of natural products containing over 230,000 unique extracts derived from plant, marine, and microbial organisms that have been collected from biodiverse regions throughout the world. Importantly, this national resource is available to the research community for the screening of extracts and the isolation of bioactive natural products. However, despite the success of natural products in drug discovery, compatibility issues that make extracts challenging for liquid handling systems, extended timelines that complicate natural product-based drug discovery efforts and the presence of pan-assay interfering compounds have reduced enthusiasm for the high-throughput screening (HTS) of crude natural product extract libraries in targeted assay systems. To address these limitations, the NCI Program for Natural Product Discovery (NPNPD), a newly launched, national program to advance natural product discovery technologies and facilitate the discovery of structurally defined, validated lead molecules ready for translation will create a prefractionated library from over 125,000 natural product extracts with the aim of producing a publicly-accessible, HTS-amenable library of >1,000,000 fractions. This library, representing perhaps the largest accumulation of natural-product based fractions in the world, will be made available free of charge in 384-well plates for screening against all disease states in an effort to reinvigorate natural product-based drug discovery.

Natural product-based nanomedicine: recent advances and issues

PubMed Central

Watkins, Rebekah; Wu, Ling; Zhang, Chenming; Davis, Richey M; Xu, Bin

2015-01-01

Natural products have been used in medicine for many years. Many top-selling pharmaceuticals are natural compounds or their derivatives. These plant- or microorganism-derived compounds have shown potential as therapeutic agents against cancer, microbial infection, inflammation, and other disease conditions. However, their success in clinical trials has been less impressive, partly due to the compounds’ low bioavailability. The incorporation of nanoparticles into a delivery system for natural products would be a major advance in the efforts to increase their therapeutic effects. Recently, advances have been made showing that nanoparticles can significantly increase the bioavailability of natural products both in vitro and in vivo. Nanotechnology has demonstrated its capability to manipulate particles in order to target specific areas of the body and control the release of drugs. Although there are many benefits to applying nanotechnology for better delivery of natural products, it is not without issues. Drug targeting remains a challenge and potential nanoparticle toxicity needs to be further investigated, especially if these systems are to be used to treat chronic human diseases. This review aims to summarize recent progress in several key areas relevant to natural products in nanoparticle delivery systems for biomedical applications. PMID:26451111

Immobilized magnetic beads-based multi-target affinity selection coupled with HPLC-MS for screening active compounds from traditional Chinese medicine and natural products.

PubMed

Chen, Yaqi; Chen, Zhui; Wang, Yi

2015-01-01

Screening and identifying active compounds from traditional Chinese medicine (TCM) and other natural products plays an important role in drug discovery. Here, we describe a magnetic beads-based multi-target affinity selection-mass spectrometry approach for screening bioactive compounds from natural products. Key steps and parameters including activation of magnetic beads, enzyme/protein immobilization, characterization of functional magnetic beads, screening and identifying active compounds from a complex mixture by LC/MS, are illustrated. The proposed approach is rapid and efficient in screening and identification of bioactive compounds from complex natural products.

Underexplored Opportunities for Natural Products in Drug Discovery.

PubMed

DeCorte, Bart L

2016-10-27

The importance of natural products in the treatment of human disease is well documented. While natural products continue to have a profound impact on human health, chemists have succeeded in generating semisynthetic analogues that sometimes overshadow the original natural product in terms of clinical significance. Synthetic efforts based on natural products have primarily focused on improving their drug-like features while targeting utility in the same biological space. A less documented phenomenon is that natural products can serve as powerful starting materials to generate drug substances with novel therapeutic utility that is unrelated to the biological space of the natural product starting material. In this Perspective, examples of natural product derived marketed drugs with therapeutic utility in clinical space that is different from the biological profile of the starting material are presented, demonstrating that this is not merely a theoretical concept but both a clinical reality and an underexplored opportunity.

Use of Natural Products as Chemical Library for Drug Discovery and Network Pharmacology

PubMed Central

Gu, Jiangyong; Gui, Yuanshen; Chen, Lirong; Yuan, Gu; Lu, Hui-Zhe; Xu, Xiaojie

2013-01-01

Background Natural products have been an important source of lead compounds for drug discovery. How to find and evaluate bioactive natural products is critical to the achievement of drug/lead discovery from natural products. Methodology We collected 19,7201 natural products structures, reported biological activities and virtual screening results. Principal component analysis was employed to explore the chemical space, and we found that there was a large portion of overlap between natural products and FDA-approved drugs in the chemical space, which indicated that natural products had large quantity of potential lead compounds. We also explored the network properties of natural product-target networks and found that polypharmacology was greatly enriched to those compounds with large degree and high betweenness centrality. In order to make up for a lack of experimental data, high throughput virtual screening was employed. All natural products were docked to 332 target proteins of FDA-approved drugs. The most potential natural products for drug discovery and their indications were predicted based on a docking score-weighted prediction model. Conclusions Analysis of molecular descriptors, distribution in chemical space and biological activities of natural products was conducted in this article. Natural products have vast chemical diversity, good drug-like properties and can interact with multiple cellular target proteins. PMID:23638153

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

High impact technologies for natural products screening.

PubMed

Koehn, Frank E

2008-01-01

Natural products have historically been a rich source of lead molecules in drug discovery. However, natural products have been de-emphasized as high throughput screening resources in the recent past, in part because of difficulties in obtaining high quality natural products screening libraries, or in applying modern screening assays to these libraries. In addition, natural products programs based on screening of extract libraries, bioassay-guided isolation, structure elucidation and subsequent production scale-up are challenged to meet the rapid cycle times that are characteristic of the modern HTS approach. Fortunately, new technologies in mass spectrometry, NMR and other spectroscopic techniques can greatly facilitate the first components of the process - namely the efficient creation of high-quality natural products libraries, bimolecular target or cell-based screening, and early hit characterization. The success of any high throughput screening campaign is dependent on the quality of the chemical library. The construction and maintenance of a high quality natural products library, whether based on microbial, plant, marine or other sources is a costly endeavor. The library itself may be composed of samples that are themselves mixtures - such as crude extracts, semi-pure mixtures or single purified natural products. Each of these library designs carries with it distinctive advantages and disadvantages. Crude extract libraries have lower resource requirements for sample preparation, but high requirements for identification of the bioactive constituents. Pre-fractionated libraries can be an effective strategy to alleviate interferences encountered with crude libraries, and may shorten the time needed to identify the active principle. Purified natural product libraries require substantial resources for preparation, but offer the advantage that the hit detection process is reduced to that of synthetic single component libraries. Whether the natural products library

A novel 9 × 9 map-based solvent selection strategy for targeted counter-current chromatography isolation of natural products.

PubMed

Liang, Junling; Meng, Jie; Wu, Dingfang; Guo, Mengzhe; Wu, Shihua

2015-06-26

Counter-current chromatography (CCC) is an efficient liquid-liquid chromatography technique for separation and purification of complex mixtures like natural products extracts and synthetic chemicals. However, CCC is still a challenging process requiring some special technical knowledge especially in the selection of appropriated solvent systems. In this work, we introduced a new 9 × 9 map-based solvent selection strategy for CCC isolation of targets, which permit more than 60 hexane-ethyl acetate-methanol-water (HEMWat) solvent systems as the start candidates for the selection of solvent systems. Among these solvent systems, there are clear linear correlations between partition coefficient (K) and the system numbers. Thus, an appropriate CCC solvent system (i.e., sweet spot for K = 1) may be hit by measurement of k values of the target only in two random solvent systems. Besides this, surprisingly, we found that through two sweet spots, we could get a line ("Sweet line") where there are infinite sweet solvent systems being suitable for CCC separation. In these sweet solvent systems, the target has the same partition coefficient (K) but different solubilities. Thus, the better sweet solvent system with higher sample solubility can be obtained for high capacity CCC preparation. Furthermore, we found that there is a zone ("Sweet zone") where all solvent systems have their own sweet partition coefficients values for the target in range of 0.4 < K< 2.5 or extended range of 0.25 < K < 16. All results were validated by using 14 pure GUESSmix mimic natural products as standards and further confirmed by isolation of several targets including honokiol and magnolol from the extracts of Magnolia officinalis Rehd. Et Wils and tanshinone IIA from Salvia miltiorrhiza Bunge. In practice, it is much easier to get a suitable solvent system only by making a simple screening two to four HEMWat two-phase solvent systems to obtain the sweet line or sweet zone without special knowledge

Dearomatization Strategies in the Synthesis of Complex Natural Products

PubMed Central

Roche, Stéphane P.; Porco, John A.

2014-01-01

Evolution in the field of the total synthesis of natural products has led to exciting developments over the last decade. Numerous chemo-selective and enantioselective methodologies have emerged from total syntheses, resulting in efficient access to many important natural product targets. This Review highlights recent developments concerning dearomatization, a powerful strategy for the total synthesis of architecturally complex natural products wherein planar, aromatic scaffolds are converted to three-dimensional molecular architectures. PMID:21506209

Natural product synthesis at the interface of chemistry and biology.

PubMed

Hong, Jiyong

2014-08-11

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. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Hepatic AMP Kinase as a Potential Target for Treating Nonalcoholic Fatty Liver Disease: Evidence from Studies of Natural Products.

PubMed

Xu, Gang; Huang, Kaixun; Zhou, Jun

2018-01-01

Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease, is the leading cause of cryptogenic cirrhosis and has consistently been implicated in related metabolic disorders, such as dyslipidemia and type 2 diabetes (T2D). However, the pathogenesis of NAFLD remains to be elucidated, and no established therapeutic regimens for treating NAFLD exist. Adenosine monophosphate (AMP)-activated protein kinase (AMPK), the main cellular energy sensor, has been implicated as a key regulator of hepatic lipid and glucose metabolism. Recently, emerging evidence indicates that many plant-derived natural products are capable of ameliorating NAFLD by targeting AMPK. The published literature in PubMed relating to this topic was searched through June 2016. Significant advances have been made with respect to understanding the protective effects of plant-derived natural products against NAFLD. A variety of natural products, including alkaloids (berberine, demethyleneberberine, nicotine, caffeine, etc.), polyphenols (resveratrol, puerarin, curcumin, caffeic acid, etc.) and other compounds (β- caryophyllene, gastrodin, compound K, betulinic acid, etc.), have demonstrated promising results in preclinical studies. Mechanistic studies of these compounds have focused on their activation of AMPK and its downstream effectors involved in lipid metabolism. The findings of this review confirm that plant-derived natural products capable of activating the AMPK signaling pathway are potential therapeutic agents for NAFLD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Natural Products Version 2.0: Connecting Genes to Molecules

PubMed Central

Walsh, Christopher T.; Fischbach, Michael A.

2009-01-01

Natural products have played a prominent role in the history of organic chemistry, and they continue to be important as drugs, biological probes, and targets of study for synthetic and analytical chemists. In this perspective, we explore how connecting Nature’s small molecules to the genes that encode them has sparked a renaissance in natural product research, focusing primarily on the biosynthesis of polyketides and nonribosomal peptides. We survey monomer biogenesis, coupling chemistries from templated and non-templated pathways, and the broad set of tailoring reactions and hybrid pathways that give rise to the diverse scaffolds and functionalization patterns of natural products. We conclude by considering two questions: What would it take to find all natural product scaffolds? What kind of scientists will be studying natural products in the future? PMID:20121095

Editorial for Special Issue on Herbal Medicines and Natural Products.

PubMed

Zhou, Zhi-Wei; Zhou, Shu-Feng

2015-11-16

Herbal medicines and natural products have been the most productive source of drug development and there is a large line of evidence on the applications of herbal medicines and natural products for the management of body function and the treatment of aliments. The multiple bioactive components in herbal medicines and natural products can explain the multiple targets effect in their medical applications. The increasing usage of state-of-art computational, molecular biological, and analytical chemistry techniques will promote the exploration of the pharmacological effect of previously inaccessible sources of herbal medicines and natural products. Notably, with the increasing reports on the safety issues regarding the medical use of herbal medicines and natural products, the awareness of pharmacovigilance in herbal medicines and natural products needs to be strengthened. To prevent the adverse drug reactions related to herbal medicines and natural products, physicians need to be aware of potential risks and alert patients in the use of herbal medicines and natural products.

Bioactive Natural Products Prioritization Using Massive Multi-informational Molecular Networks.

PubMed

Olivon, Florent; Allard, Pierre-Marie; Koval, Alexey; Righi, Davide; Genta-Jouve, Gregory; Neyts, Johan; Apel, Cécile; Pannecouque, Christophe; Nothias, Louis-Félix; Cachet, Xavier; Marcourt, Laurence; Roussi, Fanny; Katanaev, Vladimir L; Touboul, David; Wolfender, Jean-Luc; Litaudon, Marc

2017-10-20

Natural products represent an inexhaustible source of novel therapeutic agents. Their complex and constrained three-dimensional structures endow these molecules with exceptional biological properties, thereby giving them a major role in drug discovery programs. However, the search for new bioactive metabolites is hampered by the chemical complexity of the biological matrices in which they are found. The purification of single constituents from such matrices requires such a significant amount of work that it should be ideally performed only on molecules of high potential value (i.e., chemical novelty and biological activity). Recent bioinformatics approaches based on mass spectrometry metabolite profiling methods are beginning to address the complex task of compound identification within complex mixtures. However, in parallel to these developments, methods providing information on the bioactivity potential of natural products prior to their isolation are still lacking and are of key interest to target the isolation of valuable natural products only. In the present investigation, we propose an integrated analysis strategy for bioactive natural products prioritization. Our approach uses massive molecular networks embedding various informational layers (bioactivity and taxonomical data) to highlight potentially bioactive scaffolds within the chemical diversity of crude extracts collections. We exemplify this workflow by targeting the isolation of predicted active and nonactive metabolites from two botanical sources (Bocquillonia nervosa and Neoguillauminia cleopatra) against two biological targets (Wnt signaling pathway and chikungunya virus replication). Eventually, the detection and isolation processes of a daphnane diterpene orthoester and four 12-deoxyphorbols inhibiting the Wnt signaling pathway and exhibiting potent antiviral activities against the CHIKV virus are detailed. Combined with efficient metabolite annotation tools, this bioactive natural products

Seeking new anti-cancer agents from autophagy-regulating natural products.

PubMed

Hua, Fang; Shang, Shuang; Hu, Zhuo-Wei

2017-04-01

Natural products are an important original source of many widely used drugs, including anti-cancer drugs. Early research efforts for seeking anti-cancer therapy from the natural products are mainly focused on the compounds with cytotoxicity capability. The good examples include vinblastine, vincristine, the camptothecin derivatives; topotecan, irinotecan, epipodophyllotoxin derivatives and paclitaxel. In a recent decade, the fundamental progression has been made in the understanding of molecular and cellular mechanisms regarding tumor initiation, metastasis, therapeutic resistance, immune escape, and relapse, which provide a great opportunity for the development of new mechanism-based anticancer drugs, especially drugs against new molecular and cellular targets. Autophagy, a critical cell homeostasis mechanism and promising drug target involved in a verity of human diseases including cancer, can be modulated by many compounds derived from natural products. In this review, we'll give a short introduction of autophagy and discuss the roles of autophagy in the tumorigenesis and progression. And then, we summarize the accumulated evidences to show the anti-tumor effects of several compounds derived from natural products through modulation of autophagy activity.

Rationale for a natural products approach to herbicide discovery.

PubMed

Dayan, Franck E; Owens, Daniel K; Duke, Stephen O

2012-04-01

Weeds continue to evolve resistance to all the known modes of herbicidal action, but no herbicide with a new target site has been commercialized in nearly 20 years. The so-called 'new chemistries' are simply molecules belonging to new chemical classes that have the same mechanisms of action as older herbicides (e.g. the protoporphyrinogen-oxidase-inhibiting pyrimidinedione saflufenacil or the very-long-chain fatty acid elongase targeting sulfonylisoxazoline herbicide pyroxasulfone). Therefore, the number of tools to manage weeds, and in particular those that can control herbicide-resistant weeds, is diminishing rapidly. There is an imminent need for truly innovative classes of herbicides that explore chemical spaces and interact with target sites not previously exploited by older active ingredients. This review proposes a rationale for a natural-products-centered approach to herbicide discovery that capitalizes on the structural diversity and ingenuity afforded by these biologically active compounds. The natural process of extended-throughput screening (high number of compounds tested on many potential target sites over long periods of times) that has shaped the evolution of natural products tends to generate molecules tailored to interact with specific target sites. As this review shows, there is generally little overlap between the mode of action of natural and synthetic phytotoxins, and more emphasis should be placed on applying methods that have proved beneficial to the pharmaceutical industry to solve problems in the agrochemical industry. Published 2012 by John Wiley & Sons, Ltd.

Natural products to improve quality of life targeting for colon drug delivery.

PubMed

Kim, Hyunjo

2012-03-01

The colon is largely being investigated as a site for administration of protein and peptides, which are degraded by digestive enzymes in the upper GIT. Also for local diseases of the colon such as inflammatory bowel disease, colorectal cancer and ameobiasis, drug administration to the site of action can not only reduce the dose to be administered, but also decrease the side effects. Inflammatory Bowel Disease (IBD) such as Ulcerative colitis and Crohn's disease are characterized by chronic intestinal inflammation. Intestinal bacteria initiate the activation of intestinal inflammatory processes, which are mediated by pro-inflammatory cytokines and chemokine. Increased chemokine expression has also been observed in epithelial cells, endothelial cells, and smooth muscle cells. Future trials of specific agents capable of inhibiting chemokine synthesis and secretion or blocking chemokine-chemokine receptor interaction will be important to study in patients with ulcerative colitis and Crohn's disease. Many important bioactive compounds have been discovered from natural sources using bioactivity directed fractionation and isolation (BDFl) Continuing discovery has also been facilitated by the recent development of new bioassay methods. These bioactive compounds are mostly plant secondary metabolites, and many naturally occurring pure compounds have become medicines, dietary supplements, and other useful commercial products. The present review includes various approaches investigated for colon drug delivery and their site specificity. To achieve successful colonic delivery, a drug needs to be protected from absorption and the environment of the upper gastrointestinal tract and then be abruptly released into the proximal colon, which is considered the optimum site for colon targeted delivery of drugs.

Using Functional Signature Ontology (FUSION) to Identify Mechanisms of Action for Natural Products

PubMed Central

Potts, Malia B.; Kim, Hyun Seok; Fisher, Kurt W.; Hu, Youcai; Carrasco, Yazmin P.; Bulut, Gamze Betul; Ou, Yi-Hung; Herrera-Herrera, Mireya L.; Cubillos, Federico; Mendiratta, Saurabh; Xiao, Guanghua; Hofree, Matan; Ideker, Trey; Xie, Yang; Huang, Lily Jun-shen; Lewis, Robert E.; MacMillan, John B.; White, Michael A.

2014-01-01

A challenge for biomedical research is the development of pharmaceuticals that appropriately target disease mechanisms. Natural products can be a rich source of bioactive chemicals for medicinal applications but can act through unknown mechanisms and can be difficult to produce or obtain. To address these challenges, we developed a new marine-derived, renewable natural products resource and a method for linking bioactive derivatives of this library to the proteins and biological processes that they target in cells. We used cell-based screening and computational analysis to match gene expression signatures produced by natural products to those produced by siRNA and synthetic microRNA libraries. With this strategy, we matched proteins and microRNAs with diverse biological processes and also identified putative protein targets and mechanisms of action for several previously undescribed marine-derived natural products. We confirmed mechanistic relationships for selected short-interfering RNAs, microRNAs, and compounds with functional roles in autophagy, chemotaxis mediated by discoidin domain receptor 2, or activation of the kinase AKT. Thus, this approach may be an effective method for screening new drugs while simultaneously identifying their targets. PMID:24129700

Research Progress in Reversal of Tumor Multi-drug Resistance via Natural Products.

PubMed

Guo, Qi; Cao, Hongyan; Qi, Xianghui; Li, Huikai; Ye, Peizhi; Wang, Zhiguo; Wang, Danqiao; Sun, Mingyu

2017-11-24

Multidrug resistance occurs when a tumor develops resistance to multiple chemotherapeutic drugs, which may include antitumor drugs with different chemical structures and mechanisms. Multidrug resistance limits the treatment effects of antitumor drugs, and is the main cause of chemotherapy failure. Multidrug resistance is caused by numerous factors including changes in ATP-binding cassette transporters, target proteins, detoxification, deoxyribonucleic acid repair, drug metabolic enzymes, and signal pathways of apoptosis. Clinical research indicates that natural products have great potential to treat tumors and reverse multidrug resistance. Natural products, which often have multiple targets, could play an important role in tumor treatment, have beneficial effects on tumor inhibition, improve symptoms, reduce radiotherapy and chemotherapy side effects, enhance immunity, and prolong survival. Because natural products often have few adverse reactions and less drug resistance, the antitumor activities of natural products have attracted extensive research. We aimed to review the basic research and clinical application of natural products in the reversal of multidrug resistance. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries

PubMed Central

Cordier, Christopher; Morton, Daniel; Murrison, Sarah; O'Leary-Steele, Catherine

2008-01-01

The purpose of diversity-oriented synthesis is to drive the discovery of small molecules with previously unknown biological functions. Natural products necessarily populate biologically relevant chemical space, since they bind both their biosynthetic enzymes and their target macromolecules. Natural product families are, therefore, libraries of pre-validated, functionally diverse structures in which individual compounds selectively modulate unrelated macromolecular targets. This review describes examples of diversity-oriented syntheses which have, to some extent, been inspired by the structures of natural products. Particular emphasis is placed on innovations that allow the synthesis of compound libraries that, like natural products, are skeletally diverse. Mimicking the broad structural features of natural products may allow the discovery of compounds that modulate the functions of macromolecules for which ligands are not known. The ability of innovations in diversity-oriented synthesis to deliver such compounds is critically assessed. PMID:18663392

Informatic analysis reveals Legionella as a source of novel natural products.

PubMed

Johnston, Chad W; Plumb, Jonathan; Li, Xiang; Grinstein, Sergio; Magarvey, Nathan A

2016-06-01

Microbial natural products are a crucial source of bioactive molecules and unique chemical scaffolds. Despite their importance, rediscovery of known natural products from established productive microbes has led to declining interest, even while emergent genomic data suggest that the majority of microbial natural products remain to be discovered. Now, new sources of microbial natural products must be defined in order to provide chemical scaffolds for the next generation of small molecules for therapeutic, agricultural, and industrial purposes. In this work, we use specialized bioinformatic programs, genetic knockouts, and comparative metabolomics to define the genus Legionella as a new source of novel natural products. We show that Legionella spp. hold a diverse collection of biosynthetic gene clusters for the production of polyketide and nonribosomal peptide natural products. To confirm this bioinformatic survey, we create targeted mutants of L. pneumophila and use comparative metabolomics to identify a novel polyketide surfactant. Using spectroscopic techniques, we show that this polyketide possesses a new chemical scaffold, and firmly demonstrate that this unexplored genus is a source for novel natural products.

A systematic approach to identify therapeutic effects of natural products based on human metabolite information.

PubMed

Noh, Kyungrin; Yoo, Sunyong; Lee, Doheon

2018-06-13

Natural products have been widely investigated in the drug development field. Their traditional use cases as medicinal agents and their resemblance of our endogenous compounds show the possibility of new drug development. Many researchers have focused on identifying therapeutic effects of natural products, yet the resemblance of natural products and human metabolites has been rarely touched. We propose a novel method which predicts therapeutic effects of natural products based on their similarity with human metabolites. In this study, we compare the structure, target and phenotype similarities between natural products and human metabolites to capture molecular and phenotypic properties of both compounds. With the generated similarity features, we train support vector machine model to identify similar natural product and human metabolite pairs. The known functions of human metabolites are then mapped to the paired natural products to predict their therapeutic effects. With our selected three feature sets, structure, target and phenotype similarities, our trained model successfully paired similar natural products and human metabolites. When applied to the natural product derived drugs, we could successfully identify their indications with high specificity and sensitivity. We further validated the found therapeutic effects of natural products with the literature evidence. These results suggest that our model can match natural products to similar human metabolites and provide possible therapeutic effects of natural products. By utilizing the similar human metabolite information, we expect to find new indications of natural products which could not be covered by previous in silico methods.

The re-emergence of natural products for drug discovery in the genomics era.

PubMed

Harvey, Alan L; Edrada-Ebel, RuAngelie; Quinn, Ronald J

2015-02-01

Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein-protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

Nephrotoxicity of Natural Products.

PubMed

Nauffal, Mary; Gabardi, Steven

2016-01-01

The manufacture and sale of natural products constitute a multi-billion dollar industry. Nearly a third of the American population admit to using some form of complementary or alternative medicine, with many using them in addition to prescription medications. Most patients fail to inform their healthcare providers of their natural product use and physicians rarely inquire. Annually, thousands of natural product-induced adverse events are reported to Poison Control Centers nationwide. Natural product manufacturers are not responsible for proving safety and efficacy, as the FDA does not regulate them. However, concerns exist surrounding the safety of natural products. This review provides details on natural products that have been associated with renal dysfunction. We have focused on products that have been associated with direct renal injury, immune-mediated nephrotoxicity, nephrolithiasis, rhabdomyolysis with acute renal injury, hepatorenal syndrome, and common adulterants or contaminants that are associated with renal dysfunction. The potential for natural products to cause renal dysfunction is justifiable. It is imperative that natural product use be monitored closely in all patients. Healthcare practitioners must play an active role in identifying patients using natural products and provide appropriate patient education. © 2016 S. Karger AG, Basel.

Rediscovering natural products as a source of new drugs.

PubMed

Koehn, Frank E; Carter, Guy T

2005-04-01

Extract: Since the very beginnings of human medicine, physicians have relied on chemical compounds produced by animals, plants and microorganisms, so-called natural products, to treat diseases. Natural products are directly or indirectly responsible for roughly one-half of all drugs currently in use. Of the 877 small-molecule new drug molecules introduced between 1981 and 2002, 49% were natural products or natural product analogs. Despite the great success of the 70s and 80s, the pharmaceutical industry de-emphasized natural products research during the following decade. In this article, we examine the underlying reasons for the decline, and assess future prospects for natural products research in drug discovery. In the 1990s, major pharmaceutical companies moved to a lead-finding strategy based on High Throughput Screening (HTS) of very large collections (libraries) of synthetic compounds. The move arose from the belief that techniques such as combinatorial chemistry could produce larger, more cost-effective libraries with improved hit rates and quality. Additionally, advances in molecular biology, cellular biology and genomics dramatically increased the number of molecular targets, prompting shorter drug discovery timelines. In today's drug discovery environment, rapid screening and identification of potential drug molecules is essential for success. This puts traditional natural products-based programs, with their reliance on the lengthy processes of the screening of extracts library, bioassay-guided isolation of the active components, structure elucidation and subsequent production scale-up, at a competitive disadvantage.

Natural product-like virtual libraries: recursive atom-based enumeration.

PubMed

Yu, Melvin J

2011-03-28

A new molecular enumerator is described that allows chemically and architecturally diverse sets of natural product-like and drug-like structures to be generated from a core structure as simple as a single carbon atom or as complex as a polycyclic ring system. Integrated with a rudimentary machine-learning algorithm, the enumerator has the ability to assemble biased virtual libraries enriched in compounds predicted to meet target criteria. The ability to dynamically generate relatively small focused libraries in a recursive manner could reduce the computational time and infrastructure necessary to construct and manage extremely large static libraries. Depending on enumeration conditions, natural product-like structures can be produced with a wide range of heterocyclic and alicyclic ring assemblies. Because natural products represent a proven source of validated structures for identifying and designing new drug candidates, mimicking the structural and topological diversity found in nature with a dynamic set of virtual natural product-like compounds may facilitate the creation of new ideas for novel, biologically relevant lead structures in areas of uncharted chemical space.

Natural-Product-Derived Carbon Dots: From Natural Products to Functional Materials.

PubMed

Zhang, Xinyue; Jiang, Mingyue; Niu, Na; Chen, Zhijun; Li, Shujun; Liu, Shouxin; Li, Jian

2018-01-10

Nature provides an almost limitless supply of sources that inspire scientists to develop new materials with novel applications and less of an environmental impact. Recently, much attention has been focused on preparing natural-product-derived carbon dots (NCDs), because natural products have several advantages. First, natural products are renewable and have good biocompatibility. Second, natural products contain heteroatoms, which facilitate the fabrication of heteroatom-doped NCDs without the addition of an external heteroatom source. Finally, some natural products can be used to prepare NCDs in ways that are very green and simple relative to traditional methods for the preparation of carbon dots from man-made carbon sources. NCDs have shown tremendous potential in many fields, including biosensing, bioimaging, optoelectronics, and photocatalysis. This Review addresses recent progress in the synthesis, properties, and applications of NCDs. The challenges and future direction of research on NCD-based materials in this booming field are also discussed. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Informatic search strategies to discover analogues and variants of natural product archetypes.

PubMed

Johnston, Chad W; Connaty, Alex D; Skinnider, Michael A; Li, Yong; Grunwald, Alyssa; Wyatt, Morgan A; Kerr, Russell G; Magarvey, Nathan A

2016-03-01

Natural products are a crucial source of antimicrobial agents, but reliance on low-resolution bioactivity-guided approaches has led to diminishing interest in discovery programmes. Here, we demonstrate that two in-house automated informatic platforms can be used to target classes of biologically active natural products, specifically, peptaibols. We demonstrate that mass spectrometry-based informatic approaches can be used to detect natural products with high sensitivity, identifying desired agents present in complex microbial extracts. Using our specialised software packages, we could elaborate specific branches of chemical space, uncovering new variants of trichopolyn and demonstrating a way forward in mining natural products as a valuable source of potential pharmaceutical agents.

Biosynthetic Potential-Based Strain Prioritization for Natural Product Discovery: A Showcase for Diterpenoid-Producing Actinomycetes

PubMed Central

2015-01-01

Natural products remain the best sources of drugs and drug leads and serve as outstanding small-molecule probes to dissect fundamental biological processes. A great challenge for the natural product community is to discover novel natural products efficiently and cost effectively. Here we report the development of a practical method to survey biosynthetic potential in microorganisms, thereby identifying the most promising strains and prioritizing them for natural product discovery. Central to our approach is the innovative preparation, by a two-tiered PCR method, of a pool of pathway-specific probes, thereby allowing the survey of all variants of the biosynthetic machineries for the targeted class of natural products. The utility of the method was demonstrated by surveying 100 strains, randomly selected from our actinomycete collection, for their biosynthetic potential of four classes of natural products, aromatic polyketides, reduced polyketides, nonribosomal peptides, and diterpenoids, identifying 16 talented strains. One of the talented strains, Streptomyces griseus CB00830, was finally chosen to showcase the discovery of the targeted classes of natural products, resulting in the isolation of three diterpenoids, six nonribosomal peptides and related metabolites, and three polyketides. Variations of this method should be applicable to the discovery of other classes of natural products. PMID:24484381

Effective use of heterologous hosts for characterization of biosynthetic enzymes allows production of natural products and promotes new natural product discovery.

PubMed

Watanabe, Kenji

2014-01-01

In the past few years, there has been impressive progress in elucidating the mechanism of biosynthesis of various natural products accomplished through the use of genetic, molecular biological and biochemical techniques. Here, we present a comprehensive overview of the current results from our studies on fungal natural product biosynthetic enzymes, including nonribosomal peptide synthetase and polyketide synthase-nonribosomal peptide synthetase hybrid synthetase, as well as auxiliary enzymes, such as methyltransferases and oxygenases. Specifically, biosynthesis of the following compounds is described in detail: (i) Sch210972, potentially involving a Diels-Alder reaction that may be catalyzed by CghA, a functionally unknown protein identified by targeted gene disruption in the wild type fungus; (ii) chaetoglobosin A, formed via multi-step oxidations catalyzed by three redox enzymes, one flavin-containing monooxygenase and two cytochrome P450 oxygenases as characterized by in vivo biotransformation of relevant intermediates in our engineered Saccharomyces cerevisiae; (iii) (-)-ditryptophenaline, formed by a cytochrome P450, revealing the dimerization mechanism for the biosynthesis of diketopiperazine alkaloids; (iv) pseurotins, whose variations in the C- and O-methylations and the degree of oxidation are introduced combinatorially by multiple redox enzymes; and (v) spirotryprostatins, whose spiro-carbon moiety is formed by a flavin-containing monooxygenase or a cytochrome P450 as determined by heterologous de novo production of the biosynthetic intermediates and final products in Aspergillus niger. We close our discussion by summarizing some of the key techniques that have facilitated the discovery of new natural products, production of their analogs and identification of biosynthetic mechanisms in our study.

Natural Products as Anticancerous Therapeutic Molecules with Special Reference to Enzymatic Targets Topoisomerase, COX, LOX and Aromatase.

PubMed

Singh, Swati; Awasthi, Manika; Pandey, Veda P; Dwivedi, Upendra N

2018-01-01

Cancer, characterized by uncontrolled growth and proliferation of cells, is affecting millions of people every year and estimated as the second leading cause of death. Its successful treatment yet remains a challenge due to the lack of selectivity, toxicity and the development of multidrug resistant cells to the currently available drugs. Plant derived natural products hold great promise for discovery and development of new pharmaceuticals against cancer as evident by the fact that out of 121 drugs prescribed for cancer treatment till date, 90 are derived from plant sources. Furthermore, the plant derived therapeutic molecules are also considered as safer substitutes to those of synthetic ones. In this review, the therapeutic potentials of plant derived natural products belonging to secondary metabolites, namely alkaloids, flavonoids and terpenoids as anticancer molecules, involving various strategies of treatment, have been discussed with special reference to topoisomerases (Topo), cyclooxygenases (COX), lipoxygenase (LOX) and aromatase as enzymatic targets for various types of cancers. Furthermore, in view of the recent advances made in the field of computer aided drug design, the present review also discusses the use of computational approaches such as ADMET, molecular docking, molecular dynamics simulation and QSAR to assess and predict the safety, efficacy, potency and identification of such potent anticancerous therapeutic molecules. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Natural and engineered biosynthesis of fluorinated natural products.

PubMed

Walker, Mark C; Chang, Michelle C Y

2014-09-21

Both natural products and synthetic organofluorines play important roles in the discovery and design of pharmaceuticals. The combination of these two classes of molecules has the potential to be useful in the ongoing search for new bioactive compounds but our ability to produce site-selectively fluorinated natural products remains limited by challenges in compatibility between their high structural complexity and current methods for fluorination. Living systems provide an alternative route to chemical fluorination and could enable the production of organofluorine natural products through synthetic biology approaches. While the identification of biogenic organofluorines has been limited, the study of the native organisms and enzymes that utilize these compounds can help to guide efforts to engineer the incorporation of this unusual element into complex pharmacologically active natural products. This review covers recent advances in understanding both natural and engineered production of organofluorine natural products.

Flavin-catalyzed redox tailoring reactions in natural product biosynthesis.

PubMed

Teufel, Robin

2017-10-15

Natural products are distinct and often highly complex organic molecules that constitute not only an important drug source, but have also pushed the field of organic chemistry by providing intricate targets for total synthesis. How the astonishing structural diversity of natural products is enzymatically generated in biosynthetic pathways remains a challenging research area, which requires detailed and sophisticated approaches to elucidate the underlying catalytic mechanisms. Commonly, the diversification of precursor molecules into distinct natural products relies on the action of pathway-specific tailoring enzymes that catalyze, e.g., acylations, glycosylations, or redox reactions. This review highlights a selection of tailoring enzymes that employ riboflavin (vitamin B2)-derived cofactors (FAD and FMN) to facilitate unusual redox catalysis and steer the formation of complex natural product pharmacophores. Remarkably, several such recently reported flavin-dependent tailoring enzymes expand the classical paradigms of flavin biochemistry leading, e.g., to the discovery of the flavin-N5-oxide - a novel flavin redox state and oxygenating species. Copyright © 2017 Elsevier Inc. All rights reserved.

Natural products: a hope for glioblastoma patients.

PubMed

Vengoji, Raghupathy; Macha, Muzafar A; Batra, Surinder K; Shonka, Nicole A

2018-04-24

Glioblastoma (GBM) is one of the most aggressive malignant tumors with an overall dismal survival averaging one year despite multimodality therapeutic interventions including surgery, radiotherapy and concomitant and adjuvant chemotherapy. Few drugs are FDA approved for GBM, and the addition of temozolomide (TMZ) to standard therapy increases the median survival by only 2.5 months. Targeted therapy appeared promising in in vitro monolayer cultures, but disappointed in preclinical and clinical trials, partly due to the poor penetration of drugs through the blood brain barrier (BBB). Cancer stem cells (CSCs) have intrinsic resistance to initial chemoradiation therapy (CRT) and acquire further resistance via deregulation of many signaling pathways. Due to the failure of classical chemotherapies and targeted drugs, research efforts focusing on the use of less toxic agents have increased. Interestingly, multiple natural compounds have shown antitumor and apoptotic effects in TMZ resistant and p53 mutant GBM cell lines and also displayed synergistic effects with TMZ. In this review, we have summarized the current literature on natural products or product analogs used to modulate the BBB permeability, induce cell death, eradicate CSCs and sensitize GBM to CRT.

Natural products: a hope for glioblastoma patients

PubMed Central

Vengoji, Raghupathy; Macha, Muzafar A.; Batra, Surinder K.; Shonka, Nicole A.

2018-01-01

Glioblastoma (GBM) is one of the most aggressive malignant tumors with an overall dismal survival averaging one year despite multimodality therapeutic interventions including surgery, radiotherapy and concomitant and adjuvant chemotherapy. Few drugs are FDA approved for GBM, and the addition of temozolomide (TMZ) to standard therapy increases the median survival by only 2.5 months. Targeted therapy appeared promising in in vitro monolayer cultures, but disappointed in preclinical and clinical trials, partly due to the poor penetration of drugs through the blood brain barrier (BBB). Cancer stem cells (CSCs) have intrinsic resistance to initial chemoradiation therapy (CRT) and acquire further resistance via deregulation of many signaling pathways. Due to the failure of classical chemotherapies and targeted drugs, research efforts focusing on the use of less toxic agents have increased. Interestingly, multiple natural compounds have shown antitumor and apoptotic effects in TMZ resistant and p53 mutant GBM cell lines and also displayed synergistic effects with TMZ. In this review, we have summarized the current literature on natural products or product analogs used to modulate the BBB permeability, induce cell death, eradicate CSCs and sensitize GBM to CRT. PMID:29774132

Something old, something new: revisiting natural products in antibiotic drug discovery.

PubMed

Wright, Gerard D

2014-03-01

Antibiotic discovery is in crisis. Despite a growing need for new drugs resulting from the increasing number of multi-antibiotic-resistant pathogens, there have been only a handful of new antibiotics approved for clinical use in the past 2 decades. Faced with scientific, economic, and regulatory challenges, the pharmaceutical sector seems unable to respond to what has been called an "apocalyptic" threat. Natural products produced by bacteria and fungi are genetically encoded products of natural selection that have been the mainstay sources of the antibiotics in current clinical use. The pharmaceutical industry has largely abandoned these compounds in favor of large libraries of synthetic molecules because of difficulties in identifying new natural product antibiotics scaffolds. Advances in next-generation genome sequencing, bioinformatics, and analytical chemistry are combining to overcome barriers to natural products. Coupled with new strategies in antibiotic discovery, including inhibition of resistance, novel drug combinations, and new targets, natural products are poised for a renaissance to address what is a pressing health care crisis.

Plants and their active compounds: natural molecules to target angiogenesis.

PubMed

Lu, Kai; Bhat, Madhavi; Basu, Sujit

2016-07-01

Angiogenesis, or new blood vessel formation, is an important process in the pathogenesis of several diseases and thus has been targeted for the prevention and treatment for many disorders. However, the anti-angiogenic agents that are currently in use are mainly synthetic compounds and humanized monoclonal antibodies, which are either expensive or toxic, thereby limiting their use in many patients. Therefore, it is necessary to identify less toxic, inexpensive, novel and effective anti-angiogenic molecules. Several studies have indicated that natural plant products can meet these criteria. In this review, we discuss the anti-angiogenic properties of natural compounds isolated from plants and the molecular mechanisms by which these molecules act. Finally, we summarize the advantages of using plant products as anti-angiogenic agents. Compared with currently available anti-angiogenic drugs, plant products may not only have similar therapeutic potential but are also inexpensive, less toxic, and easy to administer. However, novel and effective strategies are necessary to improve their bioavailability for clinical use.

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

Natural Products to Counteract the Epidemic of Cardiovascular and Metabolic Disorders

PubMed Central

Šmejkal, Karel; Heiss, Elke H.; Atanasov, Atanas G.

2016-01-01

Natural products have always been exploited to promote health and served as a valuable source for the discovery of new drugs. In this review, the great potential of natural compounds and medicinal plants for the treatment or prevention of cardiovascular and metabolic disorders, global health problems with rising prevalence, is addressed. Special emphasis is laid on natural products for which efficacy and safety have already been proven and which are in clinical trials, as well as on plants used in traditional medicine. Potential benefits from certain dietary habits and dietary constituents, as well as common molecular targets of natural products, are also briefly discussed. A glimpse at the history of statins and biguanides, two prominent representatives of natural products (or their derivatives) in the fight against metabolic disease, is also included. The present review aims to serve as an “opening” of this special issue of Molecules, presenting key historical developments, recent advances, and future perspectives outlining the potential of natural products for prevention or therapy of cardiovascular and metabolic disease. PMID:27338339

Natural Products to Counteract the Epidemic of Cardiovascular and Metabolic Disorders.

PubMed

Waltenberger, Birgit; Mocan, Andrei; Šmejkal, Karel; Heiss, Elke H; Atanasov, Atanas G

2016-06-22

Natural products have always been exploited to promote health and served as a valuable source for the discovery of new drugs. In this review, the great potential of natural compounds and medicinal plants for the treatment or prevention of cardiovascular and metabolic disorders, global health problems with rising prevalence, is addressed. Special emphasis is laid on natural products for which efficacy and safety have already been proven and which are in clinical trials, as well as on plants used in traditional medicine. Potential benefits from certain dietary habits and dietary constituents, as well as common molecular targets of natural products, are also briefly discussed. A glimpse at the history of statins and biguanides, two prominent representatives of natural products (or their derivatives) in the fight against metabolic disease, is also included. The present review aims to serve as an "opening" of this special issue of Molecules, presenting key historical developments, recent advances, and future perspectives outlining the potential of natural products for prevention or therapy of cardiovascular and metabolic disease.

Natural Products as a Source for Novel Antibiotics.

PubMed

Moloney, Mark G

2016-08-01

Natural products have historically been of crucial importance in the identification and development of antibacterial agents. Interest in these systems has waned in recent years, but the rapid emergence of resistant bacterial strains has forced their re-evaluation as a route to identify novel chemical skeletons with antibacterial activity for elaboration in drug development. This overview examines the current situation, highlights new natural product systems which have been found, together with re-examination of some old ones, and new technologies for their identification. While natural products certainly have the potential to re-emerge as a key start-point in antibacterial drug discovery, reports of new or reinvestigated structures need to be supported with sufficient quality chemical (solubility, stability), biochemical (including toxicity in particular, along with target information) and microbiological [minimum inhibitory concentration (MIC) and resistance frequency] validation data to assist in the identification of promising hit structures and to avoid wasted effort from trawling over already cultivated territory. This is particularly important in a resource-limited research environment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products.

PubMed

Shugrue, Christopher R; Miller, Scott J

2017-09-27

The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogues of natural products by this approach is then described as a quintessential "late-stage functionalization" exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this Review is on the recent studies of nonenzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C-H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C-C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-selective alteration including polyketides, glycopeptides, terpenoids, macrolides, alkaloids, carbohydrates, and others. What emerges is a platform for chemical remodeling of naturally occurring scaffolds that targets virtually all known chemical functionalities and microenvironments. However, challenges for the design of very broad classes of catalysts, with even broader selectivity demands (e.g., stereoselectivity, functional group selectivity, and site-selectivity) persist. Yet, a significant spectrum of powerful, catalytic alterations of complex natural products now exists such that expansion of scope seems inevitable. Several instances of biological activity assays of remodeled natural product derivatives are also presented. These reports may foreshadow further interdisciplinary impacts for catalytic remodeling of natural products, including contributions to SAR development, mode of action studies, and eventually medicinal chemistry.

Natural product (-)-gossypol inhibits colon cancer cell growth by targeting RNA-binding protein Musashi-1.

PubMed

Lan, Lan; Appelman, Carl; Smith, Amber R; Yu, Jia; Larsen, Sarah; Marquez, Rebecca T; Liu, Hao; Wu, Xiaoqing; Gao, Philip; Roy, Anuradha; Anbanandam, Asokan; Gowthaman, Ragul; Karanicolas, John; De Guzman, Roberto N; Rogers, Steven; Aubé, Jeffrey; Ji, Min; Cohen, Robert S; Neufeld, Kristi L; Xu, Liang

2015-08-01

Musashi-1 (MSI1) is an RNA-binding protein that acts as a translation activator or repressor of target mRNAs. The best-characterized MSI1 target is Numb mRNA, whose encoded protein negatively regulates Notch signaling. Additional MSI1 targets include the mRNAs for the tumor suppressor protein APC that regulates Wnt signaling and the cyclin-dependent kinase inhibitor P21(WAF-1). We hypothesized that increased expression of NUMB, P21 and APC, through inhibition of MSI1 RNA-binding activity might be an effective way to simultaneously downregulate Wnt and Notch signaling, thus blocking the growth of a broad range of cancer cells. We used a fluorescence polarization assay to screen for small molecules that disrupt the binding of MSI1 to its consensus RNA binding site. One of the top hits was (-)-gossypol (Ki = 476 ± 273 nM), a natural product from cottonseed, known to have potent anti-tumor activity and which has recently completed Phase IIb clinical trials for prostate cancer. Surface plasmon resonance and nuclear magnetic resonance studies demonstrate a direct interaction of (-)-gossypol with the RNA binding pocket of MSI1. We further showed that (-)-gossypol reduces Notch/Wnt signaling in several colon cancer cell lines having high levels of MSI1, with reduced SURVIVIN expression and increased apoptosis/autophagy. Finally, we showed that orally administered (-)-gossypol inhibits colon cancer growth in a mouse xenograft model. Our study identifies (-)-gossypol as a potential small molecule inhibitor of MSI1-RNA interaction, and suggests that inhibition of MSI1's RNA binding activity may be an effective anti-cancer strategy. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Opportunities for natural products in 21st century antibiotic discovery.

PubMed

Wright, Gerard D

2017-07-01

Natural products and their derivatives are mainstays of our antibiotic drugs, but they are increasingly in peril. The combination of widespread multidrug resistance in once susceptible bacterial pathogens, disenchantment with natural products as sources of new drugs, lack of success using synthetic compounds and target-based discovery methods, along with shifting economic and regulatory issues, conspire to move investment in research and development away from the antibiotics arena. The result is a growing crisis in antibiotic drug discovery that threatens modern medicine. 21 st century natural product research is perfectly positioned to fill the antibiotic discovery gap and bring new drug candidates to the clinic. Innovations in genomics and techniques to explore new sources of antimicrobial chemical matter are revealing new chemistry. Increasing appreciation of the value of narrow-spectrum drugs and re-examination of once discarded chemical scaffolds coupled with synthetic biology methods to generate new compounds and improve yields offer new strategies to revitalize once moribund natural product programs. The increasing awareness that the combination of antibiotics with adjuvants, non-antibiotic compounds that overcome resistance and enhance drug activity, can rescue older chemical scaffolds, and concepts such as blocking pathogen virulence present orthogonal strategies to traditional antibiotics. In all these areas, natural products offer chemical matter, shaped by natural selection, that is privileged in this therapeutic area. Natural product research is poised to regain prominence in delivering new drugs to solve the antibiotic crisis.

Microsatellites as targets of natural selection.

PubMed

Haasl, Ryan J; Payseur, Bret A

2013-02-01

The ability to survey polymorphism on a genomic scale has enabled genome-wide scans for the targets of natural selection. Theory that connects patterns of genetic variation to evidence of natural selection most often assumes a diallelic locus and no recurrent mutation. Although these assumptions are suitable to selection that targets single nucleotide variants, fundamentally different types of mutation generate abundant polymorphism in genomes. Moreover, recent empirical results suggest that mutationally complex, multiallelic loci including microsatellites and copy number variants are sometimes targeted by natural selection. Given their abundance, the lack of inference methods tailored to the mutational peculiarities of these types of loci represents a notable gap in our ability to interrogate genomes for signatures of natural selection. Previous theoretical investigations of mutation-selection balance at multiallelic loci include assumptions that limit their application to inference from empirical data. Focusing on microsatellites, we assess the dynamics and population-level consequences of selection targeting mutationally complex variants. We develop general models of a multiallelic fitness surface, a realistic model of microsatellite mutation, and an efficient simulation algorithm. Using these tools, we explore mutation-selection-drift equilibrium at microsatellites and investigate the mutational history and selective regime of the microsatellite that causes Friedreich's ataxia. We characterize microsatellite selective events by their duration and cost, note similarities to sweeps from standing point variation, and conclude that it is premature to label microsatellites as ubiquitous agents of efficient adaptive change. Together, our models and simulation algorithm provide a powerful framework for statistical inference, which can be used to test the neutrality of microsatellites and other multiallelic variants.

Microsatellites as Targets of Natural Selection

PubMed Central

Haasl, Ryan J.; Payseur, Bret A.

2013-01-01

The ability to survey polymorphism on a genomic scale has enabled genome-wide scans for the targets of natural selection. Theory that connects patterns of genetic variation to evidence of natural selection most often assumes a diallelic locus and no recurrent mutation. Although these assumptions are suitable to selection that targets single nucleotide variants, fundamentally different types of mutation generate abundant polymorphism in genomes. Moreover, recent empirical results suggest that mutationally complex, multiallelic loci including microsatellites and copy number variants are sometimes targeted by natural selection. Given their abundance, the lack of inference methods tailored to the mutational peculiarities of these types of loci represents a notable gap in our ability to interrogate genomes for signatures of natural selection. Previous theoretical investigations of mutation-selection balance at multiallelic loci include assumptions that limit their application to inference from empirical data. Focusing on microsatellites, we assess the dynamics and population-level consequences of selection targeting mutationally complex variants. We develop general models of a multiallelic fitness surface, a realistic model of microsatellite mutation, and an efficient simulation algorithm. Using these tools, we explore mutation-selection-drift equilibrium at microsatellites and investigate the mutational history and selective regime of the microsatellite that causes Friedreich’s ataxia. We characterize microsatellite selective events by their duration and cost, note similarities to sweeps from standing point variation, and conclude that it is premature to label microsatellites as ubiquitous agents of efficient adaptive change. Together, our models and simulation algorithm provide a powerful framework for statistical inference, which can be used to test the neutrality of microsatellites and other multiallelic variants. PMID:23104080

Phylogeny-guided (meta)genome mining approach for the targeted discovery of new microbial natural products.

PubMed

Kang, Hahk-Soo

2017-02-01

Genomics-based methods are now commonplace in natural products research. A phylogeny-guided mining approach provides a means to quickly screen a large number of microbial genomes or metagenomes in search of new biosynthetic gene clusters of interest. In this approach, biosynthetic genes serve as molecular markers, and phylogenetic trees built with known and unknown marker gene sequences are used to quickly prioritize biosynthetic gene clusters for their metabolites characterization. An increase in the use of this approach has been observed for the last couple of years along with the emergence of low cost sequencing technologies. The aim of this review is to discuss the basic concept of a phylogeny-guided mining approach, and also to provide examples in which this approach was successfully applied to discover new natural products from microbial genomes and metagenomes. I believe that the phylogeny-guided mining approach will continue to play an important role in genomics-based natural products research.

Genomes to natural products PRediction Informatics for Secondary Metabolomes (PRISM)

PubMed Central

Skinnider, Michael A.; Dejong, Chris A.; Rees, Philip N.; Johnston, Chad W.; Li, Haoxin; Webster, Andrew L. H.; Wyatt, Morgan A.; Magarvey, Nathan A.

2015-01-01

Microbial natural products are an invaluable source of evolved bioactive small molecules and pharmaceutical agents. Next-generation and metagenomic sequencing indicates untapped genomic potential, yet high rediscovery rates of known metabolites increasingly frustrate conventional natural product screening programs. New methods to connect biosynthetic gene clusters to novel chemical scaffolds are therefore critical to enable the targeted discovery of genetically encoded natural products. Here, we present PRISM, a computational resource for the identification of biosynthetic gene clusters, prediction of genetically encoded nonribosomal peptides and type I and II polyketides, and bio- and cheminformatic dereplication of known natural products. PRISM implements novel algorithms which render it uniquely capable of predicting type II polyketides, deoxygenated sugars, and starter units, making it a comprehensive genome-guided chemical structure prediction engine. A library of 57 tailoring reactions is leveraged for combinatorial scaffold library generation when multiple potential substrates are consistent with biosynthetic logic. We compare the accuracy of PRISM to existing genomic analysis platforms. PRISM is an open-source, user-friendly web application available at http://magarveylab.ca/prism/. PMID:26442528

Search for bioactive natural products from medicinal plants of Bangladesh.

PubMed

Ahmed, Firoj; Sadhu, Samir Kumar; Ishibashi, Masami

2010-10-01

In our continuous search for bioactive natural products from natural resources, we explored medicinal plants of Bangladesh, targeting cancer-related tumor necrosis factor-related apoptosis-inducing ligand-signaling pathway, along with some other biological activities such as prostaglandin inhibitory activity, 1,1-diphenyl-2-picrylhydrazyl free-radical-scavenging activity, and cell growth inhibitory activity. Along with this, we describe a short field study on Sundarbans mangrove forests, Bangladesh, in the review.

Marine natural products: a new wave of drugs?

PubMed Central

Montaser, Rana; Luesch, Hendrik

2011-01-01

The largely unexplored marine world that presumably harbors the most biodiversity may be the vastest resource to discover novel ‘validated’ structures with novel modes of action that cover biologically relevant chemical space. Several challenges, including the supply problem and target identification, need to be met for successful drug development of these often complex molecules; however, approaches are available to overcome the hurdles. Advances in technologies such as sampling strategies, nanoscale NMR for structure determination, total chemical synthesis, fermentation and biotechnology are all crucial to the success of marine natural products as drug leads. We illustrate the high degree of innovation in the field of marine natural products, which in our view will lead to a new wave of drugs that flow into the market and pharmacies in the future. PMID:21882941

Natural Products and HIV/AIDS.

PubMed

Cary, Daniele C; Peterlin, B Matija

2018-01-01

The study of natural products in biomedical research is not a modern concept. Many of the most successful medical therapeutics are derived from natural products, including those studied in the field of HIV/AIDS. Biomedical research has a rich history of discovery based on screens of medicinal herbs and traditional medicine practices. Compounds derived from natural products, which repress HIV and those that activate latent HIV, have been reported. It is important to remember the tradition in medical research to derive therapies based on these natural products and to overcome the negative perception of natural products as an "alternative medicine."

Cyclooxygenase inhibitory natural products: current status.

PubMed

Jachak, Sanjay M

2006-01-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are of huge therapeutic benefit in the treatment of rheumatoid arthritis and various types of inflammatory conditions. The target for these drugs is cyclooxygenase (COX), a rate-limiting enzyme involved in the conversion of arachidonic acid into inflammatory prostaglandins. COX-2 selective inhibitors are believed to have the same anti-inflammatory, anti-pyretic and analgesic activities as that of nonselective inhibitor NSAIDs with little or none of the gastrointestinal side effects. Thus, in the last 6-7 years several selective COX-2 inhibitors including coxibs were discovered and introduced into clinic. Recent reports evidence that selective COX-2 inhibitor such as rofecoxib, can lead to thrombotic cardiovascular events through inhibition of prostacyclin formation in the infracted heart. This has resulted in withdrawal of rofecoxib from the clinic in September 2004. Moreover, the COX-2/COX-1 selectivity ratio is vital in the design of COX-2 inhibitory drugs, as it is clear from rofecoxib, which is more than 50-fold COX-2 selective. After looking at all above mentioned facts, natural product-based compounds seem better as these compounds are generally supposed to be devoid of severe side effects. The literature indicates that natural product-based compounds are mainly COX-1 selective. Through minor semi-synthetic changes in the structures, their selectivity towards COX-2 can be increased. The present review article addresses natural product COX inhibitors of plant and marine origin, reported during last ten years and their advantages, possible leads for further development and current status. In addition we describe our experience in the characterization, design and synthesis of potential natural COX inhibitors.

Inhibition of the ubiquitin-proteasome system by natural products for cancer therapy.

PubMed

Tsukamoto, Sachiko; Yokosawa, Hideyoshi

2010-08-01

The ubiquitin-proteasome system plays a critical role in selective protein degradation and regulates almost all cellular events such as cell cycle progression, signal transduction, cell death, immune responses, metabolism, protein quality control, development, and neuronal function. The recent approval of bortezomib, a synthetic proteasome inhibitor, for the treatment of relapsed multiple myeloma has opened the way to the discovery of drugs targeting the proteasome and ubiquitinating and deubiquitinating enzymes as well as the delivery system. To date, various synthetic and natural products have been reported to inhibit the components of the ubiquitin-proteasome system. Here, we review natural products targeting the ubiquitin-proteasome system as well as synthetic compounds with potent inhibitory effects. Georg Thieme Verlag KG Stuttgart-New York.

Strain Prioritization for Natural Product Discovery by a High-Throughput Real-Time PCR Method

PubMed Central

2015-01-01

Natural products offer unmatched chemical and structural diversity compared to other small-molecule libraries, but traditional natural product discovery programs are not sustainable, demanding too much time, effort, and resources. Here we report a strain prioritization method for natural product discovery. Central to the method is the application of real-time PCR, targeting genes characteristic to the biosynthetic machinery of natural products with distinct scaffolds in a high-throughput format. The practicality and effectiveness of the method were showcased by prioritizing 1911 actinomycete strains for diterpenoid discovery. A total of 488 potential diterpenoid producers were identified, among which six were confirmed as platensimycin and platencin dual producers and one as a viguiepinol and oxaloterpin producer. While the method as described is most appropriate to prioritize strains for discovering specific natural products, variations of this method should be applicable to the discovery of other classes of natural products. Applications of genome sequencing and genome mining to the high-priority strains could essentially eliminate the chance elements from traditional discovery programs and fundamentally change how natural products are discovered. PMID:25238028

An Overview of Some Natural Products with Two A-Level Science Club Natural Products Experiments

ERIC Educational Resources Information Center

Sosabowski, Michael Hal; Olivier, George W. J.; Jawad, Hala; Maatta, Sieja

2017-01-01

Natural products are ubiquitous in nature but do not form a large proportion of the A-level syllabuses in the UK. In this article we briefly discuss a small selection of natural products, focusing on alcohols, aldehydes and ketones, and alkaloids. We then outline two natural product experiments that are suitable for A-level chemistry clubs or…

Genomes to natural products PRediction Informatics for Secondary Metabolomes (PRISM).

PubMed

Skinnider, Michael A; Dejong, Chris A; Rees, Philip N; Johnston, Chad W; Li, Haoxin; Webster, Andrew L H; Wyatt, Morgan A; Magarvey, Nathan A

2015-11-16

Microbial natural products are an invaluable source of evolved bioactive small molecules and pharmaceutical agents. Next-generation and metagenomic sequencing indicates untapped genomic potential, yet high rediscovery rates of known metabolites increasingly frustrate conventional natural product screening programs. New methods to connect biosynthetic gene clusters to novel chemical scaffolds are therefore critical to enable the targeted discovery of genetically encoded natural products. Here, we present PRISM, a computational resource for the identification of biosynthetic gene clusters, prediction of genetically encoded nonribosomal peptides and type I and II polyketides, and bio- and cheminformatic dereplication of known natural products. PRISM implements novel algorithms which render it uniquely capable of predicting type II polyketides, deoxygenated sugars, and starter units, making it a comprehensive genome-guided chemical structure prediction engine. A library of 57 tailoring reactions is leveraged for combinatorial scaffold library generation when multiple potential substrates are consistent with biosynthetic logic. We compare the accuracy of PRISM to existing genomic analysis platforms. PRISM is an open-source, user-friendly web application available at http://magarveylab.ca/prism/. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Emerging Trends in the Discovery of Natural Product Antibacterials

PubMed Central

Bologa, Cristian G.; Ursu, Oleg; Oprea, Tudor; Melançon, Charles E.; Tegos, George P.

2013-01-01

This article highlights current trends and advances in exploiting natural sources for the deployment of novel and potent anti-infective countermeasures. The key challenge is to therapeutically target microbial pathogens exhibiting a variety of puzzling and evolutionary complex resistance mechanisms. Special emphasis is given to the strengths, weaknesses, and opportunities in the natural product antimicrobial drug discovery arena, and to emerging applications driven by advances in bioinformatics, chemical biology, and synthetic biology in concert with exploiting the microbial phenotype. These orchestrated efforts have identified a critical mass of lead natural antimicrobials chemical scaffolds and discovery technologies with high probability of successful implementation against emerging microbial pathogens. PMID:23890825

Glycosylation and Activities of Natural Products.

PubMed

Huang, Gangliang; Lv, Meijiao; Hu, Jinchuan; Huang, Kunlin; Xu, Hong

2016-01-01

Natural products are widely found in nature, their number and variety are numerous, the structures are complex and diverse. These natural products have many physiological and pharmacological activities. Glycosylation can increase the diversity of structure and function of natural product, it has become the focus of drug research and development. The impacts of glycosylation of natural products to water solubility, pharmacological activities, bioavailability, or others were described in this review, which provides a reference for the development and application of glycosylated natural products.

Modulation of oncogenic transcription factors by bioactive natural products in breast cancer.

PubMed

Hasanpourghadi, Mohadeseh; Pandurangan, Ashok Kumar; Mustafa, Mohd Rais

2018-02-01

Carcinogenesis, a multi-step phenomenon, characterized by alterations at genetic level and affecting the main intracellular pathways controlling cell growth and development. There are growing number of evidences linking oncogenes to the induction of malignancies, especially breast cancer. Modulations of oncogenes lead to gain-of-function signals in the cells and contribute to the tumorigenic phenotype. These signals yield a large number of proteins that cause cell growth and inhibit apoptosis. Transcription factors such as STAT, p53, NF-κB, c-JUN and FOXM1, are proteins that are conserved among species, accumulate in the nucleus, bind to DNA and regulate the specific genes targets. Oncogenic transcription factors resulting from the mutation or overexpression following aberrant gene expression relay the signals in the nucleus and disrupt the transcription pattern. Activation of oncogenic transcription factors is associated with control of cell cycle, apoptosis, migration and cell differentiation. Among different cancer types, breast cancer is one of top ten cancers worldwide. There are different subtypes of breast cancer cell-lines such as non-aggressive MCF-7 and aggressive and metastatic MDA-MB-231 cells, which are identified with distinct molecular profile and different levels of oncogenic transcription factor. For instance, MDA-MB-231 carries mutated and overexpressed p53 with its abnormal, uncontrolled downstream signalling pathway that account for resistance to several anticancer drugs compared to MCF-7 cells with wild-type p53. Appropriate enough, inhibition of oncogenic transcription factors has become a potential target in discovery and development of anti-tumour drugs against breast cancer. Plants produce diverse amount of organic metabolites. Universally, these metabolites with biological activities are known as "natural products". The chemical structure and function of natural products have been studied since 1850s. Investigating these properties leaded

Modulation of Toll-like receptor signaling in innate immunity by natural products.

PubMed

Chen, Luxi; Yu, Jianhua

2016-08-01

For centuries, natural products and their derivatives have provided a rich source of compounds for the development of new immunotherapies in the treatment of human disease. Many of these compounds are currently undergoing clinical trials, particularly as anti-oxidative, anti-microbial, and anti-cancer agents. However, the function and mechanism of natural products in how they interact with our immune system has yet to be extensively explored. Natural immune modulators may provide the key to control and ultimately defeat disorders affecting the immune system. They can either up- or down-regulate the immune response with few undesired adverse effects. In this review, we summarize the recent advancements made in utilizing natural products for immunomodulation and their important molecular targets, members of the Toll-like receptor (TLR) family, in the innate immune system. Copyright © 2016 Elsevier B.V. All rights reserved.

Bioactive natural products in cancer prevention and therapy: Progress and promise.

PubMed

Bishayee, Anupam; Sethi, Gautam

2016-10-01

Natural products represent a rich source for the discovery and development of cancer preventive and anticancer drugs. Nearly, 80% of all drugs approved by the United States Food and Drug Administration during the last three decades for cancer therapy are either natural products per se or are based thereon, or mimicked natural products in one form or another. With the advent and refinement of new technologies, such as genetic techniques for production of secondary plant metabolites, combinatorial synthesis and high-throughput screening, it is expected that novel compounds from natural sources, including medicinal plants, would be identified and developed as safe and effective chemopreventive and anticancer drugs. Numerous bioactive natural compounds have been shown to be useful in prevention and therapy of cancer by targeting various signaling molecules and pathways. Extensive literature underscores the anticancer and chemopreventive activity of a plethora of naturally occurring agents, including phytochemicals. Several of these molecules have been tested in clinical trials and some of them have shown promise in combination therapy when administered along with standard chemotherapeutic agents. Thus, accelerated chemopreventive and chemotherapeutic drug development from natural sources is of great importance. In this special theme issue, contributions from eminent scientists and scholars around the world presented critical analysis of the current progress and promise of natural bioactive constituents in cancer prevention and therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

PubMed

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

2015-09-28

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.

Updates on Managing Type 2 Diabetes Mellitus with Natural Products: Towards Antidiabetic Drug Development.

PubMed

Alam, Fahmida; Islam, Md Asiful; Kamal, M A; Gan, Siew Hua

2016-08-13

Over the years, natural products have shown success as antidiabetics in vitro, in vivo and in clinical trials. Because natural product-derived drugs are more affordable and effective with fewer side-effects compared to conventional therapies, pharmaceutical research is increasingly leaning towards the discovery of new antidiabetic drugs from natural products targeting pathways or components associated with type 2 diabetes mellitus (T2DM) pathophysiology. However, the drug discovery process is very lengthy and costly with significant challenges. Therefore, various techniques are currently being developed for the preclinical research phase of drug discovery with the aim of drug development with less time and efforts from natural products. In this review, we have provided an update on natural products including fruits, vegetables, spices, nuts, beverages and mushrooms with potential antidiabetic activities from in vivo, in vitro and clinical studies. Synergistic interactions between natural products and antidiabetic drugs; and potential antidiabetic active compounds from natural products are also documented to pave the way for combination treatment and new drug discovery, respectively. Additionally, a brief idea of the drug discovery process along with the challenges that arise during drug development from natural products and the methods to conquer those challenges are discussed to create a more convenient future drug discovery process.

Seeking new acne treatment from natural products, devices and synthetic drug discovery.

PubMed

Yang, Ji Hoon; Yoon, Ji Young; Kwon, Hyuck Hoon; Min, Seonguk; Moon, Jungyoon; Suh, Dae Hun

2017-01-01

Despite lots of research on the pathogenesis of acne, the development of new therapeutic agents is still stagnant. Conventional agents which target multiple pathological processes have some serious side effects and this makes seeking new treatment options important for treating acne. As new therapeutic options, researchers are focusing on natural products, synthetic drugs and devices. From natural products, epigallocatechin-3 gallate, lupeol, cannabidiol and Lactobacillus fermented Chamaecyperis obtusa were reported to be possible candidates for novel drugs, targeting multiple pathogenic factors. Synthetic anti- P.acnes agent, nitric oxide nanoparticles and α-mangostin nanoparticles are shown to be effective in acne treatment. Device or procedural methods such as fractional microneedling radiofrequency, cryolysis, photothermolysis and daylight photodynamic therapy have potential as new treatment options for acne. Further large clinical trials comparing these new treatments with existing agents will be necessary in the future.

Amorfrutins are potent antidiabetic dietary natural products

PubMed Central

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

2012-01-01

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

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

Natural products with anti-aging potential: Affected targets and molecular mechanisms.

PubMed

Cătană, Cristina-Sorina; Atanasov, Atanas G; Berindan-Neagoe, Ioana

2018-03-27

In recent years, there has been a great deal of attention toward the molecular machinery relevant to age-related progression controlled through the external intervention of polyphenols- an epigenetic-modulating diet. Natural products modulate cellular longevity through histone post-translational modification and can also induce the upregulation of autophagy, thus reducing the level of acetyl coenzyme A (AcCoA). In addition, the effect of caloric restriction (CR) on cancer-related chronic inflammation is of great significance in aging. In line with this, SIRT1 protein levels are expanded in response to calorie restriction mimetics (CRM), in this way acting as autophagy inducers relevant to cancer prevention. Copyright © 2018 Elsevier Inc. All rights reserved.

Screening of a virtual mirror-image library of natural products.

PubMed

Noguchi, Taro; Oishi, Shinya; Honda, Kaori; Kondoh, Yasumitsu; Saito, Tamio; Ohno, Hiroaki; Osada, Hiroyuki; Fujii, Nobutaka

2016-06-08

We established a facile access to an unexplored mirror-image library of chiral natural product derivatives using d-protein technology. In this process, two chemical syntheses of mirror-image substances including a target protein and hit compound(s) allow the lead discovery from a virtual mirror-image library without the synthesis of numerous mirror-image compounds.

Functional Reconstitution of a Fungal Natural Product Gene Cluster by Advanced Genome Editing.

PubMed

Weber, Jakob; Valiante, Vito; Nødvig, Christina S; Mattern, Derek J; Slotkowski, Rebecca A; Mortensen, Uffe H; Brakhage, Axel A

2017-01-20

Filamentous fungi produce varieties of natural products even in a strain dependent manner. However, the genetic basis of chemical speciation between strains is still widely unknown. One example is trypacidin, a natural product of the opportunistic human pathogen Aspergillus fumigatus, which is not produced among different isolates. Combining computational analysis with targeted gene editing, we could link a single nucleotide insertion in the polyketide synthase of the trypacidin biosynthetic pathway and reconstitute its production in a nonproducing strain. Thus, we present a CRISPR/Cas9-based tool for advanced molecular genetic studies in filamentous fungi, exploiting selectable markers separated from the edited locus.

Biomimetic syntheses of racemic natural products.

PubMed

Zask, Arie; Ellestad, George

2018-02-01

Racemic natural products are rarely produced in plants and microorganisms and are thought to be the result of nonenzymatic, spontaneous reactions. These compounds are often highly complex with multiple contiguous chiral centers that present a challenge to organic synthesis. Formation of these racemates often occurs by cyclization reactions that can generate multiple stereocenters from achiral precursors. Biomimetic synthesis of these racemic natural products provides support for their proposed nonenzymatic spontaneous biosynthesis. These elegant syntheses also provide scalable and efficient routes to these complex natural products. Although the number of reported racemic natural products is relatively low, an isolated natural product that has a very small optical rotation has been shown to be a true racemate. Thus, the occurrence of racemic natural products could be more common than thought. © 2017 Wiley Periodicals, Inc.

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

NPCARE: database of natural products and fractional extracts for cancer regulation.

PubMed

Choi, Hwanho; Cho, Sun Young; Pak, Ho Jeong; Kim, Youngsoo; Choi, Jung-Yun; Lee, Yoon Jae; Gong, Byung Hee; Kang, Yeon Seok; Han, Taehoon; Choi, Geunbae; Cho, Yeeun; Lee, Soomin; Ryoo, Dekwoo; Park, Hwangseo

2017-01-01

Natural products have increasingly attracted much attention as a valuable resource for the development of anticancer medicines due to the structural novelty and good bioavailability. This necessitates a comprehensive database for the natural products and the fractional extracts whose anticancer activities have been verified. NPCARE (http://silver.sejong.ac.kr/npcare) is a publicly accessible online database of natural products and fractional extracts for cancer regulation. At NPCARE, one can explore 6578 natural compounds and 2566 fractional extracts isolated from 1952 distinct biological species including plants, marine organisms, fungi, and bacteria whose anticancer activities were validated with 1107 cell lines for 34 cancer types. Each entry in NPCARE is annotated with the cancer type, genus and species names of the biological resource, the cell line used for demonstrating the anticancer activity, PubChem ID, and a wealth of information about the target gene or protein. Besides the augmentation of plant entries up to 743 genus and 197 families, NPCARE is further enriched with the natural products and the fractional extracts of diverse non-traditional biological resources. NPCARE is anticipated to serve as a dominant gateway for the discovery of new anticancer medicines due to the inclusion of a large number of the fractional extracts as well as the natural compounds isolated from a variety of biological resources.

Subclass-specific labeling of protein-reactive natural products with customized nucleophilic probes.

PubMed

Rudolf, Georg C; Koch, Maximilian F; Mandl, Franziska A M; Sieber, Stephan A

2015-02-23

Natural products represent a rich source of bioactive compounds that constitute a large fraction of approved drugs. Among those are molecules with electrophilic scaffolds, such as Michael acceptors, β-lactams, and epoxides that irreversibly inhibit essential enzymes based on their catalytic mechanism. In the search for novel bioactive molecules, current methods are challenged by the frequent rediscovery of known chemical entities. Herein small nucleophilic probes that attack electrophilic natural products and enhance their detection by HPLC-UV and HPLC-MS are introduced. A screen of diverse probe designs revealed one compound with a desired selectivity for epoxide- and maleimide-based antibiotics. Correspondingly, the natural products showdomycin and phosphomycin could be selectively targeted in extracts of their natural producing organism, in which the probe-modified molecules exhibited superior retention and MS detection relative to their unmodified counterparts. This method may thus help to discover small, electrophilic molecules that might otherwise easily elude detection in complex samples. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Seeking new acne treatment from natural products, devices and synthetic drug discovery

PubMed Central

Yoon, Ji Young; Kwon, Hyuck Hoon; Min, Seonguk; Suh, Dae Hun

2017-01-01

ABSTRACT Despite lots of research on the pathogenesis of acne, the development of new therapeutic agents is still stagnant. Conventional agents which target multiple pathological processes have some serious side effects and this makes seeking new treatment options important for treating acne. As new therapeutic options, researchers are focusing on natural products, synthetic drugs and devices. From natural products, epigallocatechin-3 gallate, lupeol, cannabidiol and Lactobacillus fermented Chamaecyperis obtusa were reported to be possible candidates for novel drugs, targeting multiple pathogenic factors. Synthetic anti-P.acnes agent, nitric oxide nanoparticles and α-mangostin nanoparticles are shown to be effective in acne treatment. Device or procedural methods such as fractional microneedling radiofrequency, cryolysis, photothermolysis and daylight photodynamic therapy have potential as new treatment options for acne. Further large clinical trials comparing these new treatments with existing agents will be necessary in the future. PMID:29484092

Nanoscale Delivery Systems: Actual and Potential Applications in the Natural Products Industry.

PubMed

Simona, Antal Diana; Florina, Ardelean; Rodica, Chis Aimee; Evelyne, Ollivier; Maria-Corina, Serban

2017-01-01

Compounds and extracts derived from natural sources continue to stand in the spotlight of drug design owing to their versatile interaction with enzymes, receptors and metabolic pathways. Nanomedicine offers an operative tool for the efficient delivery of natural products, in terms of increased bioavailability, targeting, and controlled release while protecting active constituents against physico-chemical alterations. The interest of the scientific community in the field of nanosized delivery of natural compounds is demonstrated by the exponential growth of the publications in this field. Beyond the presentation of successful examples of nanoscale delivery systems containing natural products, the scope of this review is to point out the yet underexplored capacities of this field with relevance for the pharmaceutical and nutraceutical market. Departing from a short presentation of plant-derived natural products and strategies to obtain nanoformulations, the current work discusses nanoparticulate drug delivery systems targeting diseases of various organs and systems: skin, central nervous system, skeletal tissue, cardiovascular apparatus, and diabetes. While notable progress has been achieved in the preparation of nanomedicines containing selected dietary polyphenols, works dealing with crude extracts or standardized fractions are much less frequent. In fact, most of the plants with solidly documented therapeutic properties and registered in pharmacopoeias still wait to benefit from advances in the field of nanotechnology. At least for some of them, adequate nanoformulation shall contribute to their removal from the group of dietary supplements and pharmaceutical preparations with suboptimal bioavailability and efficacy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Multipass Target Search in Natural Environments

PubMed Central

Otte, Michael W.; Sofge, Donald; Gupta, Satyandra K.

2017-01-01

Consider a disaster scenario where search and rescue workers must search difficult to access buildings during an earthquake or flood. Often, finding survivors a few hours sooner results in a dramatic increase in saved lives, suggesting the use of drones for expedient rescue operations. Entropy can be used to quantify the generation and resolution of uncertainty. When searching for targets, maximizing mutual information of future sensor observations will minimize expected target location uncertainty by minimizing the entropy of the future estimate. Motion planning for multi-target autonomous search requires planning over an area with an imperfect sensor and may require multiple passes, which is hindered by the submodularity property of mutual information. Further, mission duration constraints must be handled accordingly, requiring consideration of the vehicle’s dynamics to generate feasible trajectories and must plan trajectories spanning the entire mission duration, something which most information gathering algorithms are incapable of doing. If unanticipated changes occur in an uncertain environment, new plans must be generated quickly. In addition, planning multipass trajectories requires evaluating path dependent rewards, requiring planning in the space of all previously selected actions, compounding the problem. We present an anytime algorithm for autonomous multipass target search in natural environments. The algorithm is capable of generating long duration dynamically feasible multipass coverage plans that maximize mutual information using a variety of techniques such as ϵ-admissible heuristics to speed up the search. To the authors’ knowledge this is the first attempt at efficiently solving multipass target search problems of such long duration. The proposed algorithm is based on best first branch and bound and is benchmarked against state of the art algorithms adapted to the problem in natural Simplex environments, gathering the most information in the

Natural products used for diabetes.

PubMed

Shapiro, Karen; Gong, William C

2002-01-01

To review the efficacy and safety of natural products commonly used for diabetes. English and Spanish-language journals retrieved through a MEDLINE search of articles published between 1960 and December 2001 using these index terms: Opuntia, karela, gymnema, tecoma, alpha lipoic acid, thioctic acid, ginseng, panaxans, and diabetes. Natural products have long been used in traditional systems of medicine for diabetes. Products in common use include nopal (prickly pear cactus), fenu-greek, karela (bitter melon), gymnema, ginseng, tronadora, chromium, and alpha-lipoic acid. The popularity of these products varies among people of different ethnicities. Nopal is the most commonly used herbal hypoglycemic among persons of Mexican descent. Karela is more commonly used by persons from Asian countries. Some of these agents have gained universal appeal. For a select number of products, studies have revealed single or multiple mechanisms of action. For several of these, high soluble fiber content is a contributing factor. Based on the available evidence, several natural products in common use can lower blood glucose in patients with diabetes. Commonly used natural products often have a long history of traditional use, and pharmacists who have a stronger understanding of these products are better positioned to counsel patients on their appropriate use.

Decaleside: a new class of natural insecticide targeting tarsal gustatory sites

NASA Astrophysics Data System (ADS)

Rajashekar, Yallappa; Rao, Lingamallu J. M.; Shivanandappa, Thimmappa

2012-10-01

Natural sources for novel insecticide molecules hold promise in view of their eco-friendly nature, selectivity, and mammalian safety. Recent progress in understanding the biology of insect olfaction and taste offers new strategies for developing selective pest control agents. We have isolated two natural insecticidal molecules from edible roots of Decalepis hamiltonii named Decalesides I and II, which are novel trisaccharides, highly toxic to household insect pests and stored-product insects. We have experimentally shown that insecticidal activity requires contact with tarsi on the legs but is not toxic orally. The insecticidal activity of molecules is lost by hydrolysis, and various sugars modify toxic response, showing that the insecticidal activity is via gustatory sites on the tarsi. Selective toxicity to insects by virtue of their gustatory site of action and the mammalian safety of the new insecticides is inherent in their chemical structure with 1-4 or 1-1 α linkage that is easily hydrolyzed by digestive enzymes of mammals. Decalesides represent a new chemical class of natural insecticides with a unique mode of action targeting tarsal chemosensory/gustatory system of insects.

Discovery of the leinamycin family of natural products by mining actinobacterial genomes.

PubMed

Pan, Guohui; Xu, Zhengren; Guo, Zhikai; Hindra; Ma, Ming; Yang, Dong; Zhou, Hao; Gansemans, Yannick; Zhu, Xiangcheng; Huang, Yong; Zhao, Li-Xing; Jiang, Yi; Cheng, Jinhua; Van Nieuwerburgh, Filip; Suh, Joo-Won; Duan, Yanwen; Shen, Ben

2017-12-26

Nature's ability to generate diverse natural products from simple building blocks has inspired combinatorial biosynthesis. The knowledge-based approach to combinatorial biosynthesis has allowed the production of designer analogs by rational metabolic pathway engineering. While successful, structural alterations are limited, with designer analogs often produced in compromised titers. The discovery-based approach to combinatorial biosynthesis complements the knowledge-based approach by exploring the vast combinatorial biosynthesis repertoire found in Nature. Here we showcase the discovery-based approach to combinatorial biosynthesis by targeting the domain of unknown function and cysteine lyase domain (DUF-SH) didomain, specific for sulfur incorporation from the leinamycin (LNM) biosynthetic machinery, to discover the LNM family of natural products. By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF-SH didomains. Further analysis of the representative genomes from each of the clades identified 28 lnm -type gene clusters. Structural diversities encoded by the LNM-type biosynthetic machineries were predicted based on bioinformatics and confirmed by in vitro characterization of selected adenylation proteins and isolation and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature's rich biosynthetic repertoire. Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect Nature's biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity.

Construction of a 3D-shaped, natural product like fragment library by fragmentation and diversification of natural products.

PubMed

Prescher, Horst; Koch, Guido; Schuhmann, Tim; Ertl, Peter; Bussenault, Alex; Glick, Meir; Dix, Ina; Petersen, Frank; Lizos, Dimitrios E

2017-02-01

A fragment library consisting of 3D-shaped, natural product-like fragments was assembled. Library construction was mainly performed by natural product degradation and natural product diversification reactions and was complemented by the identification of 3D-shaped, natural product like fragments available from commercial sources. In addition, during the course of these studies, novel rearrangements were discovered for Massarigenin C and Cytochalasin E. The obtained fragment library has an excellent 3D-shape and natural product likeness, covering a novel, unexplored and underrepresented chemical space in fragment based drug discovery (FBDD). Copyright © 2016 Elsevier Ltd. All rights reserved.

Alternative Fuels Data Center: Natural Gas Production

Science.gov Websites

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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.

Spirolactones: Recent Advances in Natural Products, Bioactive Compounds and Synthetic Strategies.

PubMed

Quintavalla, Arianna

2018-01-01

The spirocyclic compounds have always aroused a great interest because this motif is present as structural core in a number of natural products and bioactive compounds. In particular, the spirolactone moiety has been recognized in a wide array of natural and non-natural scaffolds showing a variety of useful pharmacological properties. Extensive literature search using SciFinder (Databases: CA Plus, CAS Registry, CAS React, Chemlist, Chemcat and Medline) and Web of Science (Database: Web of Science Core Collection) was conducted. Nowadays, many efforts are being devoted to the discovery of new natural products containing the promising spirolactone framework and to the disclosure of the potential bioactivities of these chemical entities. Moreover, the medicinal relevance of many spirolactones makes these scaffolds attractive targets for the design and development of innovative and efficient synthetic strategies, enabling the construction of complex and variably substituted products. This review gives an overview on the recent advances in the spirolactones field, in terms of new compounds isolated from natural sources, recently determined bioactivity profiles and innovative synthetic approaches. The collected data demonstrate the key role played by spirolactones in medicinal chemistry and the great attention still devoted by the scientific community to these compounds. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Natural products as modulators of spermatogenesis: the search for a male contraceptive.

PubMed

Dias, Tania R; Alves, Marco G; Oliveira, Pedro F; Silva, Branca M

2014-01-01

Population growth in the last century has raised important social and economic questions. Thus, current methods of fertility control have been under debate for a long period. Birth rates are essentially dependent on several environmental and social factors but women, who are great users of contraceptives, play a major role. Regulation of male fertility has been widely studied in recent years with the aim of developing a new male contraceptive for further inclusion of men's choice in family planning. Based on the ancient people techniques to control the birth rates, natural products appeared as a promising source for the development of a male contraceptive. Over the years, many plants and their main constituents have been studied in the search for their antifertility properties. Interestingly, some antispermatogenic effects have been reported. Herein, we will discuss the antispermatogenic properties of some natural products. We propose to discuss specific targets and sites of action of the selected natural products. Despite the advances in this field in the last years, the molecular mechanisms by which natural products can control fertility, need to be disclosed to develop an effective, reversible and safe male contraceptive and avoid undesired toxicity in other organs. To date, no natural-based male contraceptive is available in the commercial market, mostly due to the difficulty in reversing the effects of these products in male fertility.

The Variation of Work Productivity and Muscle Activities at Different Levels of Production Target

NASA Astrophysics Data System (ADS)

Nur, Nurhayati Mohd; Dawal, Siti Zawiah Md; Dahari, Mahidzal; Zuhairah Mahmud Zuhudi, Nurul

2017-10-01

This paper aims to investigate the variation of work productivity and muscle activities among workers performing industrial repetitive tasks at four different levels of production target. The work productivity and muscle activities data were recorded from twenty workers at four levels of production target corresponding to “participative (PS1)”, “normal (PS2)”, “high (PS3)” and “very high (PS4)”. The results showed that worker productivity was found to increase at higher production target and there was a significant change (p < 0.005) in work productivity across the four different production targets. The muscle activities were found to increase at higher production target and correspond to more discomfort and a higher rate of muscle fatigue. The results indicated that working with a higher production target results in higher worker productivity, but could lead to higher risk of WMSDs.

Comparative analysis of chemical similarity methods for modular natural products with a hypothetical structure enumeration algorithm.

PubMed

Skinnider, Michael A; Dejong, Chris A; Franczak, Brian C; McNicholas, Paul D; Magarvey, Nathan A

2017-08-16

Natural products represent a prominent source of pharmaceutically and industrially important agents. Calculating the chemical similarity of two molecules is a central task in cheminformatics, with applications at multiple stages of the drug discovery pipeline. Quantifying the similarity of natural products is a particularly important problem, as the biological activities of these molecules have been extensively optimized by natural selection. The large and structurally complex scaffolds of natural products distinguish their physical and chemical properties from those of synthetic compounds. However, no analysis of the performance of existing methods for molecular similarity calculation specific to natural products has been reported to date. Here, we present LEMONS, an algorithm for the enumeration of hypothetical modular natural product structures. We leverage this algorithm to conduct a comparative analysis of molecular similarity methods within the unique chemical space occupied by modular natural products using controlled synthetic data, and comprehensively investigate the impact of diverse biosynthetic parameters on similarity search. We additionally investigate a recently described algorithm for natural product retrobiosynthesis and alignment, and find that when rule-based retrobiosynthesis can be applied, this approach outperforms conventional two-dimensional fingerprints, suggesting it may represent a valuable approach for the targeted exploration of natural product chemical space and microbial genome mining. Our open-source algorithm is an extensible method of enumerating hypothetical natural product structures with diverse potential applications in bioinformatics.

COPPER-64 Production Studies with Natural Zinc Targets at Deuteron Energy up to 19 Mev and Proton Energy from 141 Down to 31 Mev

NASA Astrophysics Data System (ADS)

Bonardi, Mauro L.; Birattari, Claudio; Groppi, Flavia; Song Mainard, Hae; Zhuikov, Boris L.; Kokhanyuk, Vladimir M.; Lapshina, Elena V.; Mebel, Michail V.; Menapace, Enzo

2004-07-01

High specific activity no-carrier-added 64Cu is a β-/β+ emitting radionuclide of increasing interest for PET imaging, as well as systemic and targeted radioimmunotherapy of tumors. Its peculiarity of intense Auger emitter is still under investigation. The cross-sections for production of 64Cu from Zn target of natural isotopic composition were measured in the deuteron energy range from threshold up to 19 MeV and proton energy range from 141 down to 31 MeV. The stacked-foil technique was used at both K=38 cyclotron of JRC-Ispra of CEC, Italy and 160 MeV intersection point of INR proton-LINAC in Troitsk, Russia. Several Ga, Zn, Cu, Ni, Co, V, Fe and Mn radionuclides were detected in Zn targets at the EOB. Optimized irradiation conditions are reported as a function of deuteron energy and energy loss into the Zn target, as well as target irradiation time and cooling time after radiochemistry. The activity of n.c.a. 64Cu was measured through its only γ emission of 1346 keV (i.e. 0.473 % intensity) both by instrumental and radiochemical methods, due to the non-specificity of annihilation radiation at 511 keV. To this last purpose, it was necessary to carry out a selective radiochemical separation of GaIII radionuclides by liquid/liquid extraction from the bulk of irradiated Zn targets and other spallation products, which remained in the 7 M HCl aqueous phase. Anion exchange chromatography tests had been carried out to separate the 64Cu from all others radionuclides in n.c.a. form. Theoretical calculations of cross-sections were performed with codes EMPIRE II and PENELOPE for deuteron reactions and CEF model and HMS-ALICE hybrid model for proton reactions. The theoretical results are presented and compared with the experimental values.

Mimicking/extracting structure and functions of natural products: synthetic approaches that address unexplored needs in chemical biology.

PubMed

Hirai, Go

2015-04-01

Natural products are often attractive and challenging targets for synthetic chemists, and many have interesting biological activities. However, synthetic chemists need to be more than simply suppliers of compounds to biologists. Therefore, we have been seeking ways to actively apply organic synthetic methods to chemical biology studies of natural products and their activities. In this personal review, I would like to introduce our work on the development of new biologically active compounds inspired by, or extracted from, the structures of natural products, focusing on enhancement of functional activity and specificity and overcoming various drawbacks of the parent natural products. Copyright © 2014 The Chemical Society of Japan and Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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

Toward the Dark Matter of Natural Products.

PubMed

Wakimoto, Toshiyuki

2017-11-01

Considering the dynamic features of natural products, our access toward exploring the entire diversity of natural products has been quite limited. It is challenging to assess the diversity of natural products by using conventional analytical methods, even with tandem chromatographic techniques, such as LC-MS and GC-MS. This viewpoint is supported by the sequencing analyses of microbial genomes, which have unveiled the potential of secondary metabolite production far exceeding the number of isolated molecules. Recent advancements in metabolomics, in concert with genomics analyses, have further extended the natural product diversity, prompting growing awareness of the existence of reactive or short-lived natural molecules. This personal account introduces some examples of the discoveries of hitherto elusive natural products, due to physico-chemical or biological reasons, and highlights the significance of the dark matter of natural products. © 2017 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Progress on the chemical separation of fission fragments from 236Np produced by proton irradiation of natural uranium target

NASA Astrophysics Data System (ADS)

Larijani, C.; Jerome, S. M.; Lorusso, G.; Ivanov, P.; Russell, B.; Pearce, A. K.; Regan, P. H.

2017-11-01

The aim of the current work is to develop and validate a radiochemical separation scheme capable of separating both 236gNp and 236Pu from a uranium target of natural isotopic composition ( 1 g uranium) and 200 MBq of fission decay products. A target containing 1.2 g of UO2 was irradiated with a beam of 25 MeV protons with a typical beam current of 30 μA for 19 h in December 2013 at the University of Birmingham Cyclotron facility. Using literature values for the production cross-section for fusion of protons with uranium targets, we estimate that an upper limit of approximately 250 Bq of activity from the 236Np ground state was produced in this experiment. Using a radiochemical separation scheme, Np and Pu fractions were separated from the produced fission decay products, with analyses of the target-based final reaction products made using Inductively Couple Plasma Mass Spectrometry (ICP-MS) and high-resolution α particle and γ-ray spectrometry.

Targeting Malassezia species for Novel Synthetic and Natural Antidandruff Agents.

PubMed

Angiolella, Letizia; Carradori, Simone; Maccallini, Cristina; Giusiano, Gustavo; Supuran, Claudiu T

2017-01-01

Malassezia spp. are lipophilic yeasts not only present in the normal skin microflora, but also responsible of skin-related diseases (pityriasis versicolor, seborrheic/atopic dermatitis and dandruff) as well as systemic fungal infections in humans and animals. Their treatment and eradication are mainly based on old azole drugs, which are characterized by poor compliance, unpredictable clinical efficacy, emerging resistance and several side effects. These drawbacks have prompted the research toward novel synthetic and natural derivatives/ nanomaterials targeting other pivotal enzymes/pathways such as carbonic anhydrase (MgCA) and lipases, alone or in combination, in order to improve the eradication rate of this fungus. This review accomplished an update on this important topic dealing with the latest discoveries of synthetic scaffolds and natural products for the treatment of Malassezia spp.-related diseases, thus suggesting new opportunities to design innovative and alternative anti-dandruff drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Metabolomics-based chemotaxonomy of root endophytic fungi for natural products discovery.

PubMed

Maciá-Vicente, Jose G; Shi, Yan-Ni; Cheikh-Ali, Zakaria; Grün, Peter; Glynou, Kyriaki; Kia, Sevda Haghi; Piepenbring, Meike; Bode, Helge B

2018-03-01

Fungi are prolific producers of natural products routinely screened for biotechnological applications, and those living endophytically within plants attract particular attention because of their purported chemical diversity. However, the harnessing of their biosynthetic potential is hampered by a large and often cryptic phylogenetic and ecological diversity, coupled with a lack of large-scale natural products' dereplication studies. To guide efforts to discover new chemistries among root-endophytic fungi, we analyzed the natural products produced by 822 strains using an untargeted UPLC-ESI-MS/MS-based approach and linked the patterns of chemical features to fungal lineages. We detected 17 809 compounds of which 7951 were classified in 1992 molecular families, whereas the remaining were considered unique chemistries. Our approach allowed to annotate 1191 compounds with different degrees of accuracy, many of which had known fungal origins. Approximately 61% of the compounds were specific of a fungal order, and differences were observed across lineages in the diversity and characteristics of their chemistries. Chemical profiles also showed variable chemosystematic values across lineages, ranging from relative homogeneity to high heterogeneity among related fungi. Our results provide an extensive resource to dereplicate fungal natural products and may assist future discovery programs by providing a guide for the selection of target fungi. © 2018 Society for Applied Microbiology and John Wiley & Sons Ltd.

The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective.

PubMed

Li, Ying Hong; Wang, Pan Pan; Li, Xiao Xu; Yu, Chun Yan; Yang, Hong; Zhou, Jin; Xue, Wei Wei; Tan, Jun; Zhu, Feng

2016-01-01

The human kinome is one of the most productive classes of drug target, and there is emerging necessity for treating complex diseases by means of polypharmacology (multi-target drugs and combination products). However, the advantages of the multi-target drugs and the combination products are still under debate. A comparative analysis between FDA approved multi-target drugs and combination products, targeting the human kinome, was conducted by mapping targets onto the phylogenetic tree of the human kinome. The approach of network medicine illustrating the drug-target interactions was applied to identify popular targets of multi-target drugs and combination products. As identified, the multi-target drugs tended to inhibit target pairs in the human kinome, especially the receptor tyrosine kinase family, while the combination products were able to against targets of distant homology relationship. This finding asked for choosing the combination products as a better solution for designing drugs aiming at targets of distant homology relationship. Moreover, sub-networks of drug-target interactions in specific disease were generated, and mechanisms shared by multi-target drugs and combination products were identified. In conclusion, this study performed an analysis between approved multi-target drugs and combination products against the human kinome, which could assist the discovery of next generation polypharmacology.

Molecular approaches towards development of purified natural products and their structurally known derivatives as efficient anti-cancer drugs: current trends.

PubMed

Saha, Santu Kumar; Khuda-Bukhsh, Anisur Rahman

2013-08-15

Several natural products and their derivatives, either in purified or structurally identified form, exhibit immense pharmacological and biological properties, some of them showing considerable anticancer potential. Although the molecular mechanisms of action of some of these products are yet to be elucidated, extensive research in this area continues to generate new data that are clinically exploitable. Recent advancement in molecular biology, high throughput screening, biomarker identifications, target selection and genomic approaches have enabled us to understand salient interactions of natural products and their derivatives with cancer cells vis-à-vis normal cells. In this review we highlight the recent approaches and application of innovative technologies made to improve quality as well as efficiency of structurally identified natural products and their derivatives, particularly in small molecular forms capable of being used in "targeted therapies" in oncology. These products preferentially involve multiple mechanistic pathways and overcome chemo-resistance in tumor types with cumulative action. We also mention briefly a few physico-chemical features that compare natural products with drugs in recent natural product discovery approaches. We further report here a few purified natural products as examples that provide molecular interventions in cancer therapeutics to give the reader a glimpse of the current trends of approach for discovering useful anticancer drugs. © 2013 Elsevier B.V. All rights reserved.

Diazo Reagents with Small Steric Footprints for Simultaneous Arming/SAR Studies of Alcohol-Containing Natural Products via O–H Insertion

PubMed Central

Chamni, Supakarn; He, Qing-Li; Dang, Yongjun; Bhat, Shridhar; Liu, Jun O.; Romo, Daniel

2011-01-01

Natural products are essential tools for basic cellular studies leading to the identification of medically relevant protein targets and the discovery of potential therapeutic leads. The development of methods that enable mild and selective derivatization of natural products continues to be of significant interest for mining their information-rich content. Herein, we describe novel diazo reagents for simultaneous arming and structure-activity relationship (SAR) studies of alcohol-containing natural products with a small steric footprint, namely an α-trifluoroethyl (HTFB) substituted reagent. The Rh(II)-catalyzed O–H insertion reaction of several natural products, including the potent translation inhibitor lactimidomycin, was investigated and useful reactivity and both chemo- and site (chemosite) selectivities were observed. Differential binding to the known protein targets of both FK506 and fumagillol was demonstrated, validating the advantage of the smaller steric footprint of trifluoroethyl derivatives. A p-azidophenyl diazo reagent is also described that will prove useful for photoaffinity labeling of low affinity small molecule protein receptors. PMID:21894934

Natural product-based amyloid inhibitors.

PubMed

Velander, Paul; Wu, Ling; Henderson, Frances; Zhang, Shijun; Bevan, David R; Xu, Bin

2017-09-01

Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned. Copyright © 2017 Elsevier Inc. All rights reserved.

Natural product-based amyloid inhibitors

PubMed Central

Velander, Paul; Wu, Ling; Henderson, Frances; Zhang, Shijun; Bevan, David R.; Xu, Bin

2018-01-01

Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned. PMID:28390938

Production and Evaluation of 236gNp and Reference Materials for Naturally Occurring Radioactive Materials

NASA Astrophysics Data System (ADS)

Larijani, Cyrus Kouroush

This thesis is based on the development of a radiochemical separation scheme capable of separating both 236gNp and 236Pu from a uranium target of natural isotopic composition ( 1 g uranium) and 200 MBq of fission decay products. The isobaric distribution of fission residues produced following the bombardment of a natural uranium target with a beam of 25 MeV protons has been evaluated. Decay analysis of thirteen isobarically distinct fission residues were carried out using high-resolution gamma-ray spectrometry at the UK National Physical Laboratory. Stoichiometric abundances were calculated via the determination of absolute activity concentrations associated with the longest-lived members of each isobaric chain. This technique was validated by computational modelling of likely sequential decay processes through an isobaric decay chain. The results were largely in agreement with previously published values for neutron bombardments on natural uranium at energies of 14 MeV. Higher relative yields of products with mass numbers A 110-130 were found, consistent with the increasing yield of these radionuclides as the bombarding energy is increased. Using literature values for the production cross-section for fusion of protons with uranium targets, it is estimated that an upper limit of approximately 250 Bq of activity from the 236Np ground state was produced in this experiment. Using a radiochemical separation scheme, Np and Pu fractions were separated from the produced fission decay products, with analyses of the target-based final reaction products made using Inductively Couple Plasma Mass Spectrometry (ICP-MS) and high-resolution alpha and gamma-ray spectrometry. In a separate research theme, reliable measurement of Naturally Occurring Radioactive Materials is of significance in order to comply with environmental regulations and for radiological protection purposes. The thesis describes the standardisation of three reference materials, namely Sand, Tuff and TiO2 which

Alternative Fuels Data Center: Conventional Natural Gas Production

Science.gov Websites

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Synthesis of Polycyclic Natural Products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, Tuan Hoang

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 amore » worthwhile challenge in itself. The pursuit of concise and efficient syntheses of complex molecules is both gratifying and enjoyable.« less

Beauty and charm production at fixed-target experiments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Erik E. Gottschalk

Fixed-target experiments continue to provide insights into the physics of particle production in strong interactions. The experiments are performed with different types of beam particles of varying energies, and many different target materials. Studies of beauty and charm production are of particular interest, since experimental results can be compared to perturbative QCD calculations. It is in this context that recent results from fixed-target experiments on beauty and charm production will be reviewed.

Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1) modulators from natural products as anti-cancer agents

USDA-ARS?s Scientific Manuscript database

Natural products are rich source of gene modulators for prevention and treatment of cancer. In recent days, nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) has been focused as a new target of diverse cancers like colorectal, pancreatic, prostate, and breast. A variety of natural...

[Exploring New Drug Targets through the Identification of Target Molecules of Bioactive Natural Products].

PubMed

Arai, Masayoshi

2016-01-01

With the development of cell biology and microbiology, it has become easy to culture many types of animal cells and microbes, and they are frequently used for phenotypic screening to explore medicinal seeds. On the other hand, it is recognized that cells and pathogenic microbes present in pathologic sites and infected regions of the human body display unique properties different from those under general culture conditions. We isolated several bioactive compounds from marine medicinal resources using constructed bioassay-guided separation focusing on the unique changes in the characteristics of cells and pathogenic microbes (Mycobacterium spp.) in the human body under disease conditions. In addition, we also carried out identification studies of target molecules of the bioactive compounds by methods utilizing the gene expression profile, transformants of cells or microbes, synthetic probe molecules of the isolated compounds, etc., since bioactive compounds isolated from the phenotypic screening system often target new molecules. This review presents our phenotypic screening systems, isolation of bioactive compounds from marine medicinal resources, and target identification of bioactive compounds.

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

Discovery of the leinamycin family of natural products by mining actinobacterial genomes

PubMed Central

Xu, Zhengren; Guo, Zhikai; Hindra; Ma, Ming; Zhou, Hao; Gansemans, Yannick; Zhu, Xiangcheng; Huang, Yong; Zhao, Li-Xing; Jiang, Yi; Cheng, Jinhua; Van Nieuwerburgh, Filip; Suh, Joo-Won; Duan, Yanwen

2017-01-01

Nature’s ability to generate diverse natural products from simple building blocks has inspired combinatorial biosynthesis. The knowledge-based approach to combinatorial biosynthesis has allowed the production of designer analogs by rational metabolic pathway engineering. While successful, structural alterations are limited, with designer analogs often produced in compromised titers. The discovery-based approach to combinatorial biosynthesis complements the knowledge-based approach by exploring the vast combinatorial biosynthesis repertoire found in Nature. Here we showcase the discovery-based approach to combinatorial biosynthesis by targeting the domain of unknown function and cysteine lyase domain (DUF–SH) didomain, specific for sulfur incorporation from the leinamycin (LNM) biosynthetic machinery, to discover the LNM family of natural products. By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF–SH didomains. Further analysis of the representative genomes from each of the clades identified 28 lnm-type gene clusters. Structural diversities encoded by the LNM-type biosynthetic machineries were predicted based on bioinformatics and confirmed by in vitro characterization of selected adenylation proteins and isolation and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature’s rich biosynthetic repertoire. Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect Nature’s biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity. PMID:29229819

Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction.

PubMed

Woerly, Eric M; Roy, Jahnabi; Burke, Martin D

2014-06-01

The inherent modularity of polypeptides, oligonucleotides and oligosaccharides has been harnessed to achieve generalized synthesis platforms. Importantly, like these other targets, most small-molecule natural products are biosynthesized via iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent modularity commensurate with systematic building block-based construction. Supporting this hypothesis, here we report that the polyene motifs found in >75% of all known polyene natural products can be synthesized using just 12 building blocks and one coupling reaction. Using the same general retrosynthetic algorithm and reaction conditions, this platform enabled both the synthesis of a wide range of polyene frameworks that covered all of this natural-product chemical space and the first total syntheses of the polyene natural products asnipyrone B, physarigin A and neurosporaxanthin b-D-glucopyranoside. Collectively, these results suggest the potential for a more generalized approach to making small molecules in the laboratory.

Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction

NASA Astrophysics Data System (ADS)

Woerly, Eric M.; Roy, Jahnabi; Burke, Martin D.

2014-06-01

The inherent modularity of polypeptides, oligonucleotides and oligosaccharides has been harnessed to achieve generalized synthesis platforms. Importantly, like these other targets, most small-molecule natural products are biosynthesized via iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent modularity commensurate with systematic building block-based construction. Supporting this hypothesis, here we report that the polyene motifs found in >75% of all known polyene natural products can be synthesized using just 12 building blocks and one coupling reaction. Using the same general retrosynthetic algorithm and reaction conditions, this platform enabled both the synthesis of a wide range of polyene frameworks that covered all of this natural-product chemical space and the first total syntheses of the polyene natural products asnipyrone B, physarigin A and neurosporaxanthin β-D-glucopyranoside. Collectively, these results suggest the potential for a more generalized approach to making small molecules in the laboratory.

Targeting Protein Quality Control Mechanisms by Natural Products to Promote Healthy Ageing.

PubMed

Wedel, Sophia; Manola, Maria; Cavinato, Maria; Trougakos, Ioannis P; Jansen-Dürr, Pidder

2018-05-19

Organismal ageing is associated with increased chance of morbidity or mortality and it is driven by diverse molecular pathways that are affected by both environmental and genetic factors. The progression of ageing correlates with the gradual accumulation of stressors and damaged biomolecules due to the time-dependent decline of stress resistance and functional capacity, which eventually compromise cellular homeodynamics. As protein machines carry out the majority of cellular functions, proteome quality control is critical for cellular functionality and is carried out through the curating activity of the proteostasis network (PN). Key components of the PN are the two main degradation machineries, namely the ubiquitin-proteasome and autophagy-lysosome pathways along with several stress-responsive pathways, such as that of nuclear factor erythroid 2-related factor 2 (Nrf2), which mobilises cytoprotective genomic responses against oxidative and/or xenobiotic damage. Reportedly, genetic or dietary interventions that activate components of the PN delay ageing in evolutionarily diverse organisms. Natural products (extracts or pure compounds) represent an extraordinary inventory of highly diverse structural scaffolds that offer promising activities towards meeting the challenge of increasing healthspan and/or delaying ageing (e.g., spermidine, quercetin or sulforaphane). Herein, we review those natural compounds that have been found to activate proteostatic and/or anti-stress cellular responses and hence have the potential to delay cellular senescence and/or in vivo ageing.

Natural product-inspired cascade synthesis yields modulators of centrosome integrity.

PubMed

Dückert, Heiko; Pries, Verena; Khedkar, Vivek; Menninger, Sascha; Bruss, Hanna; Bird, Alexander W; Maliga, Zoltan; Brockmeyer, Andreas; Janning, Petra; Hyman, Anthony; Grimme, Stefan; Schürmann, Markus; Preut, Hans; Hübel, Katja; Ziegler, Slava; Kumar, Kamal; Waldmann, Herbert

2011-12-25

In biology-oriented synthesis, the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is, in particular, met by the scaffolds of natural products selected in evolution. The synthesis of natural product-inspired compound collections calls for efficient reaction sequences that preferably combine multiple individual transformations in one operation. Here we report the development of a one-pot, twelve-step cascade reaction sequence that includes nine different reactions and two opposing kinds of organocatalysis. The cascade sequence proceeds within 10-30 min and transforms readily available substrates into complex indoloquinolizines that resemble the core tetracyclic scaffold of numerous polycyclic indole alkaloids. Biological investigation of a corresponding focused compound collection revealed modulators of centrosome integrity, termed centrocountins, which caused fragmented and supernumerary centrosomes, chromosome congression defects, multipolar mitotic spindles, acentrosomal spindle poles and multipolar cell division by targeting the centrosome-associated proteins nucleophosmin and Crm1.

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. © 2015 New York Academy of Sciences.

United States Department of Agriculture-Agricultural Research Service research on natural products for pest management.

PubMed

Duke, Stephen O; Baerson, Scott R; Dayan, Franck E; Rimando, Agnes M; Scheffler, Brian E; Tellez, Mario R; Wedge, David E; Schrader, Kevin K; Akey, David H; Arthur, Frank H; De Lucca, Anthony J; Gibson, Donna M; Harrison, Howard F; Peterson, Joseph K; Gealy, David R; Tworkoski, Thomas; Wilson, Charles L; Morris, J Brad

2003-01-01

Recent research of the Agricultural Research Service of USDA on the use of natural products to manage pests is summarized. Studies of the use of both phytochemicals and diatomaceous earth to manage insect pests are discussed. Chemically characterized compounds, such as a saponin from pepper (Capsicum frutescens L), benzaldehyde, chitosan and 2-deoxy-D-glucose are being studied as natural fungicides. Resin glycosides for pathogen resistance in sweet potato and residues of semi-tropical leguminous plants for nematode control are also under investigation. Bioassay-guided isolation of compounds with potential use as herbicides or herbicide leads is underway at several locations. New natural phytotoxin molecular target sites (asparagine synthetase and fructose-1,6-bisphosphate aldolase) have been discovered. Weed control in sweet potato and rice by allelopathy is under investigation. Molecular approaches to enhance allelopathy in sorghum are also being undertaken. The genes for polyketide synthases involved in production of pesticidal polyketide compounds in fungi are found to provide clues for pesticide discovery. Gene expression profiles in response to fungicides and herbicides are being generated as tools to understand more fully the mode of action and to rapidly determine the molecular target site of new, natural fungicides and herbicides.

Hierarchical virtual screening of the dual MMP-2/HDAC-6 inhibitors from natural products based on pharmacophore models and molecular docking.

PubMed

Wang, Yijun; Yang, Limei; Hou, Jiaying; Zou, Qing; Gao, Qi; Yao, Wenhui; Yao, Qizheng; Zhang, Ji

2018-02-12

The dual-target inhibitors tend to improve the response rate in treating tumors, comparing with the single-target inhibitors. Matrix metalloproteinase-2 (MMP-2) and histone deacetylase-6 (HDAC-6) are attractive targets for cancer therapy. In this study, the hierarchical virtual screening of dual MMP-2/HDAC-6 inhibitors from natural products is investigated. The pharmacophore model of MMP-2 inhibitors is built based on ligands, but the pharmacophore model of HDAC-6 inhibitors is built based on the experimental crystal structures of multiple receptor-ligand complexes. The reliability of these two pharmacophore models is validated subsequently. The hierarchical virtual screening, combining these two different pharmacophore models of MMP-2 and HDAC-6 inhibitors with molecular docking, is carried out to identify the dual MMP-2/HDAC-6 inhibitors from a database of natural products. The four potential dual MMP-2/HDAC-6 inhibitors of natural products, STOCK1 N-46177, STOCK1 N-52245, STOCK1 N-55477, and STOCK1 N-69706, are found. The studies of binding modes show that the screened four natural products can simultaneously well bind with the MMP-2 and HDAC-6 active sites by different kinds of interactions, to inhibit the MMP-2 and HDAC-6 activities. In addition, the ADMET properties of screened four natural products are assessed. These found dual MMP-2/HDAC-6 inhibitors of natural products could serve as the lead compounds for designing the new dual MMP-2/HDAC-6 inhibitors having higher biological activities by carrying out structural modifications and optimizations in the future studies.

Natural Health Products and Community Pharmacy-Remove the Mysticism Not the Product.

PubMed

Blackburn, David F; Gill, Munpreet; Krol, Ed; Taylor, Jeff

2017-12-01

The allure of natural products has captivated humans for centuries. Although they can be compatible with evidence-based care, attitudes surrounding natural products can seem almost mystical and may even be accompanied by contempt toward Western medicine. Considering the high volumes of natural products sold in community pharmacies, pharmacists can inject balanced information to minimize the mysticism and help patients make informed decisions. The aim of this article is to argue for standardized guidelines pertaining to the management of natural products in community pharmacy practice.

Synthesis of most polyene natural product motifs using just twelve building blocks and one coupling reaction

PubMed Central

Woerly, Eric M.; Roy, Jahnabi; Burke, Martin D.

2014-01-01

The inherent modularity of polypeptides, oligonucleotides, and oligosaccharides has been harnessed to achieve generalized building block-based synthesis platforms. Importantly, like these other targets, most small molecule natural products are biosynthesized via iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent modularity commensurate with systematic building block-based construction. Supporting this hypothesis, here we report that the polyene motifs found in >75% of all known polyene natural products can be synthesized using just 12 building blocks and one coupling reaction. Using the same general retrosynthetic algorithm and reaction conditions, this platform enabled the synthesis of a wide range of polyene frameworks covering all of this natural product chemical space, and first total syntheses of the polyene natural products asnipyrone B, physarigin A, and neurosporaxanthin β-D-glucopyranoside. Collectively, these results suggest the potential for a more generalized approach for making small molecules in the laboratory. PMID:24848233

Investigating the Biosynthesis of Natural Products from Marine Proteobacteria: A Survey of Molecules and Strategies

PubMed Central

Timmermans, Marshall L.; Paudel, Yagya P.; Ross, Avena C.

2017-01-01

The phylum proteobacteria contains a wide array of Gram-negative marine bacteria. With recent advances in genomic sequencing, genome analysis, and analytical chemistry techniques, a whole host of information is being revealed about the primary and secondary metabolism of marine proteobacteria. This has led to the discovery of a growing number of medically relevant natural products, including novel leads for the treatment of multidrug-resistant Staphylococcus aureus (MRSA) and cancer. Of equal interest, marine proteobacteria produce natural products whose structure and biosynthetic mechanisms differ from those of their terrestrial and actinobacterial counterparts. Notable features of secondary metabolites produced by marine proteobacteria include halogenation, sulfur-containing heterocycles, non-ribosomal peptides, and polyketides with unusual biosynthetic logic. As advances are made in the technology associated with functional genomics, such as computational sequence analysis, targeted DNA manipulation, and heterologous expression, it has become easier to probe the mechanisms for natural product biosynthesis. This review will focus on genomics driven approaches to understanding the biosynthetic mechanisms for natural products produced by marine proteobacteria. PMID:28762997

Investigating the Biosynthesis of Natural Products from Marine Proteobacteria: A Survey of Molecules and Strategies.

PubMed

Timmermans, Marshall L; Paudel, Yagya P; Ross, Avena C

2017-08-01

The phylum proteobacteria contains a wide array of Gram-negative marine bacteria. With recent advances in genomic sequencing, genome analysis, and analytical chemistry techniques, a whole host of information is being revealed about the primary and secondary metabolism of marine proteobacteria. This has led to the discovery of a growing number of medically relevant natural products, including novel leads for the treatment of multidrug-resistant Staphylococcus aureus (MRSA) and cancer. Of equal interest, marine proteobacteria produce natural products whose structure and biosynthetic mechanisms differ from those of their terrestrial and actinobacterial counterparts. Notable features of secondary metabolites produced by marine proteobacteria include halogenation, sulfur-containing heterocycles, non-ribosomal peptides, and polyketides with unusual biosynthetic logic. As advances are made in the technology associated with functional genomics, such as computational sequence analysis, targeted DNA manipulation, and heterologous expression, it has become easier to probe the mechanisms for natural product biosynthesis. This review will focus on genomics driven approaches to understanding the biosynthetic mechanisms for natural products produced by marine proteobacteria.

High power neutron production targets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wender, S.

1996-06-01

The author describes issues of concern in the design of targets and associated systems for high power neutron production facilities. The facilities include uses for neutron scattering, accelerator driven transmutation, accelerator production of tritium, short pulse spallation sources, and long pulse spallation sources. Each of these applications requires a source with different design needs and consequently different implementation in practise.

Sources for Leads: Natural Products and Libraries.

PubMed

van Herwerden, Eric F; Süssmuth, Roderich D

2016-01-01

Natural products have traditionally been a major source of leads in the drug discovery process. However, the development of high-throughput screening led to an increased interest in synthetic methods that enabled the rapid construction of large libraries of molecules. This resulted in the termination or downscaling of many natural product research programs, but the chemical libraries did not necessarily produce a larger amount of drug leads. On one hand, this chapter explores the current state of natural product research within the drug discovery process. On the other hand it evaluates the efforts made to increase the amount of leads generated from chemical libraries and considers what role natural products could play here.

New and improved tools and methods for enhanced biosynthesis of natural products in microorganisms.

PubMed

Wang, Zhiqing; Cirino, Patrick C

2016-12-01

Engineering efficient biosynthesis of natural products in microorganisms requires optimizing gene expression levels to balance metabolite flux distributions and to minimize accumulation of toxic intermediates. Such metabolic optimization is challenged with identifying the right gene targets, and then determining and achieving appropriate gene expression levels. After decades of having a relatively limited set of gene regulation tools available, metabolic engineers are recently enjoying an ever-growing repertoire of more precise and tunable gene expression platforms. Here we review recent applications of natural and designed transcriptional and translational regulatory machinery for engineering biosynthesis of natural products in microorganisms. Customized trans-acting RNAs (sgRNA, asRNA and sRNA), along with appropriate accessory proteins, are allowing for unparalleled tuning of gene expression. Meanwhile metabolite-responsive transcription factors and riboswitches have been implemented in strain screening and evolution, and in dynamic gene regulation. Further refinements and expansions on these platform technologies will circumvent many long-term obstacles in natural products biosynthesis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Water for wood products versus nature, food or feed

NASA Astrophysics Data System (ADS)

Schyns, Joep; Booij, Martijn; Hoekstra, Arjen

2017-04-01

Forests play a central interlinked role in the 2030 Agenda on Sustainable Development. The Agenda aims at an increased share of renewable energy in the global energy mix (target 7.2) and restoration and sustainable management of forests (targets 6.6, 15.1 & 15.2). Forests also play a key role in the hydrological cycle accounting for the largest water flux from land to atmosphere. However, we do not know which part of this is used for the production of wood products such as lumber, pulp and paper, firewood or biofuel. SDG target 6.4 calls for increased water-use efficiency across all sectors and requires understanding the competing demands for water and the potential conflicts between wood production and other purposes like food (SDG 2). To reach the SDGs we need to understand the interlinkages between the SDGs and know how much water is used in the forestry sector. We provide the first estimate of global water use in the forestry sector, using the water footprint (WF) as indicator and distinguishing between consumption of green water (precipitation) and blue water (groundwater through capillary rise). We estimate forest evaporation at a high spatial resolution level and attribute total water consumption to the various forest products, including ecosystem services. Global water consumption for wood production increased by 34% over 50 years to 290x109 m3/y in 2001-2010. Wood has a higher economic water productivity (EWP, US/m3) than common food or feed crops like wheat, maize and sugar beet, and bio-ethanol from wood has a small WF per unit of energy compared to first-generation bio-ethanol from these three crops. Counterintuitively, extensive wood production has a smaller WF and hence a higher EWP than intensive wood production. The reason is that extensively exploited forests host relatively more value next to wood production in the form of other ecosystem services. Recycling of wood products could effectively reduce the WF of the forestry sector, thereby leaving

The SPES High Power ISOL production target

NASA Astrophysics Data System (ADS)

Andrighetto, A.; Corradetti, S.; Ballan, M.; Borgna, F.; Manzolaro, M.; Scarpa, D.; Monetti, A.; Rossignoli, M.; Silingardi, R.; Mozzi, A.; Vivian, G.; Boratto, E.; De Ruvo, L.; Sattin, N.; Meneghetti, G.; Oboe, R.; Guerzoni, M.; Margotti, A.; Ferrari, M.; Zenoni, A.; Prete, G.

2016-11-01

SPES (Selective Production of Exotic Species) is a facility under construction at INFN-LNL (Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali di Legnaro), aimed to produce intense neutron-rich radioactive ion beams (RIBs). These will be obtained using the ISOL (Isotope Separation On-Line) method, bombarding a uranium carbide target with a proton beam of 40MeV energy and currents up to 200μA. The target configuration was designed to obtain a high number of fissions, up to 1013 per second, low power deposition and fast release of the produced isotopes. The exotic isotopes generated in the target are ionized, mass separated and re-accelerated by the ALPI superconducting LINAC at energies of 10AMeV and higher, for masses in the region of A = 130 amu , with an expected rate on the secondary target up to 109 particles per second. In this work, recent results on the R&D activities regarding the SPES RIB production target-ion source system are reported.

Leveraging ecological theory to guide natural product discovery.

PubMed

Smanski, Michael J; Schlatter, Daniel C; Kinkel, Linda L

2016-03-01

Technological improvements have accelerated natural product (NP) discovery and engineering to the point that systematic genome mining for new molecules is on the horizon. NP biosynthetic potential is not equally distributed across organisms, environments, or microbial life histories, but instead is enriched in a number of prolific clades. Also, NPs are not equally abundant in nature; some are quite common and others markedly rare. Armed with this knowledge, random 'fishing expeditions' for new NPs are increasingly harder to justify. Understanding the ecological and evolutionary pressures that drive the non-uniform distribution of NP biosynthesis provides a rational framework for the targeted isolation of strains enriched in new NP potential. Additionally, ecological theory leads to testable hypotheses regarding the roles of NPs in shaping ecosystems. Here we review several recent strain prioritization practices and discuss the ecological and evolutionary underpinnings for each. Finally, we offer perspectives on leveraging microbial ecology and evolutionary biology for future NP discovery.

Natural products as a foundation for drug discovery.

PubMed

Beutler, John A

2009-09-01

Natural products have provided chemical leads for the development of many drugs for diverse indications. While most U.S. pharmaceutical firms have reduced or eliminated their in-house natural product groups, there is a renewed interest in this source of new chemical entities. Many of the reasons for the past decline in popularity of natural products are being addressed by the development of new techniques for screening and production. The aim of this unit is to review current strategies and techniques that increase the value of natural products as a source for novel drug candidates.

Natural products and combinatorial chemistry: back to the future.

PubMed

Ortholand, Jean-Yves; Ganesan, A

2004-06-01

The introduction of high-throughput synthesis and combinatorial chemistry has precipitated a global decline in the screening of natural products by the pharmaceutical industry. Some companies terminated their natural products program, despite the unproven success of the new technologies. This was a premature decision, as natural products have a long history of providing important medicinal agents. Furthermore, they occupy a complementary region of chemical space compared with the typical synthetic compound library. For these reasons, the interest in natural products has been rekindled. Various approaches have evolved that combine the power of natural products and organic chemistry, ranging from the combinatorial total synthesis of analogues to the exploration of natural product scaffolds and the design of completely unnatural molecules that resemble natural products in their molecular characteristics.

Production of Y-86 and other radiometals for research purposes using a solution target system.

PubMed

Oehlke, Elisabeth; Hoehr, Cornelia; Hou, Xinchi; Hanemaayer, Victoire; Zeisler, Stefan; Adam, Michael J; Ruth, Thomas J; Celler, Anna; Buckley, Ken; Benard, Francois; Schaffer, Paul

2015-11-01

Diagnostic radiometals are typically obtained from cyclotrons by irradiating solid targets or from radioisotope generators. These methods have the advantage of high production yields, but require additional solid target handling infrastructure that is not readily available to many cyclotron facilities. Herein, we provide an overview of our results regarding the production of various positron-emitting radiometals using a liquid target system installed on a 13 MeV cyclotron at TRIUMF. Details about the production, purification and quality control of (89)Zr, (68)Ga and for the first time (86)Y are discussed. Aqueous solutions containing 1.35-1.65 g/mL of natural-abundance zinc nitrate, yttrium nitrate, and strontium nitrate were irradiated on a 13 MeV cyclotron using a standard liquid target. Different target body and foil materials were investigated for corrosion. Production yields were calculated using theoretical cross-sections from the EMPIRE code and compared with experimental results. The radioisotopes were extracted from irradiated target material using solid phase extraction methods adapted from previously reported methods, and used for radiolabelling experiments. We demonstrated production quantities that are sufficient for chemical and biological studies for three separate radiometals, (89)Zr (Asat = 360 MBq/μA and yield = 3.17 MBq/μA), (86)Y (Asat = 31 MBq/μA and yield = 1.44 MBq/μA), and (68)Ga (Asat = 141 MBq/μA and yield = 64 MBq/μA) from one hour long irradiations on a typical medical cyclotron. (68)Ga yields were sufficient for potential clinical applications. In order to avoid corrosion of the target body and target foil, nitrate solutions were chosen as well as niobium as target-body material. An automatic loading system enabled up to three production runs per day. The separation efficiency ranged from 82 to 99%. Subsequently, (68)Ga and (86)Y were successfully used to radiolabel DOTA-based chelators while deferoxamine was used to coordinate

Novel Natural Products from Extremophilic Fungi.

PubMed

Zhang, Xuan; Li, Shou-Jie; Li, Jin-Jie; Liang, Zi-Zhen; Zhao, Chang-Qi

2018-06-04

Extremophilic fungi have been found to develop unique defences to survive extremes of pressure, temperature, salinity, desiccation, and pH, leading to the biosynthesis of novel natural products with diverse biological activities. The present review focuses on new extremophilic fungal natural products published from 2005 to 2017, highlighting the chemical structures and their biological potential.

Deuteron irradiation of W and WO 3 for production of high specific activity 186Re: Challenges associated with thick target preparation

DOE PAGES

Balkin, Ethan R.; Gagnon, Katherine; Strong, Kevin T.; ...

2016-06-28

This investigation evaluated target fabrication and beam parameters for scale-up production of high specific activity 186Re using deuteron irradiation of enriched 186W via the 186W(d,2n) 186Re reaction. Thick W and WO 3 targets were prepared, characterized and evaluated in deuteron irradiations. Full-thickness targets, as determined using SRIM, were prepared by uniaxi-ally pressing powdered natural abundance W and WO 3, or 96.86% enriched 186W, into Al target supports. Alternatively, thick targets were prepared by pressing 186W between two layers of graphite powder or by placing pre-sintered (1105°C, 12 hours) natural abundance WO 3 pellets into an Al target support. Assessments ofmore » structural integrity were made on each target pre-pared. Prior to irradiation, material composition analyses were conducted using SEM, XRD, and Raman spectroscopy. With-in a minimum of 24 hours post irradiation, gamma-ray spectroscopy was performed on all targets to assess production yields and radionuclidic byproducts. Problems were encountered with the structural integrity of some pressed W and WO 3 pellets before and during irradiation, and target material characterization results could be correlated with the structural integrity of the pressed target pellets. Under the conditions studied, the findings suggest that all WO 3 targets prepared and studied were unacceptable. By contrast, 186W metal was found to be a viable target material for 186Re production. Lastly, thick targets prepared with powdered 186W pressed between layers of graphite provided a particularly robust target configuration.« less

Deuteron irradiation of W and WO3 for production of high specific activity (186)Re: Challenges associated with thick target preparation.

PubMed

Balkin, Ethan R; Gagnon, Katherine; Strong, Kevin T; Smith, Bennett E; Dorman, Eric F; Emery, Robert C; Pauzauskie, Peter J; Fassbender, Michael E; Cutler, Cathy S; Ketring, Alan R; Jurisson, Silvia S; Wilbur, D Scott

2016-09-01

This investigation evaluated target fabrication and beam parameters for scale-up production of high specific activity (186)Re using deuteron irradiation of enriched (186)W via the (186)W(d,2n)(186)Re reaction. Thick W and WO3 targets were prepared, characterized and evaluated in deuteron irradiations. Full-thickness targets, as determined using SRIM, were prepared by uniaxially pressing powdered natural abundance W and WO3, or 96.86% enriched (186)W, into Al target supports. Alternatively, thick targets were prepared by pressing (186)W between two layers of graphite powder or by placing pre-sintered (1105°C, 12h) natural abundance WO3 pellets into an Al target support. Assessments of structural integrity were made on each target prepared. Prior to irradiation, material composition analyses were conducted using SEM, XRD, and Raman spectroscopy. Within a minimum of 24h post irradiation, gamma-ray spectroscopy was performed on all targets to assess production yields and radionuclidic byproducts. Problems were encountered with the structural integrity of some pressed W and WO3 pellets before and during irradiation, and target material characterization results could be correlated with the structural integrity of the pressed target pellets. Under the conditions studied, the findings suggest that all WO3 targets prepared and studied were unacceptable. By contrast, (186)W metal was found to be a viable target material for (186)Re production. Thick targets prepared with powdered (186)W pressed between layers of graphite provided a particularly robust target configuration. Copyright © 2016 Elsevier Ltd. All rights reserved.

Bundle Data Approach at GES DISC Targeting Natural Hazards

NASA Technical Reports Server (NTRS)

Shie, Chung-Lin; Shen, Suhung; Kempler, Steven J.

2015-01-01

Severe natural phenomena such as hurricane, volcano, blizzard, flood and drought have the potential to cause immeasurable property damages, great socioeconomic impact, and tragic loss of human life. From searching to assessing the Big, i.e., massive and heterogeneous scientific data (particularly, satellite and model products) in order to investigate those natural hazards, it has, however, become a daunting task for Earth scientists and applications researchers, especially during recent decades. The NASA Goddard Earth Sciences Data and Information Service Center (GES DISC) has served Big Earth science data, and the pertinent valuable information and services to the aforementioned users of diverse communities for years. In order to help and guide our users to online readily (i.e., with a minimum effort) acquire their requested data from our enormous resource at GES DISC for studying their targeted hazard event, we have thus initiated a Bundle Data approach in 2014, first targeting the hurricane event topic. We have recently worked on new topics such as volcano and blizzard. The bundle data of a specific hazard event is basically a sophisticated integrated data package consisting of a series of proper datasets containing a group of relevant (knowledge--based) data variables readily accessible to users via a system-prearranged table linking those data variables to the proper datasets (URLs). This online approach has been developed by utilizing a few existing data services such as Mirador as search engine; Giovanni for visualization; and OPeNDAP for data access, etc. The online Data Cookbook site at GES DISC is the current host for the bundle data. We are now also planning on developing an Automated Virtual Collection Framework that shall eventually accommodate the bundle data, as well as further improve our management in Big Data.

"Bundle Data" Approach at GES DISC Targeting Natural Hazards

NASA Astrophysics Data System (ADS)

Shie, C. L.; Shen, S.; Kempler, S. J.

2015-12-01

Severe natural phenomena such as hurricane, volcano, blizzard, flood and drought have the potential to cause immeasurable property damages, great socioeconomic impact, and tragic loss of human life. From searching to assessing the "Big", i.e., massive and heterogeneous scientific data (particularly, satellite and model products) in order to investigate those natural hazards, it has, however, become a daunting task for Earth scientists and applications researchers, especially during recent decades. The NASA Goddard Earth Sciences Data and Information Service Center (GES DISC) has served "Big" Earth science data, and the pertinent valuable information and services to the aforementioned users of diverse communities for years. In order to help and guide our users to online readily (i.e., with a minimum effort) acquire their requested data from our enormous resource at GES DISC for studying their targeted hazard/event, we have thus initiated a "Bundle Data" approach in 2014, first targeting the hurricane event/topic. We have recently worked on new topics such as volcano and blizzard. The "bundle data" of a specific hazard/event is basically a sophisticated integrated data package consisting of a series of proper datasets containing a group of relevant ("knowledge-based") data variables readily accessible to users via a system-prearranged table linking those data variables to the proper datasets (URLs). This online approach has been developed by utilizing a few existing data services such as Mirador as search engine; Giovanni for visualization; and OPeNDAP for data access, etc. The online "Data Cookbook" site at GES DISC is the current host for the "bundle data". We are now also planning on developing an "Automated Virtual Collection Framework" that shall eventually accommodate the "bundle data", as well as further improve our management in "Big Data".

Natural Products for Cancer Prevention: Clinical Update 2016.

PubMed

Sanders, Kathleen; Moran, Zelda; Shi, Zaixing; Paul, Rachel; Greenlee, Heather

2016-08-01

To present a clinical update of natural products for cancer prevention and provide oncology nurses with an evidence-based review of natural products for patient counseling and education. Clinical trials published in PubMed. In the past 4 years since the publication of the original review there have been minimal changes in the conclusions of the published literature on the use of natural products for cancer prevention. To date, clinical trials have not demonstrated conclusive benefit of using natural products for cancer prevention, and current guidelines do not recommend their use. This review provides an update on published and ongoing trials and can serve as an updated resource for nurses. Evidence-based natural products databases can help nurses stay current with the scientific literature and be effective educators and health coaches for their patients, who can be influenced by marketing of unregulated products. Patients often discuss the use of natural products with nurses. Nurses have an opportunity to educate and coach patients in effective preventive lifestyle practices. Copyright © 2016 Elsevier Inc. All rights reserved.

Network pharmacology-based virtual screening of natural products from Clerodendrum species for identification of novel anti-cancer therapeutics.

PubMed

Gogoi, Barbi; Gogoi, Dhrubajyoti; Silla, Yumnam; Kakoti, Bibhuti Bhushan; Bhau, Brijmohan Singh

2017-01-31

Plant-derived natural products (NPs) play a vital role in the discovery of new drug molecules and these are used for development of novel therapeutic drugs for a specific disease target. Literature review suggests that natural products possess strong inhibitory efficacy against various types of cancer cells. Clerodendrum indicum and Clerodendrum serratum are reported to have anticancer activity; therefore a study was carried out to identify selective anticancer agents from these plants species. In this report, we employed a docking weighted network pharmacological approach to understand the multi-therapeutics potentiality of C. indicum and C. serratum against various types of cancer. A library of 53 natural products derived from these plants was compiled from the literature and three dimensional space analyses were performed in order to establish the drug-likeness of the NPs library. Further, an NPs-cancer network was built based on docking. We predicted five compounds, namely apigenin 7-glucoside, hispidulin, scutellarein-7-O-beta-d-glucuronate, acteoside and verbascoside, to be potential binding therapeutics for cancer target proteins. Apigenin 7-glucoside and hispidulin were found to have maximum binding interactions (relationship) with 17 cancer drug targets in terms of docking weighted network pharmacological analysis. Hence, we used an integrative approach obtained from network pharmacology for identifying combinatorial drug actions against the cancer targets. We believe that our present study may provide important clues for finding novel drug inhibitors for cancer.

[Status of libraries and databases for natural products at abroad].

PubMed

Zhao, Li-Mei; Tan, Ning-Hua

2015-01-01

For natural products are one of the important sources for drug discovery, libraries and databases of natural products are significant for the development and research of natural products. At present, most of compound libraries at abroad are synthetic or combinatorial synthetic molecules, resulting to access natural products difficult; for information of natural products are scattered with different standards, it is difficult to construct convenient, comprehensive and large-scale databases for natural products. This paper reviewed the status of current accessing libraries and databases for natural products at abroad and provided some important information for the development of libraries and database for natural products.

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

Synthetic biology for production of natural and new-to-nature terpenoids in photosynthetic organisms.

PubMed

Arendt, Philipp; Pollier, Jacob; Callewaert, Nico; Goossens, Alain

2016-07-01

With tens of thousands of characterized members, terpenoids constitute the largest class of natural compounds that are synthesized by all living organisms. Several terpenoids play primary roles in the maintenance of cell membrane fluidity, as pigments or as phytohormones, but most of them function as specialized metabolites that are involved in plant resistance to herbivores or plant-environment interactions. Terpenoids are an essential component of human nutrition, and many are economically important pharmaceuticals, aromatics and potential next-generation biofuels. Because of the often low abundance in their natural source, as well as the demand for novel terpenoid structures with new or improved bioactivities, terpenoid biosynthesis has become a prime target for metabolic engineering and synthetic biology projects. In this review we focus on the creation of new-to-nature or tailor-made plant-derived terpenoids in photosynthetic organisms, in particular by means of combinatorial biosynthesis and the activation of silent metabolism. We reflect on the characteristics of different potential photosynthetic host organisms and recent advances in synthetic biology and discuss their utility for the (heterologous) production of (novel) terpenoids. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

Biosynthesis of therapeutic natural products using synthetic biology.

PubMed

Awan, Ali R; Shaw, William M; Ellis, Tom

2016-10-01

Natural products are a group of bioactive structurally diverse chemicals produced by microorganisms and plants. These molecules and their derivatives have contributed to over a third of the therapeutic drugs produced in the last century. However, over the last few decades traditional drug discovery pipelines from natural products have become far less productive and far more expensive. One recent development with promise to combat this trend is the application of synthetic biology to therapeutic natural product biosynthesis. Synthetic biology is a young discipline with roots in systems biology, genetic engineering, and metabolic engineering. In this review, we discuss the use of synthetic biology to engineer improved yields of existing therapeutic natural products. We further describe the use of synthetic biology to combine and express natural product biosynthetic genes in unprecedented ways, and how this holds promise for opening up completely new avenues for drug discovery and production. Copyright © 2016 Elsevier B.V. All rights reserved.

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

A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products

NASA Astrophysics Data System (ADS)

Huigens, Robert W., III; Morrison, Karen C.; Hicklin, Robert W.; Flood, Timothy A., Jr.; Richter, Michelle F.; Hergenrother, Paul J.

2013-03-01

High-throughput screening is the dominant method used to identify lead compounds in drug discovery. As such, the makeup of screening libraries largely dictates the biological targets that can be modulated and the therapeutics that can be developed. Unfortunately, most compound-screening collections consist principally of planar molecules with little structural or stereochemical complexity, compounds that do not offer the arrangement of chemical functionality necessary for the modulation of many drug targets. Here we describe a novel, general and facile strategy for the creation of diverse compounds with high structural and stereochemical complexity using readily available natural products as synthetic starting points. We show through the evaluation of chemical properties (which include fraction of sp3 carbons, ClogP and the number of stereogenic centres) that these compounds are significantly more complex and diverse than those in standard screening collections, and we give guidelines for the application of this strategy to any suitable natural product.

Natural products to prevent drug resistance in cancer chemotherapy: a review.

PubMed

Yuan, Renyikun; Hou, Ying; Sun, Wen; Yu, Jie; Liu, Xin; Niu, Yanan; Lu, Jin-Jian; Chen, Xiuping

2017-08-01

Chemotherapy is the standard internal medical treatment for cancer. However, the resistance of cancer cells to nearly all kinds of chemotherapeutic drugs and targeted drugs has become prevalent, and approximately 80-90% of deaths in cancer patients are directly or indirectly attributed to drug resistance. The progress of new drug research and development has also been impeded by the occurrence of drug resistance, which has emerged as a considerable challenge in cancer therapy. Fortunately, natural products with diverse chemical structures and pharmacological effects serve as effective substances against drug resistance. Since the discovery of a series of drug-resistant proteins, drug-efflux inhibition has been applied as the primary strategy to overcome drug resistance by maintaining the intracellular concentrations of chemotherapeutic drugs. Nonapoptotic cell death is considered an alternative strategy because most cases of drug resistance result in evasion and insensitivity to apoptosis. In this concise review, we summarize two strategies using natural products against drug resistance. © 2017 New York Academy of Sciences.

Natural products as sources for new pesticides.

PubMed

Cantrell, Charles L; Dayan, Franck E; Duke, Stephen O

2012-06-22

Natural products as pesticides have been reviewed from several perspectives in the past, but no prior treatment has examined the impact of natural product and natural product-based pesticides on the U.S. market, as a function of new active ingredient registrations with the Environmental Protection Agency (EPA). Thus, EPA registration details of new active ingredients for all conventional pesticide registrations and biopesticide registrations were compiled from the years 1997-2010. Conventional pesticide registrations and biopesticide registrations were examined both collectively and independently for all 277 new active ingredients (NAI) and subsequently categorized and sorted into four types: biological (B), natural product (NP), synthetic (S), and synthetic natural derived (SND). When examining conventional pesticides alone, the S category accounted for the majority of NAI registrations, with 78.0%, followed by SND with 14.7%, NP with 6.4%, and B with 0.9%. Biopesticides alone were dominated by NPs with 54.8%, followed by B with 44.6%, SND with 0.6%, and 0% for S. When examining conventional pesticides and biopesticides combined, NPs accounted for the majority of NAI registrations, with 35.7%, followed by S with 30.7%, B with 27.4%, and SND with 6.1%. Despite the common perception that natural products may not be the best sources for NAI as pesticides, when both conventional and biopesticides are examined collectively, and considering that NP, SND, and B all have origins from natural product research, it can be argued that their combined impact with the EPA from 1997 to 2010 accounted for 69.3% of all NAI registrations.

Clustered carbohydrates as a target for natural killer cells: a model system.

PubMed

Kovalenko, Elena I; Abakushina, Elena; Telford, William; Kapoor, Veena; Korchagina, Elena; Khaidukov, Sergei; Molotkovskaya, Irina; Sapozhnikov, Alexander; Vlaskin, Pavel; Bovin, Nicolai

2007-03-01

Membrane-associated oligosaccharides are known to take part in interactions between natural killer (NK) cells and their targets and modulate NK cell activity. A model system was therefore developed using synthetic glycoconjugates as tools to modify the carbohydrate pattern on NK target cell surfaces. NK cells were then assessed for function in response to synthetic glycoconjugates, using both cytolysis-associated caspase 6 activation measured by flow cytometry and IFN-gamma production. Lipophilic neoglycoconjugates were synthesized to provide their easy incorporation into the target cell membranes and to make carbohydrate residues available for cell-cell interactions. While incorporation was successful based on fluorescence monitoring, glycoconjugate incorporation did not evoke artifactual changes in surface antigen expression, and had no negative effect on cell viability. Glycoconjugates contained Le(x), sulfated Le(x), and Le(y) sharing the common structure motif trisaccharide Le(x) were revealed to enhance cytotoxicity mediated specifically by CD16 +CD56+NK cells. The glycoconjugate effects were dependent on saccharide presentation in a polymeric form. Only polymeric, or clustered, but not monomeric glycoconjugates resulted in alteration of cytotoxicity in our system, suggesting that appropriate presentation is critical for carbohydrate recognition and subsequent biological effects.

Use of Naturally Available Reference Targets to Calibrate Airborne Laser Scanning Intensity Data

PubMed Central

Vain, Ants; Kaasalainen, Sanna; Pyysalo, Ulla; Krooks, Anssi; Litkey, Paula

2009-01-01

We have studied the possibility of calibrating airborne laser scanning (ALS) intensity data, using land targets typically available in urban areas. For this purpose, a test area around Espoonlahti Harbor, Espoo, Finland, for which a long time series of ALS campaigns is available, was selected. Different target samples (beach sand, concrete, asphalt, different types of gravel) were collected and measured in the laboratory. Using tarps, which have certain backscattering properties, the natural samples were calibrated and studied, taking into account the atmospheric effect, incidence angle and flying height. Using data from different flights and altitudes, a time series for the natural samples was generated. Studying the stability of the samples, we could obtain information on the most ideal types of natural targets for ALS radiometric calibration. Using the selected natural samples as reference, the ALS points of typical land targets were calibrated again and examined. Results showed the need for more accurate ground reference data, before using natural samples in ALS intensity data calibration. Also, the NIR camera-based field system was used for collecting ground reference data. This system proved to be a good means for collecting in situ reference data, especially for targets with inhomogeneous surface reflection properties. PMID:22574045

Pyranone natural products as inspirations for catalytic reaction discovery and development.

PubMed

McDonald, Benjamin R; Scheidt, Karl A

2015-04-21

bifunctional hydrogen bonding/Brønstead base catalyst was ultimately found to enable this transformation in analogous manner to the biosynthesis via the enzyme chalcone isomerase. Employing thiourea catalysts derived from the pseudoenantiomeric quinine and quinidine, alkylidene β-ketoesters can be isomerized to 3-carboxy flavanones and decarboxylated in a single pot operation to stereodivergently provide highly enantioenriched flavanones in excellent yield. This method was applied to the synthesis of the abyssinone family of natural products, as well as the rotenoid, deguelin. An analogous method to isomerize chalcones was developed and applied to the synthesis of isosilybin A. In both of these related endeavors, the need for novel enabling methodologies toward the efficient creation of targeted molecular complexity drove the discovery, development and deployment of these stereoselective catalytic transformations.

Kainic Acid-Induced Excitotoxicity Experimental Model: Protective Merits of Natural Products and Plant Extracts

PubMed Central

Mohd Sairazi, Nur Shafika; Sirajudeen, K. N. S.; Asari, Mohd Asnizam; Muzaimi, Mustapha; Mummedy, Swamy; Sulaiman, Siti Amrah

2015-01-01

Excitotoxicity is well recognized as a major pathological process of neuronal death in neurodegenerative diseases involving the central nervous system (CNS). In the animal models of neurodegeneration, excitotoxicity is commonly induced experimentally by chemical convulsants, particularly kainic acid (KA). KA-induced excitotoxicity in rodent models has been shown to result in seizures, behavioral changes, oxidative stress, glial activation, inflammatory mediator production, endoplasmic reticulum stress, mitochondrial dysfunction, and selective neurodegeneration in the brain upon KA administration. Recently, there is an emerging trend to search for natural sources to combat against excitotoxicity-associated neurodegenerative diseases. Natural products and plant extracts had attracted a considerable amount of attention because of their reported beneficial effects on the CNS, particularly their neuroprotective effect against excitotoxicity. They provide significant reduction and/or protection against the development and progression of acute and chronic neurodegeneration. This indicates that natural products and plants extracts may be useful in protecting against excitotoxicity-associated neurodegeneration. Thus, targeting of multiple pathways simultaneously may be the strategy to maximize the neuroprotection effect. This review summarizes the mechanisms involved in KA-induced excitotoxicity and attempts to collate the various researches related to the protective effect of natural products and plant extracts in the KA model of neurodegeneration. PMID:26793262

Synthesis and Demonstration of the Biological Relevance of sp3 -rich Scaffolds Distantly Related to Natural Product Frameworks.

PubMed

Foley, Daniel J; Craven, Philip G E; Collins, Patrick M; Doveston, Richard G; Aimon, Anthony; Talon, Romain; Churcher, Ian; von Delft, Frank; Marsden, Stephen P; Nelson, Adam

2017-10-26

The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A "top-down" synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp 3 -rich scaffolds. The scaffolds have local natural product-like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high-throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Contemporary Strategies for the Synthesis of Tetrahydropyran Derivatives: Application to Total Synthesis of Neopeltolide, a Marine Macrolide Natural Product

PubMed Central

Fuwa, Haruhiko

2016-01-01

Tetrahydropyrans are structural motifs that are abundantly present in a range of biologically important marine natural products. As such, significant efforts have been paid to the development of efficient and versatile methods for the synthesis of tetrahydropyran derivatives. Neopeltolide, a potent antiproliferative marine natural product, has been an attractive target compound for synthetic chemists because of its complex structure comprised of a 14-membered macrolactone embedded with a tetrahydropyran ring, and twenty total and formal syntheses of this natural product have been reported so far. This review summarizes the total and formal syntheses of neopeltolide and its analogues, highlighting the synthetic strategies exploited for constructing the tetrahydropyran ring. PMID:27023567

Natural Products in Caries Research: Current (Limited) Knowledge, Challenges and Future Perspective

PubMed Central

Jeon, J.-G; Rosalen, P.L.; Falsetta, M.L.; Koo, H.

2011-01-01

Dental caries is the most prevalent and costly oral infectious disease worldwide. Virulent biofilms firmly attached to tooth surfaces are prime biological factors associated with this disease. The formation of an exopolysaccharide-rich biofilm matrix, acidification of the milieu and persistent low pH at the tooth-biofilm interface are major controlling virulence factors that modulate dental caries pathogenesis. Each one offers a selective therapeutic target for prevention. Although fluoride, delivered in various modalities, remains the mainstay for the prevention of caries, additional approaches are required to enhance its effectiveness. Available antiplaque approaches are based on the use of broad-spectrum microbicidal agents, e.g. chlorhexidine. Natural products offer a rich source of structurally diverse substances with a wide range of biological activities, which could be useful for the development of alternative or adjunctive anticaries therapies. However, it is a challenging approach owing to complex chemistry and isolation procedures to derive active compounds from natural products. Furthermore, most of the studies have been focused on the general inhibitory effects on glucan synthesis as well as on bacterial metabolism and growth, often employing methods that do not address the pathophysiological aspects of the disease (e.g. bacteria in biofilms) and the length of exposure/retention in the mouth. Thus, the true value of natural products in caries prevention and/or their exact mechanisms of action remain largely unknown. Nevertheless, natural substances potentially active against virulent properties of cariogenic organisms have been identified. This review focuses on gaps in the current knowledge and presents a model for investigating the use of natural products in anticaries chemotherapy. PMID:21576957

New Synthetic Methods for Hypericum Natural Products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeon, Insik

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.

A target for production of radioxenons

NASA Technical Reports Server (NTRS)

Blue, J. W.; Leonard, R.; Jha, S.; Sodd, V. J.; Vincent, J. S.

1976-01-01

A liquid cesium target has been developed which allows the production and separate identification of the neutron deficient isotopes of xenon. The present report describes irradiations utilizing 34 to 41 MeV protons to produce millicurie quantities of Xe-127 and Xe-129m. At higher energies, however, the target could be used without modification to produce xenon isotopes as light as 119.

Engineering microbial cell factories for the production of plant natural products: from design principles to industrial-scale production.

PubMed

Liu, Xiaonan; Ding, Wentao; Jiang, Huifeng

2017-07-19

Plant natural products (PNPs) are widely used as pharmaceuticals, nutraceuticals, seasonings, pigments, etc., with a huge commercial value on the global market. However, most of these PNPs are still being extracted from plants. A resource-conserving and environment-friendly synthesis route for PNPs that utilizes microbial cell factories has attracted increasing attention since the 1940s. However, at the present only a handful of PNPs are being produced by microbial cell factories at an industrial scale, and there are still many challenges in their large-scale application. One of the challenges is that most biosynthetic pathways of PNPs are still unknown, which largely limits the number of candidate PNPs for heterologous microbial production. Another challenge is that the metabolic fluxes toward the target products in microbial hosts are often hindered by poor precursor supply, low catalytic activity of enzymes and obstructed product transport. Consequently, despite intensive studies on the metabolic engineering of microbial hosts, the fermentation costs of most heterologously produced PNPs are still too high for industrial-scale production. In this paper, we review several aspects of PNP production in microbial cell factories, including important design principles and recent progress in pathway mining and metabolic engineering. In addition, implemented cases of industrial-scale production of PNPs in microbial cell factories are also highlighted.

Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products.

PubMed

Siveen, Kodappully S; Prabhu, Kirti S; Achkar, Iman W; Kuttikrishnan, Shilpa; Shyam, Sunitha; Khan, Abdul Q; Merhi, Maysaloun; Dermime, Said; Uddin, Shahab

2018-02-19

Tyrosine kinases belong to a family of enzymes that mediate the movement of the phosphate group to tyrosine residues of target protein, thus transmitting signals from the cell surface to cytoplasmic proteins and the nucleus to regulate physiological processes. Non-receptor tyrosine kinases (NRTK) are a sub-group of tyrosine kinases, which can relay intracellular signals originating from extracellular receptor. NRTKs can regulate a huge array of cellular functions such as cell survival, division/propagation and adhesion, gene expression, immune response, etc. NRTKs exhibit considerable variability in their structural make up, having a shared kinase domain and commonly possessing many other domains such as SH2, SH3 which are protein-protein interacting domains. Recent studies show that NRTKs are mutated in several hematological malignancies, including lymphomas, leukemias and myelomas, leading to aberrant activation. It can be due to point mutations which are intragenic changes or by fusion of genes leading to chromosome translocation. Mutations that lead to constitutive kinase activity result in the formation of oncogenes, such as Abl, Fes, Src, etc. Therefore, specific kinase inhibitors have been sought after to target mutated kinases. A number of compounds have since been discovered, which have shown to inhibit the activity of NRTKs, which are remarkably well tolerated. This review covers the role of various NRTKs in the development of hematological cancers, including their deregulation, genetic alterations, aberrant activation and associated mutations. In addition, it also looks at the recent advances in the development of novel natural compounds that can target NRTKs and perhaps in combination with other forms of therapy can show great promise for the treatment of hematological malignancies.

Method for fabricating .sup.99 Mo production targets using low enriched uranium, .sup.99 Mo production targets comprising low enriched uranium

DOEpatents

Wiencek, Thomas C.; Matos, James E.; Hofman, Gerard L.

1997-01-01

A radioisotope production target and a method for fabricating a radioisotope production target is provided, wherein the target comprises an inner cylinder, a foil of fissionable material circumferentially contacting the outer surface of the inner cylinder, and an outer hollow cylinder adapted to receive the substantially foil-covered inner cylinder and compress tightly against the foil to provide good mechanical contact therewith. The method for fabricating a primary target for the production of fission products comprises preparing a first substrate to receive a foil of fissionable material so as to allow for later removal of the foil from the first substrate, preparing a second substrate to receive the foil so as to allow for later removal of the foil from the second substrate; attaching the first substrate to the second substrate such that the foil is sandwiched between the first substrate and second substrate to prevent foil exposure to ambient atmosphere, and compressing the exposed surfaces of the first and second substrate to assure snug mechanical contact between the foil, the first substrate and the second substrate.

Method for fabricating {sup 99}Mo production targets using low enriched uranium, {sup 99}Mo production targets comprising low enriched uranium

DOEpatents

Wiencek, T.C.; Matos, J.E.; Hofman, G.L.

1997-03-25

A radioisotope production target and a method for fabricating a radioisotope production target is provided, wherein the target comprises an inner cylinder, a foil of fissionable material circumferentially contacting the outer surface of the inner cylinder, and an outer hollow cylinder adapted to receive the substantially foil-covered inner cylinder and compress tightly against the foil to provide good mechanical contact therewith. The method for fabricating a primary target for the production of fission products comprises preparing a first substrate to receive a foil of fissionable material so as to allow for later removal of the foil from the first substrate, preparing a second substrate to receive the foil so as to allow for later removal of the foil from the second substrate; attaching the first substrate to the second substrate such that the foil is sandwiched between the first substrate and second substrate to prevent foil exposure to ambient atmosphere, and compressing the exposed surfaces of the first and second substrate to assure snug mechanical contact between the foil, the first substrate and the second substrate. 3 figs.

Method for fabricating .sup.99 Mo production targets using low enriched uranium, .sup.99 Mo production targets comprising low enriched uranium

DOEpatents

Wiencek, Thomas C [Orland Park, IL; Matos, James E [Oak Park, IL; Hofman, Gerard L [Downers Grove, IL

2000-12-12

A radioisotope production target and a method for fabricating a radioisotope production target is provided, wherein the target comprises an inner cylinder, a foil of fissionable material circumferentially contacting the outer surface of the inner cylinder, and an outer hollow cylinder adapted to receive the substantially foil-covered inner cylinder and compress tightly against the foil to provide good mechanical contact therewith. The method for fabricating a primary target for the production of fission products comprises preparing a first substrate to receive a foil of fissionable material so as to allow for later removal of the foil from the first substrate, preparing a second substrate to receive the foil so as to allow for later removal of the foil from the second substrate; attaching the first substrate to the second substrate such that the foil is sandwiched between the first substrate and second substrate to prevent foil exposure to ambient atmosphere, and compressing the exposed surfaces of the first and second substrate to assure snug mechanical contact between the foil, the first substrate and the second substrate.

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.

Food and Natural Materials Target Mechanisms to Effectively Regulate Allergic Responses.

PubMed

Shin, Hee Soon; Shon, Dong-Hwa

2015-01-01

An immune hypersensitivity disorder called allergy is caused by diverse allergens entering the body via skin contact, injection, ingestion, and/or inhalation. These allergic responses may develop into allergic disorders, including inflammations such as atopic dermatitis, asthma, anaphylaxis, food allergies, and allergic rhinitis. Several drugs have been developed to treat these allergic disorders; however, long-term intake of these drugs could have adverse effects. As an alternative to these medicines, food and natural materials that ameliorate allergic disorder symptoms without producing any side effects can be consumed. Food and natural materials can effectively regulate successive allergic responses in an allergic chain-reaction mechanism in the following ways: [1] Inhibition of allergen permeation via paracellular diffusion into epithelial cells, [2] suppression of type 2 T-helper (Th) cell-related cytokine production by regulating Th1/Th2 balance, [3] inhibition of pathogenic effector CD4(+) T cell differentiation by inducing regulatory T cells (Treg), and [4] inhibition of degranulation in mast cells. The immunomodulatory effects of food and natural materials on each target mechanism were scientifically verified and shown to alleviate allergic disorder symptoms. Furthermore, consumption of certain food and natural materials such as fenugreek, skullcap, chitin/chitosan, and cheonggukjang as anti-allergics have merits such as safety (no adverse side effects), multiple suppressive effects (as a mixture would contain various components that are active against allergic responses), and ease of consumption when required. These merits and anti-allergic properties of food and natural materials help control various allergic disorders.

The RIB production target for the SPES project

NASA Astrophysics Data System (ADS)

Monetti, Alberto; Andrighetto, Alberto; Petrovich, Carlo; Manzolaro, Mattia; Corradetti, Stefano; Scarpa, Daniele; Rossetto, Francesco; Martinez Dominguez, Fernando; Vasquez, Jesus; Rossignoli, Massimo; Calderolla, Michele; Silingardi, Roberto; Mozzi, Aldo; Borgna, Francesca; Vivian, Gianluca; Boratto, Enrico; Ballan, Michele; Prete, Gianfranco; Meneghetti, Giovanni

2015-10-01

Facilities making use of the Isotope Separator On-Line (ISOL) method for the production of Radioactive Ion Beams (RIB) attract interest because they can be used for nuclear structure and reaction studies, astrophysics research and interdisciplinary applications. The ISOL technique is based on the fast release of the nuclear reaction products from the chosen target material together with their ionization into short-lived nuclei beams. Within this context, the SPES (Selective Production of Exotic Species) facility is now under construction in Italy at INFN-LNL (Istituto Nazionale di Fisica Nucleare — Laboratori Nazionali di Legnaro). The SPES facility will produce RIBs mainly from n-rich isotopes obtained by a 40 MeV cyclotron proton beam (200 μA) directly impinging on a uranium carbide multi-foil fission target. The aim of this work is to describe and update, from a comprehensive point of view, the most important results obtained by the analysis of the on-line behavior of the SPES production target assembly. In particular an improved target configuration has been studied by comparing different codes and physics models: the thermal analyses and the isotope production are re-evaluated. Then some consequent radioprotection aspects, which are essential for the installation and operation of the facility, are presented.

Role of Antioxidants and Natural Products in Inflammation

PubMed Central

Fard, Masoumeh Tangestani; Tan, Woan Sean; Gothai, Sivapragasam; Kumar, S. Suresh

2016-01-01

Inflammation is a comprehensive array of physiological response to a foreign organism, including human pathogens, dust particles, and viruses. Inflammations are mainly divided into acute and chronic inflammation depending on various inflammatory processes and cellular mechanisms. Recent investigations have clarified that inflammation is a major factor for the progression of various chronic diseases/disorders, including diabetes, cancer, cardiovascular diseases, eye disorders, arthritis, obesity, autoimmune diseases, and inflammatory bowel disease. Free radical productions from different biological and environmental sources are due to an imbalance of natural antioxidants which further leads to various inflammatory associated diseases. In this review article, we have outlined the inflammatory process and its cellular mechanisms involved in the progression of various chronic modern human diseases. In addition, we have discussed the role of free radicals-induced tissue damage, antioxidant defence, and molecular mechanisms in chronic inflammatory diseases/disorders. The systematic knowledge regarding the role of inflammation and its associated adverse effects can provide a clear understanding in the development of innovative therapeutic targets from natural sources that are intended for suppression of various chronic inflammations associated diseases. PMID:27803762

Natural products and the athlete: facts and folklore.

PubMed

Barron, R L; Vanscoy, G J

1993-05-01

To contrast scientific facts with suggested manufacturers' claims regarding food supplements (natural products) marketed for enhanced athletic prowess. A MEDLINE search was performed to obtain documentation supporting the claims of natural-product manufacturers. In addition, several references pertaining to pharmacognosy, natural products, herbs, pharmacy practice, and sports medicine were reviewed. Claims were obtained from promotional advertisements in bodybuilding magazines, product labels, and fact sheets for sales representatives in nutrition and health-food stores. We reviewed all of the clinical trials, published between 1966 and 1992, relative to the manufacturers' claims regarding these products. Pertinent human and/or animal studies supporting each natural product were compared with the manufacturers' claims. We found that there was no published scientific evidence to support the promotional claims for a large proportion of the products (8/19, 42 percent). Only 4 of 19 products (21 percent) were associated with any documented human clinical trials supporting their promotional claims. Six of 19 agents (32 percent) had some scientific documentation to support their promotional claims; however, these products were judged to be marketed in a misleading manner.

Scale-up of high specific activity 186gRe production using graphite-encased thick 186W targets and demonstration of an efficient target recycling process

DOE PAGES

Balkin, Ethan R.; Gagnon, Katherine; Dorman, Eric; ...

2017-08-18

Production of high specific activity 186gRe is of interest for development of theranostic radiopharmaceuticals. Previous studies have shown that high specific activity 186gRe can be obtained by cyclotron irradiation of enriched 186W via the 186W(d,2n) 186gRe reaction, but most irradiations were conducted at low beam currents and for short durations. In this paper, enriched 186W metal targets were irradiated at high incident deuteron beam currents to demonstrate production rates and contaminants produced when using thick targets. Full-stopping thick targets, as determined using SRIM, were prepared by uniaxial pressing of powdered natural abundance W metal or 96.86% enriched 186W metal encasedmore » between two layers of graphite flakes for target material stabilization. An assessment of structural integrity was made on each target preparation. To assess the performance of graphite-encased thick 186W metal targets, along with the impact of encasing on the separation chemistry, targets were first irradiated using a 22 MeV deuteron beam for 10 min at 10, 20, and 27 μA, with an estimated nominal deuteron energy of 18.7 MeV on the 186W target material (after energy degradation correction from top graphite layer). Gamma-ray spectrometry was performed post EOB on all targets to assess production yields and radionuclidic byproducts. The investigation also evaluated a method to recover and recycle enriched target material from a column isolation procedure. Material composition analyses of target materials, pass-through/wash solutions and recycling process isolates were conducted with SEM, FTIR, XRD, EDS and ICP-MS spectrometry. Finally, to demonstrate scaled-up production, a graphite-encased 186W target made from recycled 186W was irradiated for ~2 h with 18.7 MeV deuterons at a beam current of 27 μA to provide 0.90 GBq (24.3 mCi) of 186gRe, decay-corrected to the end of bombardment. ICP-MS analysis of the isolated 186gRe solution provided data that indicated the

Scale-up of high specific activity 186gRe production using graphite-encased thick 186W targets and demonstration of an efficient target recycling process

DOE Office of Scientific and Technical Information (OSTI.GOV)

Balkin, Ethan R.; Gagnon, Katherine; Dorman, Eric

Production of high specific activity 186gRe is of interest for development of theranostic radiopharmaceuticals. Previous studies have shown that high specific activity 186gRe can be obtained by cyclotron irradiation of enriched 186W via the 186W(d,2n) 186gRe reaction, but most irradiations were conducted at low beam currents and for short durations. In this paper, enriched 186W metal targets were irradiated at high incident deuteron beam currents to demonstrate production rates and contaminants produced when using thick targets. Full-stopping thick targets, as determined using SRIM, were prepared by uniaxial pressing of powdered natural abundance W metal or 96.86% enriched 186W metal encasedmore » between two layers of graphite flakes for target material stabilization. An assessment of structural integrity was made on each target preparation. To assess the performance of graphite-encased thick 186W metal targets, along with the impact of encasing on the separation chemistry, targets were first irradiated using a 22 MeV deuteron beam for 10 min at 10, 20, and 27 μA, with an estimated nominal deuteron energy of 18.7 MeV on the 186W target material (after energy degradation correction from top graphite layer). Gamma-ray spectrometry was performed post EOB on all targets to assess production yields and radionuclidic byproducts. The investigation also evaluated a method to recover and recycle enriched target material from a column isolation procedure. Material composition analyses of target materials, pass-through/wash solutions and recycling process isolates were conducted with SEM, FTIR, XRD, EDS and ICP-MS spectrometry. Finally, to demonstrate scaled-up production, a graphite-encased 186W target made from recycled 186W was irradiated for ~2 h with 18.7 MeV deuterons at a beam current of 27 μA to provide 0.90 GBq (24.3 mCi) of 186gRe, decay-corrected to the end of bombardment. ICP-MS analysis of the isolated 186gRe solution provided data that indicated the

Screening of broad spectrum natural pesticides against conserved target arginine kinase in cotton pests by molecular modeling.

PubMed

Sakthivel, Seethalakshmi; Habeeb, S K M; Raman, Chandrasekar

2018-03-12

Cotton is an economically important crop and its production is challenged by the diversity of pests and related insecticide resistance. Identification of the conserved target across the cotton pest will help to design broad spectrum insecticide. In this study, we have identified conserved sequences by Expressed Sequence Tag profiling from three cotton pests namely Aphis gossypii, Helicoverpa armigera, and Spodoptera exigua. One target protein arginine kinase having a key role in insect physiology and energy metabolism was studied further using homology modeling, virtual screening, molecular docking, and molecular dynamics simulation to identify potential biopesticide compounds from the Zinc natural database. We have identified four compounds having excellent inhibitor potential against the identified broad spectrum target which are highly specific to invertebrates.

Enriching the biological space of natural products and charting drug metabolites, through real time biotransformation monitoring: The NMR tube bioreactor.

PubMed

Chatzikonstantinou, Alexandra V; Chatziathanasiadou, Maria V; Ravera, Enrico; Fragai, Marco; Parigi, Giacomo; Gerothanassis, Ioannis P; Luchinat, Claudio; Stamatis, Haralambos; Tzakos, Andreas G

2018-01-01

Natural products offer a wide range of biological activities, but they are not easily integrated in the drug discovery pipeline, because of their inherent scaffold intricacy and the associated complexity in their synthetic chemistry. Enzymes may be used to perform regioselective and stereoselective incorporation of functional groups in the natural product core, avoiding harsh reaction conditions, several protection/deprotection and purification steps. Herein, we developed a three step protocol carried out inside an NMR-tube. 1st-step: STD-NMR was used to predict the: i) capacity of natural products as enzyme substrates and ii) possible regioselectivity of the biotransformations. 2nd-step: The real-time formation of multiple-biotransformation products in the NMR-tube bioreactor was monitored in-situ. 3rd-step: STD-NMR was applied in the mixture of the biotransformed products to screen ligands for protein targets. Herein, we developed a simple and time-effective process, the "NMR-tube bioreactor", that is able to: (i) predict which component of a mixture of natural products can be enzymatically transformed, (ii) monitor in situ the transformation efficacy and regioselectivity in crude extracts and multiple substrate biotransformations without fractionation and (iii) simultaneously screen for interactions of the biotransformation products with pharmaceutical protein targets. We have developed a green, time-, and cost-effective process that provide a simple route from natural products to lead compounds for drug discovery. This process can speed up the most crucial steps in the early drug discovery process, and reduce the chemical manipulations usually involved in the pipeline, improving the environmental compatibility. Copyright © 2017 Elsevier B.V. All rights reserved.

Bioengineering natural product biosynthetic pathways for therapeutic applications.

PubMed

Wu, Ming-Cheng; Law, Brian; Wilkinson, Barrie; Micklefield, Jason

2012-12-01

With the advent of next-generation DNA sequencing technologies, the number of microbial genome sequences has increased dramatically, revealing a vast array of new biosynthetic gene clusters. Genomics data provide a tremendous opportunity to discover new natural products, and also to guide the bioengineering of new and existing natural product scaffolds for therapeutic applications. Notably, it is apparent that the vast majority of biosynthetic gene clusters are either silent or produce very low quantities of the corresponding natural products. It is imperative therefore to devise methods for activating unproductive biosynthetic pathways to provide the quantities of natural products needed for further development. Moreover, on the basis of our expanding mechanistic and structural knowledge of biosynthetic assembly-line enzymes, new strategies for re-programming biosynthetic pathways have emerged, resulting in focused libraries of modified products with potentially improved biological properties. In this review we will focus on the latest bioengineering approaches that have been utilised to optimise yields and increase the structural diversity of natural product scaffolds for future clinical applications. Copyright © 2012 Elsevier Ltd. All rights reserved.

Bridging the gap: basic metabolomics methods for natural product chemistry.

PubMed

Jones, Oliver A H; Hügel, Helmut M

2013-01-01

Natural products and their derivatives often have potent physiological activities and therefore play important roles as both frontline treatments for many diseases and as the inspiration for chemically synthesized therapeutics. However, the detection and synthesis of new therapeutic compounds derived from, or inspired by natural compounds has declined in recent years due to the increased difficulty of identifying and isolating novel active compounds. A new strategy is therefore necessary to jumpstart this field of research. Metabolomics, including both targeted and global metabolite profiling strategies, has the potential to be instrumental in this effort since it allows a systematic study of complex mixtures (such as plant extracts) without the need for prior isolation of active ingredients (or mixtures thereof). Here we describe the basic steps for conducting metabolomics experiments and analyzing the results using some of the more commonly used analytical and statistical methodologies.

Protein Engineering Towards Natural Product Synthesis and Diversification

PubMed Central

Zabala, Angelica O.; Cacho, Ralph A.; Tang, Yi

2014-01-01

A dazzling array of enzymes is used by nature in making structurally complex natural products. These enzymes constitute a molecular toolbox that may be used in the construction and fine-tuning of pharmaceutically active molecules. Aided by technological advancements in protein engineering, it is now possible to tailor the activities and specificities of these enzymes as biocatalysts in the production of both natural products and their unnatural derivatives. These efforts are crucial in drug discovery and development, where there is a continuous quest for more potent agents. Both rational and random evolution techniques have been utilized in engineering these enzymes. This review will highlight some examples from several large families of natural products. PMID:22006344

Spectral reflectances of natural targets for use in remote sensing studies

NASA Technical Reports Server (NTRS)

Bowker, D. E.; Davis, R. E.; Myrick, D. L.; Stacy, K.; Jones, W. T.

1985-01-01

A collection of spectral reflectances of 156 natural targets is presented in a uniform format. For each target both a graphical plot and a digital tabulation of reflectance is given. The data were taken from the literature and include laboratory, field, and aircraft measurements. A discussion of the different measurements of reflectance is given, along with the changes in apparent reflectance when targets are viewed through the atmosphere. The salient features of the reflectance curves of common target types are presented and discussed.

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

Forest Products Laboratory natural finish

Treesearch

J. M. Black; D. F. Laughnan; E. A. Mraz

1979-01-01

A simple and durable exterior natural finish developed at the Forest Products Laboratory is described. The finish is classified as a semi-transparent oil-base penetrating stain that effectively retains much of the natural grain and texture of wood when exposed to the weather. The directions for preparation are included as are the recommendations for application to both...

Natural Products in the Discovery of Agrochemicals.

PubMed

Loiseleur, Olivier

2017-12-01

Natural products have a long history of being used as, or serving as inspiration for, novel crop protection agents. Many of the discoveries in agrochemical research in the last decades have their origin in a wide range of natural products from a variety of sources. In light of the continuing need for new tools to address an ever-changing array of fungal, weed and insect pests, new agricultural practices and evolving regulatory requirements, the needs for new agrochemical tools remains as critical as ever. In that respect, nature continues to be an important source for novel chemical structures and biological mechanisms to be applied for the development of pest control agents. Here we review several of the natural products and their derivatives which contributed to shape crop protection research in past and present.

Natural products from filamentous fungi and production by heterologous expression.

PubMed

Alberti, Fabrizio; Foster, Gary D; Bailey, Andy M

2017-01-01

Filamentous fungi represent an incredibly rich and rather overlooked reservoir of natural products, which often show potent bioactivity and find applications in different fields. Increasing the naturally low yields of bioactive metabolites within their host producers can be problematic, and yield improvement is further hampered by such fungi often being genetic intractable or having demanding culturing conditions. Additionally, total synthesis does not always represent a cost-effective approach for producing bioactive fungal-inspired metabolites, especially when pursuing assembly of compounds with complex chemistry. This review aims at providing insights into heterologous production of secondary metabolites from filamentous fungi, which has been established as a potent system for the biosynthesis of bioactive compounds. Numerous advantages are associated with this technique, such as the availability of tools that allow enhanced production yields and directing biosynthesis towards analogues of the naturally occurring metabolite. Furthermore, a choice of hosts is available for heterologous expression, going from model unicellular organisms to well-characterised filamentous fungi, which has also been shown to allow the study of biosynthesis of complex secondary metabolites. Looking to the future, fungi are likely to continue to play a substantial role as sources of new pharmaceuticals and agrochemicals-either as producers of novel natural products or indeed as platforms to generate new compounds through synthetic biology.

Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents

PubMed Central

Cragg, Gordon M.; Pezzuto, John M.

2016-01-01

Throughout history, natural products have played a dominant role in the treatment of human ailments. For example, the legendary discovery of penicillin transformed global existence. Presently, natural products comprise a large portion of current-day pharmaceutical agents, most notably in the area of cancer therapy. Examples include Taxol, vinblastine, and camptothecin. These structurally unique agents function by novel mechanisms of action; isolation from natural sources is the only plausible method that could have led to their discovery. In addition to terrestrial plants as sources for starting materials, the marine environment (e.g., ecteinascidin 743, halichondrin B, and dolastatins), microbes (e.g., bleomycin, doxorubicin, and staurosporin), and slime molds (e.g., epothilone B) have yielded remarkable cancer chemotherapeutic agents. Irrespective of these advances, cancer remains a leading cause of death worldwide. Undoubtedly, the prevention of human cancer is highly preferable to treatment. Cancer chemoprevention, the use of vaccines or pharmaceutical agents to inhibit, retard, or reverse the process of carcinogenesis, is another important approach for easing this formidable public health burden. Similar to cancer chemotherapeutic agents, natural products play an important role in this field. There are many examples, including dietary phytochemicals such as sulforaphane and phenethyl isothiocyanate (cruciferous vegetables) and resveratrol (grapes and grape products). Overall, natural product research is a powerful approach for discovering biologically active compounds with unique structures and mechanisms of action. Given the unfathomable diversity of nature, it is reasonable to suggest that chemical leads can be generated that are capable of interacting with most or possibly all therapeutic targets. PMID:26679767

SIV Coreceptor Specificity in Natural and Non-Natural Host Infection: Implications for Cell Targeting and Differential Outcomes from Infection.

PubMed

Wetzel, Katherine S; Elliott, Sarah T C; Collman, Ronald G

2018-01-01

Pathogenic HIV-1 infection of humans and SIVmac infection of macaques are the result of zoonotic transfer of primate immunodeficiency viruses from their natural hosts into non-natural host species. Natural host infections do not result in pathogenesis despite high levels of virus replication, and evidence suggests that differences in anatomical location and specific subsets of CD4+ T cells infected may underlie distinct outcomes from infection. The coreceptor CCR5 has long been considered the sole pathway for SIV entry and the key determinant of CD4+ cell targeting, but it has also been known that natural hosts express exceedingly low levels of CCR5 despite maintaining high levels of virus replication. This review details emerging data indicating that in multiple natural host species, CCR5 is dispensable for SIV infection ex vivo and/or in vivo and, contrary to the established dogma, alternative coreceptors, particularly CXCR6, play a central role in infection and cell targeting. Infections of non-natural hosts, however, are characterized by CCR5-exclusive entry. These findings suggest that alternative coreceptor-mediated cell targeting in natural hosts, combined with low CCR5 expression, may direct the virus to distinct populations of cells that are dispensable for immune homeostasis, particularly extralymphoid and more differentiated CD4+ T cells. In contrast, CCR5-mediated entry in non-natural hosts results in targeting of CD4+ T cells that are located in lymphoid tissues, critical for immune homeostasis, or necessary for gut barrier integrity. Thus, fundamental differences in viral entry coreceptor use may be central determinants of infection outcome. These findings redefine the normal SIV/host relationship in natural host species, shed new light on key features linked to zoonotic immunodeficiency virus transfer, and highlight important questions regarding how and why this coreceptor bottleneck occurs and the coevolutionary equilibrium is lost following cross

Effects of oncoming target velocities on rapid force production and accuracy of force production intensity and timing.

PubMed

Ohta, Yoichi

2017-12-01

The present study aimed to clarify the effects of oncoming target velocities on the ability of rapid force production and accuracy and variability of simultaneous control of both force production intensity and timing. Twenty male participants (age: 21.0 ± 1.4 years) performed rapid gripping with a handgrip dynamometer to coincide with the arrival of an oncoming target by using a horizontal electronic trackway. The oncoming target velocities were 4, 8, and 12 m · s -1 , which were randomly produced. The grip force required was 30% of the maximal voluntary contraction. Although the peak force (Pf) and rate of force development (RFD) increased with increasing target velocity, the value of the RFD to Pf ratio was constant across the 3 target velocities. The accuracy of both force production intensity and timing decreased at higher target velocities. Moreover, the intrapersonal variability in temporal parameters was lower in the fast target velocity condition, but constant variability in 3 target velocities was observed in force intensity parameters. These results suggest that oncoming target velocity does not intrinsically affect the ability for rapid force production. However, the oncoming target velocity affects accuracy and variability of force production intensity and timing during rapid force production.

Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries.

PubMed

Lee, M L; Schneider, G

2001-01-01

Natural products were analyzed to determine whether they contain appealing novel scaffold architectures for potential use in combinatorial chemistry. Ring systems were extracted and clustered on the basis of structural similarity. Several such potential scaffolds for combinatorial chemistry were identified that are not present in current trade drugs. For one of these scaffolds a virtual combinatorial library was generated. Pharmacophoric properties of natural products, trade drugs, and the virtual combinatorial library were assessed using a self-organizing map. Obviously, current trade drugs and natural products have several topological pharmacophore patterns in common. These features can be systematically explored with selected combinatorial libraries based on a combination of natural product-derived and synthetic molecular building blocks.

Natural product mode of action (MOA) studies: a link between natural and synthetic worlds.

PubMed

La Clair, James J

2010-07-01

In our understanding of matter, natural products deliver plots that would stun even the best productions of the legendary filmmaker, Sergio Leone. While every decade heralds a new genre of film (as well as avenues of small-molecule discovery), natural products and their "untamed prehistoric" plots continue to dazzle the fields of biotechnology, drug discovery, fragrances, food additives and agrochemistry. This review provides an abridged synopsis of the modes of natural product action discovered within the last decade and the tools and methods used in their discovery. Their stories are united in a common theme that unveils one of the more vital aspects of chemical biological research:understanding the global activity of Nature's arsenal of secondary metabolites.

Theoretical modeling of yields for proton-induced reactions on natural and enriched molybdenum targets.

PubMed

Celler, A; Hou, X; Bénard, F; Ruth, T

2011-09-07

Recent acute shortage of medical radioisotopes prompted investigations into alternative methods of production and the use of a cyclotron and ¹⁰⁰Mo(p,2n)(99m)Tc reaction has been considered. In this context, the production yields of (99m)Tc and various other radioactive and stable isotopes which will be created in the process have to be investigated, as these may affect the diagnostic outcome and radiation dosimetry in human studies. Reaction conditions (beam and target characteristics, and irradiation and cooling times) need to be optimized in order to maximize the amount of (99m)Tc and minimize impurities. Although ultimately careful experimental verification of these conditions must be performed, theoretical calculations can provide the initial guidance allowing for extensive investigations at little cost. We report the results of theoretically determined reaction yields for (99m)Tc and other radioactive isotopes created when natural and enriched molybdenum targets are irradiated by protons. The cross-section calculations were performed using a computer program EMPIRE for the proton energy range 6-30 MeV. A computer graphical user interface for automatic calculation of production yields taking into account various reaction channels leading to the same final product has been created. The proposed approach allows us to theoretically estimate the amount of (99m)Tc and its ratio relative to (99g)Tc and other radioisotopes which must be considered reaction contaminants, potentially contributing to additional patient dose in diagnostic studies.

Using natural products to promote caspase-8-dependent cancer cell death.

PubMed

Tewary, Poonam; Gunatilaka, A A Leslie; Sayers, Thomas J

2017-02-01

The selective killing of cancer cells without toxicity to normal nontransformed cells is an idealized goal of cancer therapy. Thus, there has been much interest in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a protein that appears to selectively kill cancer cells. TRAIL has been reported to trigger apoptosis and under some circumstances, an alternate death signaling pathway termed necroptosis. The relative importance of necroptosis for cell death induction in vivo is under intensive investigation. Nonetheless, many cancer cells (particularly those freshly isolated from cancer patients) are highly resistant to TRAIL-mediated cell death. Therefore, there is an underlying interest in identifying agents that can be combined with TRAIL to improve its efficacy. There are numerous reports in which combination of TRAIL with standard antineoplastic drugs has resulted in enhanced cancer cell death in vitro. However, many of these chemotherapeutic drugs are nonspecific and associated with adverse effects, which raise serious concerns for cancer therapy in patients. By contrast, natural products have been shown to be safer and efficacious alternatives. Recently, a number of studies have suggested that certain natural products when combined with TRAIL can enhance cancer cell death. In this review, we highlight molecular pathways that might be targeted by various natural products to promote cell death, and focus on our recent work with withanolides as TRAIL sensitizers. Finally, we will suggest synergistic approaches for combining active withanolides with various forms of immunotherapy to promote cancer cell death and an effective antitumor immune response.

Industrial recovered-materials-utilization targets for the textile-mill-products industry

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

1979-01-01

The Congress, in the National Energy Conservation and Policy Act of 1978 (NECPA), directed the Department of Energy to establish materials recovery targets for the metals and metal products, paper and allied products, rubber, and textile-mill-products industries. The targets were developed to provide incentives for using energy-saving recorded materials and to provied a yardstick for measuring progress and improvement in this endeavor. The NECPA indicates that the targets should represent the maximum technically and economically feasible increase in the use of energy-saving recovered materials that each industry can achieve progressively by January 1, 1987. Materials affected by recovered-materials targets includemore » and are limited to aluminum, copper, lead, zinc, iron, steel, paper and associated products, textile-mill, products, and rubber. Using information gathered from the textile-mill-products industry and from other textile-relaed sources, DOE has developed recovered materials targets for that industry. This report presents those targets and their basis and justification. Following an overview of the textile industry, the chapters are: Textile-Mill-Products Industry Operations; Economic Analysis of the Textile-Mill-Products Industry; Governmental and Regulatory Influence on the US Textile Industry; Current Mill Use of Recovered Materials in the Textile-Mill-Products Industry; Limitations on the Use of Recovered Materials in the US Textile-Mill-Products Industry; Materials-Recovery Targets; and Government and Industry Actions That Could Increase the Use of Recovered Materials.« less

Marinopyrroles: Unique Drug Discoveries Based on Marine Natural Products.

PubMed

Li, Rongshi

2016-01-01

Natural products provide a successful supply of new chemical entities (NCEs) for drug discovery to treat human diseases. Approximately half of the NCEs are based on natural products and their derivatives. Notably, marine natural products, a largely untapped resource, have contributed to drug discovery and development with eight drugs or cosmeceuticals approved by the U.S. Food and Drug Administration and European Medicines Agency, and ten candidates undergoing clinical trials. Collaborative efforts from drug developers, biologists, organic, medicinal, and natural product chemists have elevated drug discoveries to new levels. These efforts are expected to continue to improve the efficiency of natural product-based drugs. Marinopyrroles are examined here as a case study for potential anticancer and antibiotic agents. © 2015 Wiley Periodicals, Inc.

Strategies for the Discovery and Development of New Antibiotics from Natural Products: Three Case Studies.

PubMed

Herrmann, Jennifer; Lukežič, Tadeja; Kling, Angela; Baumann, Sascha; Hüttel, Stephan; Petković, Hrvoje; Müller, Rolf

Natural products continue to be a predominant source for new anti-infective agents. Research at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the Helmholtz Centre for Infection Research (HZI) is dedicated to the development of new lead structures against infectious diseases and, in particular, new antibiotics against hard-to-treat and multidrug-resistant bacterial pathogens. In this chapter, we introduce some of the concepts currently being employed in the field of antibiotic discovery. In particular, we will exemplarily illustrate three approaches: (1) Current sources for novel compounds are mainly soil-dwelling bacteria. In the course of our antimicrobial discovery program, a biodiverse collection of myxobacterial strains has been established and screened for antibiotic activities. Based on this effort, one successful example is presented in this chapter: Antibacterial cystobactamids were discovered and their molecular target, the DNA gyrase, was identified soon after the analysis of myxobacterial self-resistance making use of the information found in the respective biosynthesis gene cluster. (2) Besides our focus on novel natural products, we also apply strategies to further develop either neglected drugs or widely used antibiotics for which development of resistance in the clinical setting is an issue: Antimycobacterial griselimycins were first described in the 1960s but their development and use in tuberculosis therapy was not further pursued. We show how a griselimycin derivative with improved pharmacokinetic properties and enhanced potency against Mycobacterium tuberculosis revealed and validated a novel target for antibacterial therapy, the DNA sliding clamp. (3) In a third approach, biosynthetic engineering was used to modify and optimize natural products regarding their pharmaceutical properties and their production scale: The atypical tetracycline chelocardin is a natural product scaffold that was modified to yield a more potent

High-speed counter-current chromatography coupled online to high performance liquid chromatography-diode array detector-mass spectrometry for purification, analysis and identification of target compounds from natural products.

PubMed

Liang, Xuejuan; Zhang, Yuping; Chen, Wei; Cai, Ping; Zhang, Shuihan; Chen, Xiaoqin; Shi, Shuyun

2015-03-13

A challenge in coupling high-speed counter-current chromatography (HSCCC) online with high performance liquid chromatography (HPLC) for purity analysis was their time incompatibility. Consequently, HSCCC-HPLC was conducted by either controlling HPLC analysis time and HSCCC flow rate or using stop-and-go scheme. For natural products containing compounds with a wide range of polarities, the former would optimize experimental conditions, while the latter required more time. Here, a novel HSCCC-HPLC-diode array detector-mass spectrometry (HSCCC-HPLC-DAD-MS) was developed for undisrupted purification, analysis and identification of multi-compounds from natural products. Two six-port injection valves and a six-port switching valve were used as interface for collecting key HSCCC effluents alternatively for HPLC-DAD-MS analysis and identification. The ethyl acetate extract of Malus doumeri was performed on the hyphenated system to verify its efficacy. Five main flavonoids, 3-hydroxyphloridzin (1), phloridzin (2), 4',6'-dihydroxyhydrochalcone-2'-O-β-D-glucopyranoside (3, first found in M. doumeri), phloretin (4), and chrysin (5), were purified with purities over 99% by extrusion elution and/or stepwise elution mode in two-step HSCCC, and 25mM ammonium acetate solution was selected instead of water to depress emulsification in the first HSCCC. The online system shortened manipulation time largely compared with off-line analysis procedure and stop-and-go scheme. The results indicated that the present method could serve as a simple, rapid and effective way to achieve target compounds with high purity from natural products. Copyright © 2015 Elsevier B.V. All rights reserved.

Target validation: linking target and chemical properties to desired product profile.

PubMed

Wyatt, Paul G; Gilbert, Ian H; Read, Kevin D; Fairlamb, Alan H

2011-01-01

The discovery of drugs is a lengthy, high-risk and expensive business taking at least 12 years and is estimated to cost upwards of US$800 million for each drug to be successfully approved for clinical use. Much of this cost is driven by the late phase clinical trials and therefore the ability to terminate early those projects destined to fail is paramount to prevent unwanted costs and wasted effort. Although neglected diseases drug discovery is driven more by unmet medical need rather than financial considerations, the need to minimise wasted money and resources is even more vital in this under-funded area. To ensure any drug discovery project is addressing the requirements of the patients and health care providers and delivering a benefit over existing therapies, the ideal attributes of a novel drug needs to be pre-defined by a set of criteria called a target product profile. Using a target product profile the drug discovery process, clinical study design, and compound characteristics can be defined all the way back through to the suitability or druggability of the intended biochemical target. Assessment and prioritisation of the most promising targets for entry into screening programmes is crucial for maximising chances of success.

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

Natural products from the genus tephrosia.

PubMed

Chen, Yinning; Yan, Tao; Gao, Chenghai; Cao, Wenhao; Huang, Riming

2014-01-27

The genus Tephrosia, belonging to the Leguminosae family, is a large pantropical genus of more than 350 species, many of which have important traditional uses in agriculture. This review not only outlines the source, chemistry and biological evaluations of natural products from the genus Tephrosia worldwide that have appeared in literature from 1910 to December 2013, but also covers work related to proposed biosynthetic pathways and synthesis of some natural products from the genus Tephrosia, with 105 citations and 168 new compounds.

Natural products as a rich source of tau-targeting drugs for Alzheimer’s disease

PubMed Central

Calcul, Laurent; Zhang, Bo; Jinwal, Umesh K; Dickey, Chad A; Baker, Bill J

2013-01-01

Alzheimer’s disease (AD) is a neurodegenerative disorder and the most common form of dementia, affecting more than 5.4 million people in the USA. Although the cause of AD is not well understood, the cholinergic, amyloid and tau hypotheses were proposed to explain its development. Drug discovery for AD based on the cholinergic and amyloid theories have not been effective. In this article we summarize tau-based natural products as AD therapeutics from a variety of biological sources, including the anti-amyloid agent curcumin, isolated from turmeric, the microtubule stabilizer paclitaxel, from the Pacific Yew Taxus brevifolia, and the Streptomyces-derived Hsp90 inhibitor, geldanamycin. The overlooked approach of clearing tau aggregation will most likely be the next objective for AD drug discovery. PMID:22924511

Antibiotics: natural products essential to human health.

PubMed

Demain, Arnold L

2009-11-01

For more than 50 years, natural products have served us well in combating infectious bacteria and fungi. Microbial and plant secondary metabolites helped to double our life span during the 20th century, reduced pain and suffering, and revolutionized medicine. Most antibiotics are either (i) natural products of microorganisms, (ii) semi-synthetically produced from natural products, or (iii) chemically synthesized based on the structure of the natural products. Production of antibiotics began with penicillin in the late 1940s and proceeded with great success until the 1970-1980s when it became harder and harder to discover new and useful products. Furthermore, resistance development in pathogens became a major problem, which is still with us today. In addition, new pathogens are continually emerging and there are still bacteria that are not eliminated by any antibiotic, e.g., Pseudomonas aeruginosa. In addition to these problems, many of the major pharmaceutical companies have abandoned the antibiotic field, leaving much of the discovery efforts to small companies, new companies, and the biotechnology industries. Despite these problems, development of new antibiotics has continued, albeit at a much lower pace than in the last century. We have seen the (i) appearance of newly discovered antibiotics (e.g., candins), (ii) development of old but unutilized antibiotics (e.g., daptomycin), (iii) production of new semi-synthetic versions of old antibiotics (e.g., glycylcyclines, streptogrammins), as well as the (iv) very useful application of old but underutilized antibiotics (e.g., teicoplanin).

Indole diterpenoid natural products as the inspiration for new synthetic methods and strategies.

PubMed

Corsello, Michael A; Kim, Junyong; Garg, Neil K

2017-09-01

Indole terpenoids comprise a large class of natural products with diverse structural topologies and a broad range of biological activities. Accordingly, indole terpenoids have and continue to serve as attractive targets for chemical synthesis. Many synthetic efforts over the past few years have focused on a subclass of this family, the indole diterpenoids. This minireview showcases the role indole diterpenoids have played in inspiring the recent development of clever synthetic strategies, and new chemical reactions.

Fungi as a source of natural coumarins production.

PubMed

Costa, Tania Maria; Tavares, Lorena Benathar Ballod; de Oliveira, Débora

2016-08-01

Natural coumarins and derivatives are compounds that occur naturally in several organisms (plant, bacteria, and fungi) consisting of fused benzene and α-pyrone rings. These compounds show high technological potential applications in agrochemical, food, pharmaceuticals, and cosmetics industries. Therefore, the need for bulk production of coumarins and the advancement of the chemical and pharmaceutical industries led to the development of synthetic coumarin. However, biotransformation process, synthetic bioengineering, metabolic engineering, and bioinformatics have proven effective in the production of natural products. Today, these biological systems are recognized as green chemistry innovation and business strategy. This review article aims to report the potential of fungi for synthesis of coumarin. These microorganisms are described as a source of natural products capable of synthesizing many bioactive metabolites. The features, classification, properties, and industrial applications of natural coumarins as well as new molecules obtained by basidiomycetes and ascomycetes fungi are reported in order to explore a topic not yet discussed in the scientific literature.

Natural Killer Cell Immunotherapy Targeting Cancer Stem Cells

PubMed Central

Luna, Jesus I; Grossenbacher, Steven K.; Murphy, William J; Canter, Robert J

2017-01-01

Introduction Standard cytoreductive cancer therapy, such as chemotherapy and radiotherapy, are frequently resisted by a small portion of cancer cells with “stem-cell” like properties including quiescence and repopulation. Immunotherapy represents a breakthrough modality for improving oncologic outcomes in cancer patients. Since the success of immunotherapy is not contingent on target cell proliferation, it may also be uniquely suited to address the problem of resistance and repopulation exerted by cancer stem cells (CSCs). Areas covered Natural killer (NK) cells have long been known for their ability to reject allogeneic hematopoietic stem cells, and there are increasing data demonstrating that NK cells can selectively identify and lyse CSCs. In this report, we review the current knowledge of CSCs and NK cells and highlight recent studies that support the concept that NK cells are capable of targeting CSC in solid tumors, especially in the context of combination therapy simultaneously targeting non-CSCs and CSCs. Expert Opinion Unlike cytotoxic cancer treatments, NK cells are able to target and eliminate quiescent/non-proliferating cells such as CSCs, and these enigmatic cells are an important source of relapse and metastasis. NK targeting of CSCs represents a novel and potentially high impact method to capitalize on the intrinsic therapeutic potential of NK cells. PMID:27960589

NPACT: Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database

PubMed Central

Mangal, Manu; Sagar, Parul; Singh, Harinder; Raghava, Gajendra P. S.; Agarwal, Subhash M.

2013-01-01

Plant-derived molecules have been highly valued by biomedical researchers and pharmaceutical companies for developing drugs, as they are thought to be optimized during evolution. Therefore, we have collected and compiled a central resource Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database (NPACT, http://crdd.osdd.net/raghava/npact/) that gathers the information related to experimentally validated plant-derived natural compounds exhibiting anti-cancerous activity (in vitro and in vivo), to complement the other databases. It currently contains 1574 compound entries, and each record provides information on their structure, manually curated published data on in vitro and in vivo experiments along with reference for users referral, inhibitory values (IC50/ED50/EC50/GI50), properties (physical, elemental and topological), cancer types, cell lines, protein targets, commercial suppliers and drug likeness of compounds. NPACT can easily be browsed or queried using various options, and an online similarity tool has also been made available. Further, to facilitate retrieval of existing data, each record is hyperlinked to similar databases like SuperNatural, Herbal Ingredients’ Targets, Comparative Toxicogenomics Database, PubChem and NCI-60 GI50 data. PMID:23203877

Synthesis and Demonstration of the Biological Relevance of sp3‐rich Scaffolds Distantly Related to Natural Product Frameworks

PubMed Central

Foley, Daniel J.; Craven, Philip G. E.; Collins, Patrick M.; Doveston, Richard G.; Aimon, Anthony; Talon, Romain; Churcher, Ian; von Delft, Frank

2017-01-01

Abstract The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A “top‐down” synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp3‐rich scaffolds. The scaffolds have local natural product‐like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high‐throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space. PMID:28983993

Direct Capture Technologies for Genomics-Guided Discovery of Natural Products.

PubMed

Chan, Andrew N; Santa Maria, Kevin C; Li, Bo

2016-01-01

Microbes are important producers of natural products, which have played key roles in understanding biology and treating disease. However, the full potential of microbes to produce natural products has yet to be realized; the overwhelming majority of natural product gene clusters encoded in microbial genomes remain "cryptic", and have not been expressed or characterized. In contrast to the fast-growing number of genomic sequences and bioinformatic tools, methods to connect these genes to natural product molecules are still limited, creating a bottleneck in genome-mining efforts to discover novel natural products. Here we review developing technologies that leverage the power of homologous recombination to directly capture natural product gene clusters and express them in model hosts for isolation and structural characterization. Although direct capture is still in its early stages of development, it has been successfully utilized in several different classes of natural products. These early successes will be reviewed, and the methods will be compared and contrasted with existing traditional technologies. Lastly, we will discuss the opportunities for the development of direct capture in other organisms, and possibilities to integrate direct capture with emerging genome-editing techniques to accelerate future study of natural products.

Preliminary report on the commercial viability of gas production from natural gas hydrates

USGS Publications Warehouse

Walsh, M.R.; Hancock, S.H.; Wilson, S.J.; Patil, S.L.; Moridis, G.J.; Boswell, R.; Collett, T.S.; Koh, C.A.; Sloan, E.D.

2009-01-01

Economic studies on simulated gas hydrate reservoirs have been compiled to estimate the price of natural gas that may lead to economically viable production from the most promising gas hydrate accumulations. As a first estimate, $CDN2005 12/Mscf is the lowest gas price that would allow economically viable production from gas hydrates in the absence of associated free gas, while an underlying gas deposit will reduce the viability price estimate to $CDN2005 7.50/Mscf. Results from a recent analysis of the simulated production of natural gas from marine hydrate deposits are also considered in this report; on an IROR basis, it is $US2008 3.50-4.00/Mscf more expensive to produce marine hydrates than conventional marine gas assuming the existence of sufficiently large marine hydrate accumulations. While these prices represent the best available estimates, the economic evaluation of a specific project is highly dependent on the producibility of the target zone, the amount of gas in place, the associated geologic and depositional environment, existing pipeline infrastructure, and local tariffs and taxes. ?? 2009 Elsevier B.V.

Bioactive activities of natural products against herpesvirus infection.

PubMed

Son, Myoungki; Lee, Minjung; Sung, Gi-Ho; Lee, Taeho; Shin, Yu Su; Cho, Hyosun; Lieberman, Paul M; Kang, Hyojeung

2013-10-01

More than 90% of adults have been infected with at least one human herpesvirus, which establish long-term latent infection for the life of the host. While anti-viral drugs exist that limit herpesvirus replication, many of these are ineffective against latent infection. Moreover, drug-resistant strains of herpesvirus emerge following chemotherapeutic treatment. For example, resistance to acyclovir and related nucleoside analogues can occur when mutations arise in either HSV thymidine kinase or DNA polymerases. Thus, there exists an unmet medical need to develop new anti-herpesvirus agents with different mechanisms of action. In this Review, we discuss the promise of anti-herpetic substances derived from natural products including extracts and pure compounds from potential herbal medicines. One example is Glycyrrhizic acid isolated from licorice that shows promising antiviral activity towards human gammaherpesviruses. Secondly, we discuss anti-herpetic mechanisms utilized by several natural products in molecular level. While nucleoside analogues inhibit replicating herpesviruses in lytic replication, some natural products can disrupt the herpesvirus latent infection in the host cell. In addition, natural products can stimulate immune responses against herpesviral infection. These findings suggest that natural products could be one of the best choices for development of new treatments for latent herpesvirus infection, and may provide synergistic anti-viral activity when supplemented with nucleoside analogues. Therefore, it is important to identify which natural products are more efficacious anti-herpetic agents, and to understand the molecular mechanism in detail for further advance in the anti-viral therapies.

Effects of bioenergy production on European nature conservation options

NASA Astrophysics Data System (ADS)

Schleupner, C.; Schneider, U. A.

2009-04-01

To increase security of energy supply and reduce greenhouse gas (GHG) emissions the European Commission set out a long-term strategy for renewable energy in the European Union (EU). Bioenergy from forestry and agriculture plays a key role for both. Since the last decade a significant increase of biomass energy plantations has been observed in Europe. Concurrently, the EU agreed to halt the loss of biodiversity within its member states. One measure is the Natura2000 network of important nature sites that actually covers about 20% of the EU land surface. However, to fulfil the biodiversity target more nature conservation and restoration sites need to be designated. There are arising concerns that an increased cultivation of bioenergy crops will decrease the land available for nature reserves and for "traditional" agriculture and forestry. In the following the economic and ecological impacts of structural land use changes are demonstrated by two examples. First, a case study of land use changes on the Eiderstedt peninsula in Schleswig-Holstein/Germany evaluates the impacts of grassland conversion into bioenergy plantations under consideration of selected meadow birds. Scenarios indicate not only a quantitative loss of habitats but also a reduction of habitat quality. The second study assesses the role of bioenergy production in light of possible negative impacts on potential wetland conservation sites in Europe. By coupling the spatial wetland distribution model "SWEDI" (cf. SCHLEUPNER 2007) to the European Forest and Agricultural Sector Optimization Model (EUFASOM; cf. SCHNEIDER ET AL. 2008) economic and environmental aspects of land use are evaluated simultaneously. This way the costs and benefits of the appropriate measures and its consequences for agriculture and forestry are investigated. One aim is to find the socially optimal balance between alternative wetland uses by integrating biological benefits - in this case wetlands - and economic opportunities - here

Natural Compounds as Anticancer Agents Targeting DNA Topoisomerases

PubMed Central

Jain, Chetan Kumar; Majumder, Hemanta Kumar; Roychoudhury, Susanta

2017-01-01

DNA topoisomerases are important cellular enzymes found in almost all types of living cells (eukaryotic and prokaryotic). These enzymes are essential for various DNA metabolic processes e.g. replication, transcription, recombination, chromosomal decatenation etc. These enzymes are important molecular drug targets and inhibitors of these enzymes are widely used as effective anticancer and antibacterial drugs. However, topoisomerase inhibitors have some therapeutic limitations and they exert serious side effects during cancer chemotherapy. Thus, development of novel anticancer topoisomerase inhibitors is necessary for improving cancer chemotherapy. Nature serves as a repertoire of structurally and chemically diverse molecules and in the recent years many DNA topoisomerase inhibitors have been identified from natural sources. The present review discusses anticancer properties and therapeutic importance of eighteen recently identified natural topoisomerase inhibitors (from the year 2009 to 2015). Structural characteristics of these novel inhibitors provide backbones for designing and developing new anticancer drugs. PMID:28503091

Natural products modulating the hERG channel: heartaches and hope.

PubMed

Kratz, Jadel M; Grienke, Ulrike; Scheel, Olaf; Mann, Stefan A; Rollinger, Judith M

2017-08-02

Covering: 1996-December 2016The human Ether-à-go-go Related Gene (hERG) channel is a voltage-gated potassium channel playing an essential role in the normal electrical activity in the heart. It is involved in the repolarization and termination of action potentials in excitable cardiac cells. Mutations in the hERG gene and hERG channel blockage by small molecules are associated with increased risk of fatal arrhythmias. Several drugs have been withdrawn from the market due to hERG channel-related cardiotoxicity. Moreover, as a result of its notorious ligand promiscuity, this ion channel has emerged as an important antitarget in early drug discovery and development. Surprisingly, the hERG channel blocking profile of natural compounds present in frequently consumed botanicals (i.e. dietary supplements, spices, and herbal medicinal products) is not routinely assessed. This comprehensive review will address these issues and provide a critical compilation of hERG channel data for isolated natural products and extracts over the past two decades (1996-2016). In addition, the review will provide (i) a solid basis for the molecular understanding of the physiological functions of the hERG channel, (ii) the translational potential of in vitro/in vivo results to cardiotoxicity in humans, (iii) approaches for the identification of hERG channel blockers from natural sources, (iv) future perspectives for cardiac safety guidelines and their applications within phytopharmaceuticals and dietary supplements, and (v) novel applications of hERG channel modulation (e.g. as a drug target).

Plants as natural antioxidants for meat products

NASA Astrophysics Data System (ADS)

Tomović, V.; Jokanović, M.; Šojić, B.; Škaljac, S.; Ivić, M.

2017-09-01

The meat industry is demanding antioxidants from natural sources to replace synthetic antioxidants because of the negative health consequences or beliefs regarding some synthetic ones. Plants materials provide good alternatives. Spices and herbs, generally used for their flavouring characteristics, can be added to meat products in various forms: whole, ground, or as isolates from their extracts. These natural antioxidants contain some active compounds, which exert antioxidative potential in meat products. This antioxidant activity is most often due to phenolic acids, phenolic diterpenes, flavonoids and volatile oils. Each of these compounds often has strong H-donating activity, thus making them extremely effective antioxidants; some compounds can chelate metals and donate H to oxygen radicals, thus slowing oxidation via two mechanisms. Numerous studies have demonstrated the efficacy of natural antioxidants when used in meat products. Based on this literature review, it can be concluded that natural antioxidants are added to fresh and processed meat and meat products to delay, retard, or prevent lipid oxidation, retard development of off-flavours (rancidity), improve colour stability, improve microbiological quality and extend shelf-life, without any damage to the sensory or nutritional properties.

Environmental Impact of Natural Gas Hydrate Production

NASA Astrophysics Data System (ADS)

Max, M. D.; Johnson, A. H.

2017-12-01

Unmet conventional energy demand is encouraging a number of deep energy importing nations closer to production of their potentially very large Natural Gas Hydrate (NGH) resources. As methane and other natural gases are potent greenhouse gases, concerns exist about the possible environmental risks associated NGH development. Accidental of natural gas would have environmental consequences. However, the special characteristics of NGH and production models indicate a very low environmental risk from the reservoir to the deepwater wellhead that is much lower than for conventional deepwater gas. NGH is naturally stable in its solid form in the reservoir and shutting in the gas can be achieved by stopping NGH conversion and gas production in the reservoir. Rapid shut down results in re-crystallization of gas and stabilization of the reservoir through NGH reformation. In addition, new options for innovative technologies have the potential to allow safe development of NGH at a fraction of the current estimated cost. Gas produced from NGH is about the same as processed conventional gas, although almost certainly more pure. Leakage of gas during transport is not a production issue. Gas transport leakage is a matter for best practices regulation that is rigorously enforced.

Data Resources for the Computer-Guided Discovery of Bioactive Natural Products.

PubMed

Chen, Ya; de Bruyn Kops, Christina; Kirchmair, Johannes

2017-09-25

Natural products from plants, animals, marine life, fungi, bacteria, and other organisms are an important resource for modern drug discovery. Their biological relevance and structural diversity make natural products good starting points for drug design. Natural product-based drug discovery can benefit greatly from computational approaches, which are a valuable precursor or supplementary method to in vitro testing. We present an overview of 25 virtual and 31 physical natural product libraries that are useful for applications in cheminformatics, in particular virtual screening. The overview includes detailed information about each library, the extent of its structural information, and the overlap between different sources of natural products. In terms of chemical structures, there is a large overlap between freely available and commercial virtual natural product libraries. Of particular interest for drug discovery is that at least ten percent of known natural products are readily purchasable and many more natural products and derivatives are available through on-demand sourcing, extraction and synthesis services. Many of the readily purchasable natural products are of small size and hence of relevance to fragment-based drug discovery. There are also an increasing number of macrocyclic natural products and derivatives becoming available for screening.

New Scaffold for Angiogenesis Inhibitors Discovered by Targeted Chemical Transformations of Wondonin Natural Products.

PubMed

Yu, Shuai; Oh, Jedo; Li, Feng; Kwon, Yongseok; Cho, Hyunkyung; Shin, Jongheon; Lee, Sang Kook; Kim, Sanghee

2017-10-12

The structure of wondonin marine natural products was renovated to attain new drug-like scaffolds. Wondonins have novel antiangiogenic properties without overt cytotoxicity. However, the chemical instability and synthetic complexity of wondonins have hindered their development as a new type of antiangiogenesis agent. Using a structure-based bioisosterism, the benzodioxole moiety was changed to benzothiazole, and the imidazole moiety was replaced by 1,2,3-triazole. Our efforts resulted in a new scaffold with enhanced antiangiogenic activity and minimized cytotoxicity. One compound with this scaffold effectively inhibited hyaloid vessel formation in diabetic retinopathy mimic zebrafish model. The biological findings together suggested the potential of the scaffold as a lead structure for development of antiangiogenic drugs with novel functions and as a probe to elucidate new biological mechanisms associated with angiogenesis.

Target-fueled nuclear reactor for medical isotope production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coats, Richard L.; Parma, Edward J.

A small, low-enriched, passively safe, low-power nuclear reactor comprises a core of target and fuel pins that can be processed to produce the medical isotope .sup.99Mo and other fission product isotopes. The fuel for the reactor and the targets for the .sup.99Mo production are the same. The fuel can be low enriched uranium oxide, enriched to less than 20% .sup.235U. The reactor power level can be 1 to 2 MW. The reactor is passively safe and maintains negative reactivity coefficients. The total radionuclide inventory in the reactor core is minimized since the fuel/target pins are removed and processed after 7more » to 21 days.« less

Discovery of Repellents from Natural Products

USDA-ARS?s Scientific Manuscript database

Natural products are an ideal source of chemicals for topical application to human skin, and can be a means of personal protection from the bites of mosquitoes and other arthropods. This report covers a diverse array of natural compounds, and includes descriptions of observed correlations between ch...

Impact of natural products in modern drug development.

PubMed

Dev, Sukh

2010-03-01

Usage of natural substances as therapeutic agents in modern medicine has sharply declined from the predominant position held in the early decades of last century, but search for bioactive molecules from nature (plants, animals, microflora) continues to play an important role in fashioning new medicinal agents. With the advent of modern techniques, instrumentation and automation in isolation and structural characterisation, we have on hand an enormous repository of natural compounds. In parallel to this, biology has also made tremendous progress in expanding its frontiers of knowledge. An interplay of these two disciplines constitutes the modern thrust in research in the realm of compounds elaborated by nature. The purpose of this article is to underline how natural products research continues to make significant contributions in the domain of discovery and development of new medicinal products. It is proposed to present the material under several heads, each of which has made natural products research relevant in the search for new and better medication.

Potential of Natural Products in the Inhibition of Adipogenesis through Regulation of PPARγ Expression and/or Its Transcriptional Activity.

PubMed

Feng, Shi; Reuss, Laura; Wang, Yu

2016-09-23

Obesity is a global health problem characterized as an increase in the mass of adipose tissue. Adipogenesis is one of the key pathways that increases the mass of adipose tissue, by which preadipocytes mature into adipocytes through cell differentiation. Peroxisome proliferator-activated receptor γ (PPARγ), the chief regulator of adipogenesis, has been acutely investigated as a molecular target for natural products in the development of anti-obesity treatments. In this review, the regulation of PPARγ expression by natural products through inhibition of CCAAT/enhancer-binding protein β (C/EBPβ) and the farnesoid X receptor (FXR), increased expression of GATA-2 and GATA-3 and activation of the Wnt/β-catenin pathway were analyzed. Furthermore, the regulation of PPARγ transcriptional activity associated with natural products through the antagonism of PPARγ and activation of Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK) were discussed. Lastly, regulation of mitogen-activated protein kinase (MAPK) by natural products, which might regulate both PPARγ expression and PPARγ transcriptional activity, was summarized. Understanding the role natural products play, as well as the mechanisms behind their regulation of PPARγ activity is critical for future research into their therapeutic potential for fighting obesity.

Beauty and charm production in fixed target experiments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kidonakis, Nikolaos; Vogt, Ramona

We present calculations of NNLO threshold corrections for beauty and charm production in {pi}{sup -} p and pp interactions at fixed-target experiments. Recent calculations for heavy quark hadroproduction have included next-to-next-to-leading-order (NNLO) soft-gluon corrections [1] to the double differential cross section from threshold resummation techniques [2]. These corrections are important for near-threshold beauty and charm production at fixed-target experiments, including HERA-B and some of the current and future heavy ion experiments.

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

PubMed

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

2014-09-01

Antiapoptotic Bcl-2 family proteins are validated cancer targets composed of six related proteins. From a drug discovery perspective, these are challenging targets that exert their cellular functions through protein-protein interactions (PPIs). Although 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 antiapoptotic Bcl-2 family proteins using fluorochrome-conjugated peptide ligands that mimic functionally relevant PPIs. The screens were conducted in 1536-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% and 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. © 2014 Society for Laboratory Automation and Screening.

Collective synthesis of natural products by means of organocascade catalysis

PubMed Central

Jones, Spencer B.; Simmons, Bryon; Mastracchio, Anthony; MacMillan, David W. C.

2012-01-01

Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine. PMID:21753848

[The recent research progress of chemistry of marine natural products].

PubMed

Shi, Qing-wen; Li, Li-geng; Wang, Yu-fang; Huo, Chang-hong; Zhang, Man-li

2010-10-01

Ocean is a unique and excellent resource that provides a diverse array of intriguing natural products. Marine natural products have demonstrated significant and extremely potent biological activities and have captured the attention of natural products chemists in the past few decades. It is increasingly recognized that a wealth of fascinating natural products and novel chemical entities will play a dominant role in the discovery of useful leads for the development of pharmaceutical agents and provide useful probes to lead to breakthroughs in a variety of life-science fields. This article focused on the research progress of chemistry of marine natural products in recent five years.

Natural Product Biosynthetic Diversity and Comparative Genomics of the Cyanobacteria.

PubMed

Dittmann, Elke; Gugger, Muriel; Sivonen, Kaarina; Fewer, David P

2015-10-01

Cyanobacteria are an ancient lineage of slow-growing photosynthetic bacteria and a prolific source of natural products with intricate chemical structures and potent biological activities. The bulk of these natural products are known from just a handful of genera. Recent efforts have elucidated the mechanisms underpinning the biosynthesis of a diverse array of natural products from cyanobacteria. Many of the biosynthetic mechanisms are unique to cyanobacteria or rarely described from other organisms. Advances in genome sequence technology have precipitated a deluge of genome sequences for cyanobacteria. This makes it possible to link known natural products to biosynthetic gene clusters but also accelerates the discovery of new natural products through genome mining. These studies demonstrate that cyanobacteria encode a huge variety of cryptic gene clusters for the production of natural products, and the known chemical diversity is likely to be just a fraction of the true biosynthetic capabilities of this fascinating and ancient group of organisms. Copyright © 2015. Published by Elsevier Ltd.

Monthly Crude Oil and Natural Gas Production Report

EIA Publications

2017-01-01

Crude oil production (including lease condensate) and natural gas production (gross withdrawals) from data collected on Form EIA-914 (Monthly Crude Oil, Lease Condensate, and Natural Gas Production Report) for Federal Offshore Gulf of Mexico, Texas, Louisiana, New Mexico, Oklahoma, Texas, Wyoming, other states and lower 48 states. Alaska data are from the Alaska state government and included to obtain a U.S. total.

Techniques for extraction and isolation of natural products: a comprehensive review.

PubMed

Zhang, Qing-Wen; Lin, Li-Gen; Ye, Wen-Cai

2018-01-01

Natural medicines were the only option for the prevention and treatment of human diseases for thousands of years. Natural products are important sources for drug development. The amounts of bioactive natural products in natural medicines are always fairly low. Today, it is very crucial to develop effective and selective methods for the extraction and isolation of those bioactive natural products. This paper intends to provide a comprehensive view of a variety of methods used in the extraction and isolation of natural products. This paper also presents the advantage, disadvantage and practical examples of conventional and modern techniques involved in natural products research.

Indole alkaloid marine natural products: An established source of cancer drug leads with considerable promise for the control of parasitic, neurological and other diseases

PubMed Central

Gul, Waseem; Hamann, Mark T.

2016-01-01

The marine environment produces natural products from a variety of structural classes exhibiting activity against numerous disease targets. Historically marine natural products have largely been explored as anticancer agents. The indole alkaloids are a class of marine natural products that show unique promise in the development of new drug leads. This report reviews the literature on indole alkaloids of marine origin and also highlights our own research. Specific biological activities of indole alkaloids presented here include: cytotoxicity, antiviral, antiparasitic, anti-inflammatory, serotonin antagonism, Ca-releasing, calmodulin antagonism, and other pharmacological activities. PMID:16236327

Function-Oriented Synthesis: How to Design Simplified Analogues of Antibacterial Nucleoside Natural Products?

PubMed

Ichikawa, Satoshi

2016-06-01

It is important to pursue function-oriented synthesis (FOS), a strategy for the design of less structurally complex targets with comparable or superior activity that can be made in a practical manner, because compared to synthetic drugs, many biologically relevant natural products possess large and complex chemical structures that may restrict chemical modifications in a structure-activity relationship study. In this account, we describe recent efforts to simplify complex nucleoside natural products including caprazamycins. Considering the structure-activity relationship study with several truncated analogues, three types of simplified derivatives, namely, oxazolidine, isoxazolidine, and lactam-fused isoxazolidine-containing uridine derivatives, were designed and efficiently synthesized. These simplified derivatives have exhibited promising antibacterial activities. A significant feature of our studies is the rational and drastic simplification of the molecular architecture of caprazamycins. This study provides a novel strategy for the development of a new type of antibacterial agent effective against drug-resistant bacteria. © 2016 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Collective synthesis of natural products by means of organocascade catalysis.

PubMed

Jones, Spencer B; Simmons, Bryon; Mastracchio, Anthony; MacMillan, David W C

2011-07-13

Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine. ©2011 Macmillan Publishers Limited. All rights reserved

Discovery of Natural Products as Novel and Potent FXR Antagonists by Virtual Screening

NASA Astrophysics Data System (ADS)

Diao, Yanyan; Jiang, Jing; Zhang, Shoude; Li, Shiliang; Shan, Lei; Huang, Jin; Zhang, Weidong; Li, Honglin

2018-04-01

Farnesoid X receptor (FXR) is a member of nuclear receptor family involved in multiple physiological processes through regulating specific target genes. The critical role of FXR as a transcriptional regulator makes it a promising target for diverse diseases, especially those related to metabolic disorders such as diabetes and cholestasis. However, the underlying activation mechanism of FXR is still a blur owing to the absence of proper FXR modulators. To identify potential FXR modulators, an in-house natural product database (NPD) containing over 4000 compounds was screened by structure-based virtual screening strategy and subsequent hit-based similarity searching method. After the yeast two-hybrid (Y2H) assay, six natural products were identified as FXR antagonists which blocked the CDCA-induced SRC-1 association. The IC50 values of compounds 2a, a diterpene bearing polycyclic skeleton, and 3a, named daphneone with chain scaffold, are as low as 1.29 μM and 1.79 μM, respectively. Compared to the control compound guggulsterone (IC50 = 6.47 μM), compounds 2a and 3a displayed 5-fold and 3-fold higher antagonistic activities against FXR, respectively. Remarkably, the two representative compounds shared low topological similarities with other reported FXR antagonists. According to the putative binding poses, the molecular basis of these antagonists against FXR was also elucidated in this report.

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

Natural products as promising drug candidates for the treatment of Alzheimer's disease: molecular mechanism aspect.

PubMed

Ansari, Niloufar; Khodagholi, Fariba

2013-07-01

Alzheimer's disease (AD) is the most common neurodegenerative disorder to date, with no curative or preventive therapy. Histopathological hallmarks of AD include deposition of β-amyloid plaques and formation of neurofibrillary tangles. Extent studies on pathology of the disease have made important discoveries regarding mechanism of disease and potential therapeutic targets. Many cellular changes including oxidative stress, disruption of Ca2+ homeostasis, inflammation, metabolic disturbances, and accumulation of unfolded/misfolded proteins can lead to programmed cell death in AD. Despite intensive research, only five approved drugs are available for the management of AD. Hence, there is a need to look at alternative therapies. Use of natural products and culinary herbs in medicine has gained popularity in recent years. Several natural substances with neuroprotective effects have been widely studied. Most of these compounds have remarkable antioxidant properties and act mainly by scavenging free radical species. Some of them increase cell survival and improve cognition by directly affecting amyloidogenesis and programmed cell death pathways. Further studies on these natural products and their mechanism of action, parallel with the use of novel pharmaceutical drug design and delivery techniques, enable us to offer an addition to conventional medicine. This review discussed some natural products with potential neuroprotective properties against Aβ with respect to their mechanism of action.

Natural Product-Derived Drugs for the Treatment of Inflammatory Bowel Diseases

PubMed Central

2014-01-01

Natural products have been used as drugs for millennia, and the therapeutic potential of natural products has been studied for more than a century. Since the mid-1880s, approximately 60% of drugs have originated from natural products. Recently, the importance of using natural products has increased, as has interest in discovering efficient new drugs. Natural drugs are desirable for the treatment of inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. This review discusses the discovery and development of drugs derived from natural products for the treatment of inflammatory bowel diseases. PMID:25349576

Plant-Derived Natural Products as Sources of Anti-Quorum Sensing Compounds

PubMed Central

Koh, Chong-Lek; Sam, Choon-Kook; Yin, Wai-Fong; Tan, Li Ying; Krishnan, Thiba; Chong, Yee Meng; Chan, Kok-Gan

2013-01-01

Quorum sensing is a system of stimuli and responses in relation to bacterial cell population density that regulates gene expression, including virulence determinants. Consequently, quorum sensing has been an attractive target for the development of novel anti-infective measures that do not rely on the use of antibiotics. Anti-quorum sensing has been a promising strategy to combat bacterial infections as it is unlikely to develop multidrug resistant pathogens since it does not impose any selection pressure. A number of anti-quorum sensing approaches have been documented and plant-based natural products have been extensively studied in this context. Plant matter is one of the major sources of chemicals in use today in various industries, ranging from the pharmaceutical, cosmetic, and food biotechnology to the textile industries. Just like animals and humans, plants are constantly exposed to bacterial infections, it is therefore logical to expect that plants have developed sophisticated of chemical mechanisms to combat pathogens. In this review, we have surveyed the various types of plant-based natural products that exhibit anti-quorum sensing properties and their anti-quorum sensing mechanisms. PMID:23669710

Natural production of biological optical systems

NASA Astrophysics Data System (ADS)

Choi, Seung Ho; Kim, Young L.

2015-03-01

Synthesis and production in nature often provide ideas to design and fabricate advanced biomimetic photonic materials and structures, leading to excellent physical properties and enhanced performance. In addition, the recognition and utilization of natural or biological substances have been typical routes to develop biocompatible and biodegradable materials for medical applications. In this respect, biological lasers utilizing such biomaterials and biostructures have been received considerable attention, given a variety of implications and potentials for bioimaging, biosensing, implantation, and therapy. However, without relying on industrial facilities, eco-friendly massive production of such optical components or systems has not yet been investigated. We show examples of bioproduction of biological lasers using agriculture and fisheries. We anticipate that such approaches will open new possibilities for scalable eco-friendly `green' production of biological photonics components and systems.

Towards Integrating Soil Quality Monitoring Targets as Measures of Soil Natural Capital Stocks with the Provision of Ecosystem Services

NASA Astrophysics Data System (ADS)

Taylor, M. D.; Mackay, A. D.; Dominati, E.; Hill, R. B.

2012-04-01

This paper presents the process used to review soil quality monitoring in New Zealand to better align indicators and indicator target ranges with critical values of change in soil function. Since its inception in New Zealand 15 year ago, soil quality monitoring has become an important state of the environment reporting tool for Regional Councils. This tool assists councils to track the condition of soils resources, assess the impact of different land management practices, and provide timely warning of emerging issues to allow early intervention and avoid irreversible loss of natural capital stocks. Critical to the effectiveness of soil quality monitoring is setting relevant, validated thresholds or target ranges. Provisional Target Ranges were set in 2003 using expert knowledge available and data on production responses. Little information was available at that time for setting targets for soil natural capital stocks other than those for food production. The intention was to revise these provisional ranges as further information became available and extend target ranges to cover the regulating and cultural services provided by soils. A recently developed ecosystems service framework was used to explore the feasibility of linking soil natural capital stocks measured by the current suite of soil quality indicators to the provision of ecosystem services by soils. Importantly the new approach builds on and utilises the time series data sets collected by current suite of soil quality indicators, adding value to the current effort, and has the potential to set targets ranges based on the economic and environmental outcomes required for a given farm, catchment or region. It is now timely to develop a further group of environmental indicators for measuring specific soil issues. As with the soil quality indicators, these environmental indicators would be aligned with the provision of ecosystem services. The toolbox envisaged is a set of indicators for specific soil issues

Targeted marketing and public health.

PubMed

Grier, Sonya A; Kumanyika, Shiriki

2010-01-01

Targeted marketing techniques, which identify consumers who share common needs or characteristics and position products or services to appeal to and reach these consumers, are now the core of all marketing and facilitate its effectiveness. However, targeted marketing, particularly of products with proven or potential adverse effects (e.g., tobacco, alcohol, entertainment violence, or unhealthful foods) to consumer segments defined as vulnerable raises complex concerns for public health. It is critical that practitioners, academics, and policy makers in marketing, public health, and other fields recognize and understand targeted marketing as a specific contextual influence on the health of children and adolescents and, for different reasons, ethnic minority populations and other populations who may benefit from public health protections. For beneficial products, such understanding can foster more socially productive targeting. For potentially harmful products, understanding the nature and scope of targeted marketing influences will support identification and implementation of corrective policies.

Divergent Synthesis of Quinolone Natural Products from Pseudonocardia sp. CL38489.

PubMed

Geddis, Stephen M; Carro, Laura; Hodgkinson, James T; Spring, David R

2016-12-01

Two divergent synthetic routes are reported offering access to four quinolone natural products from Pseudonocardia sp. CL38489. Key steps to the natural products involved a regioselective epoxidation, an intramolecular Buchwald-Hartwig amination and a final acid-catalysed 1,3-allylic-alcohol rearrangement to give two of the natural products in one step. This study completes the synthesis of all eight antibacterial quinolone natural products reported in the family. In addition, this modular strategy enables an improved synthesis towards two natural products previously reported.

Divergent Synthesis of Quinolone Natural Products from Pseudonocardia sp. CL38489

PubMed Central

Geddis, Stephen M.; Carro, Laura; Hodgkinson, James T.

2016-01-01

Two divergent synthetic routes are reported offering access to four quinolone natural products from Pseudonocardia sp. CL38489. Key steps to the natural products involved a regioselective epoxidation, an intramolecular Buchwald–Hartwig amination and a final acid‐catalysed 1,3‐allylic‐alcohol rearrangement to give two of the natural products in one step. This study completes the synthesis of all eight antibacterial quinolone natural products reported in the family. In addition, this modular strategy enables an improved synthesis towards two natural products previously reported. PMID:28111524

The Natural Product Phyllanthusmin C Enhances IFN-γ Production by Human Natural Killer Cells through Upregulation of TLR-Mediated NF-κB Signaling

PubMed Central

Deng, Youcai; Chu, Jianhong; Ren, Yulin; Fan, Zhijin; Ji, Xiaotian; Mundy, Bethany; Yuan, Shunzong; Hughes, Tiffany; Zhang, Jianying; Cheema, Baljash; Camardo, Andrew T.; Xia, Yong; Wu, Lai-Chu; Wang, Li-Shu; He, Xiaoming; Kinghorn, A. Douglas; Li, Xiaohui; Caligiuri, Michael A; Yu, Jianhua

2014-01-01

Natural products are a major source for cancer drug development. NK cells are a critical component of innate immunity with the capacity to destroy cancer cells, cancer initiating cells, and clear viral infections. However, few reports describe a natural product that selectively stimulates NK cell IFN-γ production and unravel a mechanism of action. In this study, through screening, we found that a natural product, phyllanthusmin C (PL-C), alone enhanced IFN-γ production by human NK cells. PL-C also synergized with IL-12, even at the low cytokine concentration of 0.1 mg/ml, and stimulated IFN-γ production in both human CD56bright and CD56dim NK cell subsets. Mechanistically, TLR1 and/or TLR6 mediated PL-C’s activation of the NF-κB p65 subunit that in turn bound to the proximal promoter of IFNG and subsequently resulted in increased IFN-γ production in NK cells. However, IL-12/IL-15 receptors and their related STAT signaling pathways were not significantly modulated by PL-C. PL-C induced little or no T cell IFN-γ production or NK cell cytotoxicity. Collectively, we identify a natural product with the capacity to selectively activate human NK cell IFN-γ. Given the role of IFN-γ in immune surveillance, additional studies to understand the role of this natural product in prevention of cancer or infection in select populations are warranted. PMID:25122922

Natural products as reservoirs of novel therapeutic agents.

PubMed

Mushtaq, Sadaf; Abbasi, Bilal Haider; Uzair, Bushra; Abbasi, Rashda

2018-01-01

Since ancient times, natural products from plants, animals, microbial and marine sources have been exploited for treatment of several diseases. The knowledge of our ancestors is the base of modern drug discovery process. However, due to the presence of extensive biodiversity in natural sources, the percentage of secondary metabolites screened for bioactivity is low. This review aims to provide a brief overview of historically significant natural therapeutic agents along with some current potential drug candidates. It will also provide an insight into pros and cons of natural product discovery and how development of recent approaches has answered the challenges associated with it.

Antifungal potential of marine natural products.

PubMed

El-Hossary, Ebaa M; Cheng, Cheng; Hamed, Mostafa M; El-Sayed Hamed, Ashraf Nageeb; Ohlsen, Knut; Hentschel, Ute; Abdelmohsen, Usama Ramadan

2017-01-27

Fungal diseases represent an increasing threat to human health worldwide which in some cases might be associated with substantial morbidity and mortality. However, only few antifungal drugs are currently available for the treatment of life-threatening fungal infections. Furthermore, plant diseases caused by fungal pathogens represent a worldwide economic problem for the agriculture industry. The marine environment continues to provide structurally diverse and biologically active secondary metabolites, several of which have inspired the development of new classes of therapeutic agents. Among these secondary metabolites, several compounds with noteworthy antifungal activities have been isolated from marine microorganisms, invertebrates, and algae. During the last fifteen years, around 65% of marine natural products possessing antifungal activities have been isolated from sponges and bacteria. This review gives an overview of natural products from diverse marine organisms that have shown in vitro and/or in vivo potential as antifungal agents, with their mechanism of action whenever applicable. The natural products literature is covered from January 2000 until June 2015, and we are reporting the chemical structures together with their biological activities, as well as the isolation source. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

An analysis of FDA-approved drugs: natural products and their derivatives.

PubMed

Patridge, Eric; Gareiss, Peter; Kinch, Michael S; Hoyer, Denton

2016-02-01

Natural products contribute greatly to the history and landscape of new molecular entities (NMEs). An assessment of all FDA-approved NMEs reveals that natural products and their derivatives represent over one-third of all NMEs. Nearly one-half of these are derived from mammals, one-quarter from microbes and one-quarter from plants. Since the 1930s, the total fraction of natural products has diminished, whereas semisynthetic and synthetic natural product derivatives have increased. Over time, this fraction has also become enriched with microbial natural products, which represent a significant portion of approved antibiotics, including more than two-thirds of all antibacterial NMEs. In recent years, the declining focus on natural products has impacted the pipeline of NMEs from specific classes, and this trend is likely to continue without specific investment in the pursuit of natural products. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Traditional Medicine and Modern Medicine from Natural Products.

PubMed

Yuan, Haidan; Ma, Qianqian; Ye, Li; Piao, Guangchun

2016-04-29

Natural products and traditional medicines are of great importance. Such forms of medicine as traditional Chinese medicine, Ayurveda, Kampo, traditional Korean medicine, and Unani have been practiced in some areas of the world and have blossomed into orderly-regulated systems of medicine. This study aims to review the literature on the relationship among natural products, traditional medicines, and modern medicine, and to explore the possible concepts and methodologies from natural products and traditional medicines to further develop drug discovery. The unique characteristics of theory, application, current role or status, and modern research of eight kinds of traditional medicine systems are summarized in this study. Although only a tiny fraction of the existing plant species have been scientifically researched for bioactivities since 1805, when the first pharmacologically-active compound morphine was isolated from opium, natural products and traditional medicines have already made fruitful contributions for modern medicine. When used to develop new drugs, natural products and traditional medicines have their incomparable advantages, such as abundant clinical experiences, and their unique diversity of chemical structures and biological activities.

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

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

Does species diversity limit productivity in natural grassland communities?

USGS Publications Warehouse

Grace, J.B.; Anderson, T.M.; Smith, M.D.; Seabloom, E.; Andelman, S.J.; Meche, G.; Weiher, E.; Allain, L.K.; Jutila, H.; Sankaran, M.; Knops, J.; Ritchie, M.; Willig, M.R.

2007-01-01

Theoretical analyses and experimental studies of synthesized assemblages indicate that under particular circumstances species diversity can enhance community productivity through niche complementarity. It remains unclear whether this process has important effects in mature natural ecosystems where competitive feedbacks and complex environmental influences affect diversity-productivity relationships. In this study, we evaluated diversity-productivity relationships while statistically controlling for environmental influences in 12 natural grassland ecosystems. Because diversity-productivity relationships are conspicuously nonlinear, we developed a nonlinear structural equation modeling (SEM) methodology to separate the effects of diversity on productivity from the effects of productivity on diversity. Meta-analysis was used to summarize the SEM findings across studies. While competitive effects were readily detected, enhancement of production by diversity was not. These results suggest that the influence of small-scale diversity on productivity in mature natural systems is a weak force, both in absolute terms and relative to the effects of other controls on productivity. ?? 2007 Blackwell Publishing Ltd/CNRS.

Elaborating the role of natural products-induced autophagy in cancer treatment: achievements and artifacts in the state of the art.

PubMed

Wang, Ning; Feng, Yibin

2015-01-01

Autophagy is a homeostatic process that is highly conserved across different types of mammalian cells. Autophagy is able to relieve tumor cell from nutrient and oxidative stress during the rapid expansion of cancer. Excessive and sustained autophagy may lead to cell death and tumor shrinkage. It was shown in literature that many anticancer natural compounds and extracts could initiate autophagy in tumor cells. As summarized in this review, the tumor suppressive action of natural products-induced autophagy may lead to cell senescence, provoke apoptosis-independent cell death, and complement apoptotic cell death by robust or target-specific mechanisms. In some cases, natural products-induced autophagy could protect tumor cells from apoptotic death. Technical variations in detecting autophagy affect data quality, and study focus should be made on elaborating the role of autophagy in deciding cell fate. In vivo study monitoring of autophagy in cancer treatment is expected to be the future direction. The clinical-relevant action of autophagy-inducing natural products should be highlighted in future study. As natural products are an important resource in discovery of lead compound of anticancer drug, study on the role of autophagy in tumor suppressive effect of natural products continues to be necessary and emerging.

Marine actinobacteria: an important source of bioactive natural products.

PubMed

Manivasagan, Panchanathan; Kang, Kyong-Hwa; Sivakumar, Kannan; Li-Chan, Eunice C Y; Oh, Hyun-Myung; Kim, Se-Kwon

2014-07-01

Marine environment is largely an untapped source for deriving actinobacteria, having potential to produce novel, bioactive natural products. Actinobacteria are the prolific producers of pharmaceutically active secondary metabolites, accounting for about 70% of the naturally derived compounds that are currently in clinical use. Among the various actinobacterial genera, Actinomadura, Actinoplanes, Amycolatopsis, Marinispora, Micromonospora, Nocardiopsis, Saccharopolyspora, Salinispora, Streptomyces and Verrucosispora are the major potential producers of commercially important bioactive natural products. In this respect, Streptomyces ranks first with a large number of bioactive natural products. Marine actinobacteria are unique enhancing quite different biological properties including antimicrobial, anticancer, antiviral, insecticidal and enzyme inhibitory activities. They have attracted global in the last ten years for their ability to produce pharmaceutically active compounds. In this review, we have focused attention on the bioactive natural products isolated from marine actinobacteria, possessing unique chemical structures that may form the basis for synthesis of novel drugs that could be used to combat resistant pathogenic microorganisms. Copyright © 2014 Elsevier B.V. All rights reserved.

Natural products as reservoirs of novel therapeutic agents

PubMed Central

Mushtaq, Sadaf; Abbasi, Bilal Haider; Uzair, Bushra; Abbasi, Rashda

2018-01-01

Since ancient times, natural products from plants, animals, microbial and marine sources have been exploited for treatment of several diseases. The knowledge of our ancestors is the base of modern drug discovery process. However, due to the presence of extensive biodiversity in natural sources, the percentage of secondary metabolites screened for bioactivity is low. This review aims to provide a brief overview of historically significant natural therapeutic agents along with some current potential drug candidates. It will also provide an insight into pros and cons of natural product discovery and how development of recent approaches has answered the challenges associated with it. PMID:29805348

Comparison of bulk and pitcher-catcher targets for laser-driven neutron production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Willingale, L.; Maksimchuk, A.; Joglekar, A. S.

2011-08-15

Laser-driven d(d, n)-{sup 3}He beam-target fusion neutron production from bulk deuterated plastic (CD) targets is compared with a pitcher-catcher target scheme using an identical laser and detector arrangement. For laser intensities in the range of (1-3) x 10{sup 19} W cm{sup -2}, it was found that the bulk targets produced a high yield (5 x 10{sup 4} neutrons per steradian) beamed preferentially in the laser propagation direction. Numerical modeling shows the importance of considering the temperature adjusted stopping powers to correctly model the neutron production. The bulk CD targets have a high background target temperature leading to a reduced stoppingmore » power for the deuterons, which increases the probability of generating neutrons by fusion. Neutron production from the pitcher-catcher targets was not as efficient since it does not benefit from the reduced stopping power in the cold catcher target. Also, the inhibition of the deuteron acceleration by a proton rich contamination layer significantly reduces the pitcher-catcher neutron production.« less

Fractal active contour model for segmenting the boundary of man-made target in nature scenes

NASA Astrophysics Data System (ADS)

Li, Min; Tang, Yandong; Wang, Lidi; Shi, Zelin

2006-02-01

In this paper, a novel geometric active contour model based on the fractal dimension feature to extract the boundary of man-made target in nature scenes is presented. In order to suppress the nature clutters, an adaptive weighting function is defined using the fractal dimension feature. Then the weighting function is introduced into the geodesic active contour model to detect the boundary of man-made target. Curve driven by our proposed model can evolve gradually from the initial position to the boundary of man-made target without being disturbed by nature clutters, even if the initial curve is far away from the true boundary. Experimental results validate the effectiveness and feasibility of our model.

Profiling unauthorized natural resource users for better targeting of conservation interventions

PubMed Central

Baker, Julia; Twinamatsiko, Medard; Milner‐Gulland, E.J.

2015-01-01

Abstract Unauthorized use of natural resources is a key threat to many protected areas. Approaches to reducing this threat include law enforcement and integrated conservation and development (ICD) projects, but for such ICDs to be targeted effectively, it is important to understand who is illegally using which natural resources and why. The nature of unauthorized behavior makes it difficult to ascertain this information through direct questioning. Bwindi Impenetrable National Park, Uganda, has many ICD projects, including authorizing some local people to use certain nontimber forest resources from the park. However, despite over 25 years of ICD, unauthorized resource use continues. We used household surveys, indirect questioning (unmatched count technique), and focus group discussions to generate profiles of authorized and unauthorized resource users and to explore motivations for unauthorized activity. Overall, unauthorized resource use was most common among people from poor households who lived closest to the park boundary and farthest from roads and trading centers. Other motivations for unauthorized resource use included crop raiding by wild animals, inequity of revenue sharing, and lack of employment, factors that created resentment among the poorest communities. In some communities, benefits obtained from ICD were reported to be the greatest deterrents against unauthorized activity, although law enforcement ranked highest overall. Despite the sensitive nature of exploring unauthorized resource use, management‐relevant insights into the profiles and motivations of unauthorized resource users can be gained from a combination of survey techniques, as adopted here. To reduce unauthorized activity at Bwindi, we suggest ICD benefit the poorest people living in remote areas and near the park boundary by providing affordable alternative sources of forest products and addressing crop raiding. To prevent resentment from driving further unauthorized activity, ICDs

Profiling unauthorized natural resource users for better targeting of conservation interventions.

PubMed

Harrison, Mariel; Baker, Julia; Twinamatsiko, Medard; Milner-Gulland, E J

2015-12-01

Unauthorized use of natural resources is a key threat to many protected areas. Approaches to reducing this threat include law enforcement and integrated conservation and development (ICD) projects, but for such ICDs to be targeted effectively, it is important to understand who is illegally using which natural resources and why. The nature of unauthorized behavior makes it difficult to ascertain this information through direct questioning. Bwindi Impenetrable National Park, Uganda, has many ICD projects, including authorizing some local people to use certain nontimber forest resources from the park. However, despite over 25 years of ICD, unauthorized resource use continues. We used household surveys, indirect questioning (unmatched count technique), and focus group discussions to generate profiles of authorized and unauthorized resource users and to explore motivations for unauthorized activity. Overall, unauthorized resource use was most common among people from poor households who lived closest to the park boundary and farthest from roads and trading centers. Other motivations for unauthorized resource use included crop raiding by wild animals, inequity of revenue sharing, and lack of employment, factors that created resentment among the poorest communities. In some communities, benefits obtained from ICD were reported to be the greatest deterrents against unauthorized activity, although law enforcement ranked highest overall. Despite the sensitive nature of exploring unauthorized resource use, management-relevant insights into the profiles and motivations of unauthorized resource users can be gained from a combination of survey techniques, as adopted here. To reduce unauthorized activity at Bwindi, we suggest ICD benefit the poorest people living in remote areas and near the park boundary by providing affordable alternative sources of forest products and addressing crop raiding. To prevent resentment from driving further unauthorized activity, ICDs should be

Advances in the Research and Development of Natural Health Products as Main Stream Cancer Therapeutics

PubMed Central

Ovadje, Pamela; Roma, Alessia; Steckle, Matthew; Nicoletti, Leah; Arnason, John Thor; Pandey, Siyaram

2015-01-01

Natural health products (NHPs) are defined as natural extracts containing polychemical mixtures; they play a leading role in the discovery and development of drugs, for disease treatment. More than 50% of current cancer therapeutics are derived from natural sources. However, the efficacy of natural extracts in treating cancer has not been explored extensively. Scientific research into the validity and mechanism of action of these products is needed to develop NHPs as main stream cancer therapy. The preclinical and clinical validation of NHPs would be essential for this development. This review summarizes some of the recent advancements in the area of NHPs with anticancer effects. This review also focuses on various NHPs that have been studied to scientifically validate their claims as anticancer agents. Furthermore, this review emphasizes the efficacy of these NHPs in targeting the multiple vulnerabilities of cancer cells for a more selective efficacious treatment. The studies reviewed here have paved the way for the introduction of more NHPs from traditional medicine to the forefront of modern medicine, in order to provide alternative, safer, and cheaper complementary treatments for cancer therapy and possibly improve the quality of life of cancer patients. PMID:25883673

Culture-independent discovery of natural products from soil metagenomes.

PubMed

Katz, Micah; Hover, Bradley M; Brady, Sean F

2016-03-01

Bacterial natural products have proven to be invaluable starting points in the development of many currently used therapeutic agents. Unfortunately, traditional culture-based methods for natural product discovery have been deemphasized by pharmaceutical companies due in large part to high rediscovery rates. Culture-independent, or "metagenomic," methods, which rely on the heterologous expression of DNA extracted directly from environmental samples (eDNA), have the potential to provide access to metabolites encoded by a large fraction of the earth's microbial biosynthetic diversity. As soil is both ubiquitous and rich in bacterial diversity, it is an appealing starting point for culture-independent natural product discovery efforts. This review provides an overview of the history of soil metagenome-driven natural product discovery studies and elaborates on the recent development of new tools for sequence-based, high-throughput profiling of environmental samples used in discovering novel natural product biosynthetic gene clusters. We conclude with several examples of these new tools being employed to facilitate the recovery of novel secondary metabolite encoding gene clusters from soil metagenomes and the subsequent heterologous expression of these clusters to produce bioactive small molecules.

Production of 9Be targets for nuclear physics experiments

NASA Astrophysics Data System (ADS)

Marín-Lámbarri, D. J.; Kheswa, N. Y.

2018-05-01

Self-supporting beryllium (9Be) targets were produced by mechanical rolling method in which a double pack technique was implemented. Targets were used for the investigation of the low-lying excitation energy region in 9B through the 9Be(3He,t)9B reaction at the K600 spectrometer, at iThemba LABS facility. Beryllium is a semi-metal in nature and this makes it hard to deform by rolling or vacuum evaporate as a self-supporting target. Therefore heat treatment was needed to avoid brittleness and breakage of the material during rolling process. A description is given on how beryllium targets were manufactured.

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).

Utilization of natural products for treatment of blood diseases.

PubMed

Miles, D H; Nguyen, C L; Miles, D H

1998-12-01

This chapter presents an introduction to several diseases of the blood including infectious mononucleosis, leukemia, thrombosis and coagulation, bone marrow disorders, malaria, and anemia. In addition a survey of the recent literature is presented relative to natural products that have been utilized for the treatment of these diseases. The natural products that are reported represent a wide range of structural types and present interesting mechanisms of action. Thus the possibility exists that new drugs may be developed from these natural products which are more effective than those currently on the market.

Natural personal care products-analysis of ingredient lists and legal situation.

PubMed

Klaschka, Ursula

2016-01-01

Many natural substances are classified as dangerous substances according to the European regulation on classification and labelling. Are they used in natural personal care products today? One hundred ingredient lists were analyzed to find this out. All products with natural substances contained dangerous natural substances or they contained natural substances, for which the information about their classification as dangerous substances is not available. 54 natural substances quoted in the ingredient lists were found to be classified, with 37 substances being classified due to hazardous effects for skin and eyes. However, the most frequently used natural substances are not classified as dangerous. Natural substances are multi-constituent compounds, leading to two main problems in personal care products: the potential interactions of a multitude of substances and the fact that dangerous constituents are not disclosed in the ingredient lists. For example, the fragrance allergens citral, farnesol, limonene, and linalool are frequent components of the natural substances employed. In addition, 82 products listed allergenic fragrance ingredients as single substances in their ingredient lists. Recommendations for sensitive skin in a product's name do not imply that the '26 fragrance allergens' are omitted. Furthermore, 80 products listed 'parfum'/'aroma', and 50 products listed ethanol. The data show that the loopholes for natural substances and for personal care products in the present European chemical legislation (e.g. the exception for classification and labelling of cosmetic products and the exception for information transfer in the supply chain) are not in line with an adequate consumer and environmental protection.

Analysis of Operating Strategies Using Different Target Designs For 238Pu Production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thomas, Tomcy; Sherman, Steven R; Sawhney, Dr. Rapinder

2017-01-01

An engineering effort is underway to re-establish capability to produce 238Pu oxide at the kilogram scale in the United States. A multi-step batch process is being developed to produce this important material. Recently, a portion of this process was studied using discrete-event simulation tools to determine whether the conceptual process might achieve its yearly production goal. The study showed the conceptual process can meet the yearly production goal under some circumstances, but process improvements would be needed to ensure greater likelihood of success. This study extends the work performed previously by examining the effects of changing the reactor target designmore » on the yearly process output. Two new reactor target configurations are considered an aluminum-clad reactor target containing 50% greater 237Np oxide content than the original target, and a zirconium alloy-clad target using no aluminum. The results indicate that use of the new aluminum-clad target configuration may allow the process to achieve the same yearly production goal in less time using fewer targets. If the zirconium alloy-clad target is used, then even fewer targets would be needed to reach the production goal, but some process changes would be required to handle the zirconium cladding. The number of days needed to process a target batch to completion, and the steady state 238Pu oxide production rate, for each configuration are compared to the results from the initial simulation study.« less

Molecular scaffold analysis of natural products databases in the public domain.

PubMed

Yongye, Austin B; Waddell, Jacob; Medina-Franco, José L

2012-11-01

Natural products represent important sources of bioactive compounds in drug discovery efforts. In this work, we compiled five natural products databases available in the public domain and performed a comprehensive chemoinformatic analysis focused on the content and diversity of the scaffolds with an overview of the diversity based on molecular fingerprints. The natural products databases were compared with each other and with a set of molecules obtained from in-house combinatorial libraries, and with a general screening commercial library. It was found that publicly available natural products databases have different scaffold diversity. In contrast to the common concept that larger libraries have the largest scaffold diversity, the largest natural products collection analyzed in this work was not the most diverse. The general screening library showed, overall, the highest scaffold diversity. However, considering the most frequent scaffolds, the general reference library was the least diverse. In general, natural products databases in the public domain showed low molecule overlap. In addition to benzene and acyclic compounds, flavones, coumarins, and flavanones were identified as the most frequent molecular scaffolds across the different natural products collections. The results of this work have direct implications in the computational and experimental screening of natural product databases for drug discovery. © 2012 John Wiley & Sons A/S.

Cheminformatic comparison of approved drugs from natural product versus synthetic origins.

PubMed

Stratton, Christopher F; Newman, David J; Tan, Derek S

2015-11-01

Despite the recent decline of natural product discovery programs in the pharmaceutical industry, approximately half of all new drug approvals still trace their structural origins to a natural product. Herein, we use principal component analysis to compare the structural and physicochemical features of drugs from natural product-based versus completely synthetic origins that were approved between 1981 and 2010. Drugs based on natural product structures display greater chemical diversity and occupy larger regions of chemical space than drugs from completely synthetic origins. Notably, synthetic drugs based on natural product pharmacophores also exhibit lower hydrophobicity and greater stereochemical content than drugs from completely synthetic origins. These results illustrate that structural features found in natural products can be successfully incorporated into synthetic drugs, thereby increasing the chemical diversity available for small-molecule drug discovery. Copyright © 2015 Elsevier Ltd. All rights reserved.

Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery.

PubMed

Thomford, Nicholas Ekow; Senthebane, Dimakatso Alice; Rowe, Arielle; Munro, Daniella; Seele, Palesa; Maroyi, Alfred; Dzobo, Kevin

2018-05-25

The therapeutic properties of plants have been recognised since time immemorial. Many pathological conditions have been treated using plant-derived medicines. These medicines are used as concoctions or concentrated plant extracts without isolation of active compounds. Modern medicine however, requires the isolation and purification of one or two active compounds. There are however a lot of global health challenges with diseases such as cancer, degenerative diseases, HIV/AIDS and diabetes, of which modern medicine is struggling to provide cures. Many times the isolation of "active compound" has made the compound ineffective. Drug discovery is a multidimensional problem requiring several parameters of both natural and synthetic compounds such as safety, pharmacokinetics and efficacy to be evaluated during drug candidate selection. The advent of latest technologies that enhance drug design hypotheses such as Artificial Intelligence, the use of 'organ-on chip' and microfluidics technologies, means that automation has become part of drug discovery. This has resulted in increased speed in drug discovery and evaluation of the safety, pharmacokinetics and efficacy of candidate compounds whilst allowing novel ways of drug design and synthesis based on natural compounds. Recent advances in analytical and computational techniques have opened new avenues to process complex natural products and to use their structures to derive new and innovative drugs. Indeed, we are in the era of computational molecular design, as applied to natural products. Predictive computational softwares have contributed to the discovery of molecular targets of natural products and their derivatives. In future the use of quantum computing, computational softwares and databases in modelling molecular interactions and predicting features and parameters needed for drug development, such as pharmacokinetic and pharmacodynamics, will result in few false positive leads in drug development. This review

Antimicrobial activity of natural products against Clostridium difficile in vitro.

PubMed

Roshan, N; Riley, T V; Hammer, K A

2017-05-10

To investigate the antimicrobial activity of various natural products against Clostridium difficile in vitro. The antibacterial activity of 20 natural products was determined by the agar well diffusion and broth microdilution assays against four C. difficile strains, three comparator organisms and four gastrointestinal commensal organisms. Of the raw natural products, garlic juice had the highest activity. The most active processed products were peppermint oil and the four pure compounds trans-cinnamaldehyde, allicin, menthol and zingerone. Furthermore, Bacteroides species had similar susceptibility to C. difficile to most natural products; however, Lactobacillus casei was less susceptible. The combined effect of natural products with vancomycin or metronidazole was determined using the conventional checkerboard titration method and the fractional inhibitory concentration index was calculated. The results showed a possible synergism between trans-cinnamaldehyde and vancomycin and partial synergy between trans-cinnamaldehyde and metronidazole. The study indicates a range of antimicrobial activity of natural products against C. difficile and suggests that they may be useful as alternative or complementary treatments for C. difficile infection (CDI), particularly as most are able to be given orally. This study encourages further investigation of natural products for treatment of CDI. © 2017 The Society for Applied Microbiology.

Docking of Natural Products against Neurodegenerative Diseases: General Concepts.

PubMed

Ribeiro, Frederico F; Mendonca Junior, Francisco J B; Ghasemi, Jahan B; Ishiki, Hamilton M; Scotti, Marcus T; Scotti, Luciana

2018-01-01

Since antiquity, humanity has used medicinal plant preparations to cure its ills, and, as research has progressed, new technologies have enabled more investigations on natural compounds which originate from plants, fungi, and marine species. The health benefits that these natural products provide have become a motive for treatment studies of various diseases. Among them, the neurodegenerative diseases like Alzheimer's and Parkinson's, a major age-related neurodegenerative disorder. Studies with natural products for neurodegenerative diseases (particularly through molecular docking) search for, and then focus on those ligands which offer effective inhibition of the enzymes monoamine oxidase and acetylcholinesterase. This review introduces the main concepts involved in docking studies with natural products: and also in our group, which has conducted a docking study of natural products isolated from Tetrapterys mucronata for inhibition of acetylcholinesterase. We observed that compounds 4 and 5 formed more interactions than the theoretical ligand, but that ligands with greater activity also interacted with residues HIS 381 and GLN 527. We have reported on our docking study performed with AChE and alkaloids isolated from the plant Tetrapterys mucronata. Our docking results corroborate the experiments conducted, and emphasize the positive contribution that these theoretical studies involving natural products bring to the fight against neurodegenerative diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A luminescence assay for natural product inhibitors of the Mycobacterium tuberculosis proteasome.

PubMed

Gunderwala, Amber; Porter, John

2016-01-01

Mycobacterium tuberculosis (Mtb) causes a large global burden of disease, with a high mortality rate in healthy and immuno-compromised patients. A number of molecular targets have been identified for treatment of this disease, including the Mtb proteasome. The Mtb proteasome enhances Mtb survival during nitrosative and oxidative stress in the latent, non-replicative phase. Therefore, Mtb proteasome inhibition could help to combat Mtb infections that do not respond to current therapies. To develop and validate a novel biochemical assay to assess Mtb proteasome activity in the presence of organic and aqueous plant test extracts. Fluorescence (photoluminescence) and luminescence (chemiluminescence) assays were investigated as potential methods to determine the robustness and repeatability for use in screening natural product extracts for Mtb proteasome inhibitors. The fluorescence assay, used widely for Mtb proteasome activity assays, was subject to interference due to the natural fluorescence of compounds in many of the extracts; there is little interference with the luminescence approach. As proof of principle, we used the luminescence assay to screen a small set of plant test extracts. Luminescence is the more suitable assay for assay of plant natural product extracts. The sensitivities of the luminescence and fluorescence assays are comparable. A Z'-factor of 0.58 for the luminescence assay makes it suitable for medium-to-high throughput screening efforts. Copyright © 2016 John Wiley & Sons, Ltd.

Marine Natural Products as Models to Circumvent Multidrug Resistance.

PubMed

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

2016-07-08

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.

Cross-sections for (p,x) reactions on natural chromium for the production of 52,52m,54Mn radioisotopes

DOE PAGES

Wooten, A. Lake; Lewis, Benjamin C.; Lapi, Suzanne E.

2014-12-11

The production of positron-emitting isotopes of manganese is potentially important for developing contrast agents for dual-modality positron emission tomography and magnetic resonance (PET/MR) imaging, as well as for in vivo imaging of the biodistribution and toxicity of manganese. Furthermore, the decay properties of 52Mn make it an excellent candidate for these applications, and it can easily be produced by bombardment of a chromium target with protons or deuterons from a low-energy biomedical cyclotron. There are several parameters essential to this mode of production—target thickness, beam energy, beam current, and bombardment time—depend heavily on the availability of reliable, reproducible cross-section data.more » Our paper contributes to the routine production of 52gMn for biomedical research by contributing experimental cross-sections for natural chromium ( natCr) targets for the natCr(p,x) 52gMn reaction, as well as for the production of the radiocontaminants 52m, 54Mn.« less

Role of dietary bioactive natural products in estrogen receptor-positive breast cancer

PubMed Central

Bak, Min Ji; Das Gupta, Soumyasri; Wahler, Joseph; Suh, Nanjoo

2016-01-01

Estrogen receptor (ER)-positive breast cancer, including luminal-A and -B, is the most common type of breast cancer. Extended exposure to estrogen is associated with an increased risk of breast cancer. Both ER-dependent and ER-independent mechanisms have been implicated in estrogen-mediated carcinogenesis. The ER-dependent pathway involves cell growth and proliferation triggered by the binding of estrogen to the ER. The ER-independent mechanisms depend on the metabolism of estrogen to generate genotoxic metabolites, free radicals and reactive oxygen species to induce breast cancer. A better understanding of the mechanisms that drive ER-positive breast cancer will help optimize targeted approaches to prevent or treat breast cancer. A growing emphasis is being placed on alternative medicine and dietary approaches toward the prevention and treatment of breast cancer. Many natural products and bioactive compounds found in foods have been shown to inhibit breast carcinogenesis via inhibition of estrogen induced oxidative stress as well as ER signaling. This review summarizes the role of bioactive natural products that are involved in the prevention and treatment of estrogen-related and ER-positive breast cancer. PMID:27016037

Retrospective analysis of natural products provides insights for future discovery trends.

PubMed

Pye, Cameron R; Bertin, Matthew J; Lokey, R Scott; Gerwick, William H; Linington, Roger G

2017-05-30

Understanding of the capacity of the natural world to produce secondary metabolites is important to a broad range of fields, including drug discovery, ecology, biosynthesis, and chemical biology, among others. Both the absolute number and the rate of discovery of natural products have increased significantly in recent years. However, there is a perception and concern that the fundamental novelty of these discoveries is decreasing relative to previously known natural products. This study presents a quantitative examination of the field from the perspective of both number of compounds and compound novelty using a dataset of all published microbial and marine-derived natural products. This analysis aimed to explore a number of key questions, such as how the rate of discovery of new natural products has changed over the past decades, how the average natural product structural novelty has changed as a function of time, whether exploring novel taxonomic space affords an advantage in terms of novel compound discovery, and whether it is possible to estimate how close we are to having described all of the chemical space covered by natural products. Our analyses demonstrate that most natural products being published today bear structural similarity to previously published compounds, and that the range of scaffolds readily accessible from nature is limited. However, the analysis also shows that the field continues to discover appreciable numbers of natural products with no structural precedent. Together, these results suggest that the development of innovative discovery methods will continue to yield compounds with unique structural and biological properties.

Retrospective analysis of natural products provides insights for future discovery trends

PubMed Central

Pye, Cameron R.; Bertin, Matthew J.; Lokey, R. Scott; Gerwick, William H.

2017-01-01

Understanding of the capacity of the natural world to produce secondary metabolites is important to a broad range of fields, including drug discovery, ecology, biosynthesis, and chemical biology, among others. Both the absolute number and the rate of discovery of natural products have increased significantly in recent years. However, there is a perception and concern that the fundamental novelty of these discoveries is decreasing relative to previously known natural products. This study presents a quantitative examination of the field from the perspective of both number of compounds and compound novelty using a dataset of all published microbial and marine-derived natural products. This analysis aimed to explore a number of key questions, such as how the rate of discovery of new natural products has changed over the past decades, how the average natural product structural novelty has changed as a function of time, whether exploring novel taxonomic space affords an advantage in terms of novel compound discovery, and whether it is possible to estimate how close we are to having described all of the chemical space covered by natural products. Our analyses demonstrate that most natural products being published today bear structural similarity to previously published compounds, and that the range of scaffolds readily accessible from nature is limited. However, the analysis also shows that the field continues to discover appreciable numbers of natural products with no structural precedent. Together, these results suggest that the development of innovative discovery methods will continue to yield compounds with unique structural and biological properties. PMID:28461474

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

PubMed Central

Crane, Erika A.

2016-01-01

Abstract Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody–drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products. PMID:26833854

Isotope production and target preparation for nuclear astrophysics data

NASA Astrophysics Data System (ADS)

Schumann, Dorothea; Dressler, Rugard; Maugeri, Emilio Andrea; Heinitz, Stephan

2017-09-01

Targets are in many cases an indispensable ingredient for successful experiments aimed to produce nuclear data. With the recently observed shift to study nuclear reactions on radioactive targets, this task can become extremely challenging. Concerted actions of a certain number of laboratories able to produce isotopes and manufacture radioactive targets are urgently needed. We present here some examples of successful isotope and target production at PSI, in particular the production of 60Fe samples used for half-life measurements and neutron capture cross section experiments, the chemical processing and fabrication of lanthanide targets for capture cross section experiments at n_TOF (European Organization for Nuclear Research (CERN), Switzerland) as well as the recently performed manufacturing of highly-radioactive 7Be targets for the measurement of the 7Be(n,α)4He cross section in the energy range of interest for the Big-Bang nucleosynthesis contributing to the solving of the cosmological Li-problem. The two future projects: "Determination of the half-life and experiments on neutron capture cross sections of 53Mn" and "32Si - a new chronometer for nuclear dating" are briefly described. Moreover, we propose to work on the establishment of a dedicated network on isotope and target producing laboratories.

Bluegenics: Bioactive Natural Products of Medicinal Relevance and Approaches to Their Diversification.

PubMed

Zarins-Tutt, Joseph S; Abraham, Emily R; Bailey, Christopher S; Goss, Rebecca J M

Nature provides a valuable resource of medicinally relevant compounds, with many antimicrobial and antitumor agents entering clinical trials being derived from natural products. The generation of analogues of these bioactive natural products is important in order to gain a greater understanding of structure activity relationships; probing the mechanism of action, as well as to optimise the natural product's bioactivity and bioavailability. This chapter critically examines different approaches to generating natural products and their analogues, exploring the way in which synthetic and biosynthetic approaches may be blended together to enable expeditious access to new designer natural products.

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

Chemoprevention of obesity by dietary natural compounds targeting mitochondrial regulation.

PubMed

Lai, Ching-Shu; Wu, Jia-Ching; Ho, Chi-Tang; Pan, Min-Hsiung

2017-06-01

Mitochondria are at the center stage in the control of energy homeostasis in many organs and tissues including adipose tissue. Recently, abundant evidence from experimental studies has clearly supported the strong correlation between mitochondrial dysfunction in adipocytes and obesity. Various physiological conditions such as excessive nutrition, genetic factors, hypoxia, and toxins disrupt mitochondrial function by impairing mitochondrial biogenesis, dynamics, and oxidative capacity. Mitochondrial dysfunction in adipocytes could have an impact on differentiation, adipogenesis, insulin sensitivity, and the significant alteration in their metabolic function, which ultimately results in obesity and type 2 diabetes. Numerous dietary natural compounds are the subject of research for the prevention and treatment of obesity through reprogramming multiple metabolic pathways. Some of them have the potential against obesity by modulating insulin signaling, decreasing oxidative damage, downregulating adipokines secretion, and increasing mitochondrial DNA that improves mitochondrial function and thus maintain metabolic homeostasis. Here, we focus on and summarize and briefly discuss the currently known targets and the mitochondria-targeting effects of dietary natural compounds in the intervention of obesity. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The impact of natural products upon modern drug discovery.

PubMed

Ganesan, A

2008-06-01

In the period 1970-2006, a total of 24 unique natural products were discovered that led to an approved drug. We analyze these successful leads in terms of drug-like properties, and show that they can be divided into two equal subsets. The first falls in the 'Lipinski universe' and complies with the Rule of Five. The second is a 'parallel universe' that violates the rules. Nevertheless, the latter compounds remain largely compliant in terms of logP and H-bond donors, highlighting the importance of these two metrics in predicting bioavailability. Natural products are often cited as an exception to Lipinski's rules. We believe this is because nature has learned to maintain low hydrophobicity and intermolecular H-bond donating potential when it needs to make biologically active compounds with high molecular weight and large numbers of rotatable bonds. In addition, natural products are more likely than purely synthetic compounds to resemble biosynthetic intermediates or endogenous metabolites, and hence take advantage of active transport mechanisms. Interestingly, the natural product leads in the Lipinski and parallel universe had an identical success rate (50%) in delivering an oral drug.

Natural products, an important resource for discovery of multitarget drugs and functional food for regulation of hepatic glucose metabolism.

PubMed

Li, Jian; Yu, Haiyang; Wang, Sijian; Wang, Wei; Chen, Qian; Ma, Yanmin; Zhang, Yi; Wang, Tao

2018-01-01

Imbalanced hepatic glucose homeostasis is one of the critical pathologic events in the development of metabolic syndromes (MSs). Therefore, regulation of imbalanced hepatic glucose homeostasis is important in drug development for MS treatment. In this review, we discuss the major targets that regulate hepatic glucose homeostasis in human physiologic and pathophysiologic processes, involving hepatic glucose uptake, glycolysis and glycogen synthesis, and summarize their changes in MSs. Recent literature suggests the necessity of multitarget drugs in the management of MS disorder for regulation of imbalanced glucose homeostasis in both experimental models and MS patients. Here, we highlight the potential bioactive compounds from natural products with medicinal or health care values, and focus on polypharmacologic and multitarget natural products with effects on various signaling pathways in hepatic glucose metabolism. This review shows the advantage and feasibility of discovering multicompound-multitarget drugs from natural products, and providing a new perspective of ways on drug and functional food development for MSs.

Natural products, an important resource for discovery of multitarget drugs and functional food for regulation of hepatic glucose metabolism

PubMed Central

Wang, Sijian; Wang, Wei; Chen, Qian; Ma, Yanmin; Zhang, Yi; Wang, Tao

2018-01-01

Imbalanced hepatic glucose homeostasis is one of the critical pathologic events in the development of metabolic syndromes (MSs). Therefore, regulation of imbalanced hepatic glucose homeostasis is important in drug development for MS treatment. In this review, we discuss the major targets that regulate hepatic glucose homeostasis in human physiologic and pathophysiologic processes, involving hepatic glucose uptake, glycolysis and glycogen synthesis, and summarize their changes in MSs. Recent literature suggests the necessity of multitarget drugs in the management of MS disorder for regulation of imbalanced glucose homeostasis in both experimental models and MS patients. Here, we highlight the potential bioactive compounds from natural products with medicinal or health care values, and focus on polypharmacologic and multitarget natural products with effects on various signaling pathways in hepatic glucose metabolism. This review shows the advantage and feasibility of discovering multicompound–multitarget drugs from natural products, and providing a new perspective of ways on drug and functional food development for MSs. PMID:29391777

University of Texas Southwestern Medical Center: U01 Natural Products Screening | Office of Cancer Genomics

Cancer.gov

The goal of this project was to enlarge the chemical space probed by Project 1 (High-Throughput siRNA Screening of a Non-Small Cell Lung Cancer Cell Line Panel) by screening an expanded natural products library (~40,000) in an effort to further define vulnerabilities and therapeutic targets in non-small cell lung cancer. This new library is derived from a diverse collection of marine bacteria (prepared by Dr. John MacMillan, University of Texas Southwestern).

Regulation of natural health products in Canada.

PubMed

Smith, Alysyn; Jogalekar, Sumedha; Gibson, Adam

2014-12-02

In Canada, all natural health products (NHPs) are regulated by Health Canada (HC) under the Food and Drugs Act and the Natural Health Product Regulations. All authorized products undergo pre-market assessment for safety, efficacy and quality and the degree of pre-market oversight varies depending on the risk of the product. In Canada, over 70,000 products have been authorized for sale and over 2000 sites have been licensed to produce NHPs. In the management of NHPs on the Canadian market, HC employs a number of active and collaborative methods to address the most common issues such as contamination, adulteration and deceptive or misleading advertising practices. HC is currently evolving its approaches to NHPs to recognize them as part of the larger group of health products available without a prescription. As such, the regulatory responsibility for all over-the-counter (OTC) drugs, including non-prescription drugs and NHPs, has been transferred to a single federal division. As a result of this transition a number of benefits are being realized with respect to government efficiency, clarity for industry, support for new innovations and consolidated government interactions with the Canadian market. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Introducing N-glycans into natural products through a chemoenzymatic approach.

PubMed

Huang, Wei; Ochiai, Hirofumi; Zhang, Xinyu; Wang, Lai-Xi

2008-11-24

The present study describes an efficient chemoenzymatic method for introducing a core N-glycan of glycoprotein origin into various lipophilic natural products. It was found that the endo-beta-N-acetylglucosaminidase from Arthrobactor protophormiae (Endo-A) had broad substrate specificity and can accommodate a wide range of glucose (Glc)- or N-acetylglucosamine (GlcNAc)-containing natural products as acceptors for transglycosylation, when an N-glycan oxazoline was used as a donor substrate. Using lithocholic acid as a model compound, we have shown that introduction of an N-glycan could be achieved by a two-step approach: chemical glycosylation to introduce a monosaccharide (Glc or GlcNAc) as a handle, and then Endo-A catalyzed transglycosylation to accomplish the site-specific N-glycan attachment. For those natural products that already carry terminal Glc or GlcNAc residues, direct enzymatic transglycosylation using sugar oxazoline as the donor substrate was achievable to introduce an N-glycan. It was also demonstrated that simultaneous double glycosylation could be fulfilled when the natural product contains two Glc residues. This chemoenzymatic method is concise, site-specific, and highly convergent. Because N-glycans of glycoprotein origin can serve as ligands for diverse lectins and cell-surface receptors, introduction of a defined N-glycan into biologically significant natural products may bestow novel properties onto these natural products for drug discovery and development.

Target identification by image analysis.

PubMed

Fetz, V; Prochnow, H; Brönstrup, M; Sasse, F

2016-05-04

Covering: 1997 to the end of 2015Each biologically active compound induces phenotypic changes in target cells that are characteristic for its mode of action. These phenotypic alterations can be directly observed under the microscope or made visible by labelling structural elements or selected proteins of the cells with dyes. A comparison of the cellular phenotype induced by a compound of interest with the phenotypes of reference compounds with known cellular targets allows predicting its mode of action. While this approach has been successfully applied to the characterization of natural products based on a visual inspection of images, recent studies used automated microscopy and analysis software to increase speed and to reduce subjective interpretation. In this review, we give a general outline of the workflow for manual and automated image analysis, and we highlight natural products whose bacterial and eucaryotic targets could be identified through such approaches.

Natural products in medicine: transformational outcome of synthetic chemistry.

PubMed

Szychowski, Janek; Truchon, Jean-François; Bennani, Youssef L

2014-11-26

This review brings to the forefront key synthetic modifications on natural products (NPs) that have yielded successful drugs. The emphasis is placed on the power of targeted chemical transformations in enhancing the therapeutic value of NPs through optimization of pharmacokinetics, stability, potency, and/or selectivity. Multiple classes of NPs such as macrolides, opioids, steroids, and β-lactams used to treat a variety of conditions such as cancers, infections, inflammation are exemplified. Molecular modeling or X-ray structures of NP/protein complexes supporting the observed boost in therapeutic value of the modified NPs are also discussed. Significant advancement in synthetic chemistry, in structure determination, and in the understanding of factors controlling pharmacokinetics can now better position drug discovery teams to undertake NPs as valuable leads. We hope that the beneficial NPs synthetic modifications outlined here will reignite medicinal chemists' interest in NPs and their derivatives.

Human contact imagined during the production process increases food naturalness perceptions.

PubMed

Abouab, Nathalie; Gomez, Pierrick

2015-08-01

It is well established that food processing and naturalness are not good friends, but is food processing always detrimental to naturalness? Building on the contagion principle, this research examines how production mode (handmade vs. machine-made) influences naturalness perceptions. In a pilot study (n = 69) and an experiment (n = 133), we found that compared with both a baseline condition and a condition in which the mode of production process was portrayed as machine-made, a handmade production mode increases naturalness ratings of a grape juice. A mediation analysis demonstrates that these effects result from higher perceived human contact suggesting that the production process may preserve food naturalness when humanized. Copyright © 2015 Elsevier Ltd. All rights reserved.

Natural products discovery from micro-organisms in the post-genome era.

PubMed

Ikeda, Haruo

2017-01-01

With the decision to award the Nobel Prize in Physiology or Medicine to Drs. S. Ōmura, W.C. Campbell, and Y. Tu, the importance and usefulness of natural drug discovery and development have been revalidated. Since the end of the twentieth century, many genome analyses of organisms have been conducted, and accordingly, numerous microbial genomes have been decoded. In particular, genomic studies of actinomycetes, micro-organisms that readily produce natural products, led to the discovery of biosynthetic gene clusters responsible for producing natural products. New explorations for natural products through a comprehensive approach combining genomic information with conventional methods show great promise for the discovery of new natural products and even systematic generation of unnaturally occurring compounds.

Breaking the silence: new strategies for discovering novel natural products.

PubMed

Ren, Hengqian; Wang, Bin; Zhao, Huimin

2017-12-01

Natural products have been a prolific source of antibacterial and anticancer drugs for decades. One of the major challenges in natural product discovery is that the vast majority of natural product biosynthetic gene clusters (BGCs) have not been characterized, partially due to the fact that they are either transcriptionally silent or expressed at very low levels under standard laboratory conditions. Here we describe the strategies developed in recent years (mostly between 2014-2016) for activating silent BGCs. These strategies can be broadly divided into two categories: approaches in native hosts and approaches in heterologous hosts. In addition, we briefly discuss recent advances in developing new computational tools for identification and characterization of BGCs and high-throughput methods for detection of natural products. Copyright © 2017 Elsevier Ltd. All rights reserved.

University of Texas Southwestern Medical Center: Lung Cancer Oncogenotype-Selective Drug Target Discovery (Natural Products Focus) | Office of Cancer Genomics

Cancer.gov

The goal of this project is to use small molecules and RNAi to functionally define subtypes of non-small cell lung cancer (NSCLC) using a panel of cell lines prepared and molecularly annotated by Drs. John Minna and Adi Gazdar. Experimental Approaches Lung Cancer Natural Products Screening/Chemical Library Screening

Natural products in soil microbe interactions and evolution.

PubMed

Traxler, Matthew F; Kolter, Roberto

2015-07-01

In recent years, bacterial interspecies interactions mediated by small molecule natural products have been found to give rise to a surprising array of phenotypes in soil-dwelling bacteria, especially among Streptomyces and Bacillus species. This review examines these interspecies interactions, and the natural products involved, as they have been presented in literature stemming from four disciplines: soil science, interspecies microbiology, ecology, and evolutionary biology. We also consider how these interactions fit into accepted paradigms of signaling, cueing, and coercion.

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

PubMed

Choi, Chang-Ik

2016-08-27

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.

α-Haloaldehydes: versatile building blocks for natural product synthesis.

PubMed

Britton, Robert; Kang, Baldip

2013-02-01

The diastereoselective addition of organometallic reagents to α-chloroaldehydes was first reported in 1959 and occupies a historically significant role as the prototypical reaction for Cornforth's model of stereoinduction. Despite clear synthetic potential for these reagents, difficulties associated with producing enantiomerically enriched α-haloaldehydes limited their use in natural product synthesis through the latter half of the 20th century. In recent years, however, a variety of robust, organocatalytic processes have been reported that now provide direct access to optically enriched α-haloaldehydes and have motivated renewed interest in their use as building blocks for natural product synthesis. This Highlight summarizes the methods available for the enantioselective preparation of α-haloaldehydes and their stereoselective conversion into natural products.

Electroplating targets for production of unique PET radionuclides

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bui, V.; Sheh, Y.; Finn, R.

1994-12-31

The past decade has witnessed the applications of Positron Emission Tomography (PET) evolving from a purely research endeavour to a procedure which has specific clinical applications in the areas of cardiology, neurology and oncology. The growth of PET has been facilitated by developments in medical instrumentation and radiopharmaceutical chemistry efforts. Included in this latter effort has been the low energy accelerator production and processing of unique PET radionuclides appropriate for the radiolabeling of biomolecules i.e. monoclonal antibodies and pepetides. The development and application of electroplated targets of antimony and copper for the production of iodine-124 and gallium-66 respectively, utilizing themore » Memorial Sloan-Kettering Cancer Center cyclotron are examples of target design and development applicable to many medical accelerators.« less

Electroplated targets for production of unique PET radionuclides

NASA Astrophysics Data System (ADS)

Bui, V.; Sheh, Y.; Finn, R.; Francesconi, L.; Cai, S.; Schlyer, D.; Wieland, B.

1995-12-01

The past decade has witnessed the applications of positron emission tomography (PET) evolving from a purely research endeavor to a procedure which has specific clinical applications in the areas of cardiology, neurology and oncology. The growth of PET has been facilitated by developments in both medical instrumentation and radiopharmaceutical chemistry efforts. Included in this latter effort has been the low energy accelerator production and processing of unique PET radionuclides appropriate for the radiolabeling of biomolecules, i.e. monoclonal antibodies and peptides. The development and application of electroplated targets of antimony and copper for the production of iodine-124 and gallium-66 respectively, utilizing the Memorial Sloan-Kettering Cancer Center (MSKCC) cyclotron are examples of target design and development applicable to many medical accelerators.

Photo-affinity labelling and biochemical analyses identify the target of trypanocidal simplified natural product analogues

PubMed Central

Tulloch, Lindsay B.; Menzies, Stefanie K.; Fraser, Andrew L.; Gould, Eoin R.; King, Elizabeth F.; Zacharova, Marija K.; Florence, Gordon J.

2017-01-01

Current drugs to treat African sleeping sickness are inadequate and new therapies are urgently required. As part of a medicinal chemistry programme based upon the simplification of acetogenin-type ether scaffolds, we previously reported the promising trypanocidal activity of compound 1, a bis-tetrahydropyran 1,4-triazole (B-THP-T) inhibitor. This study aims to identify the protein target(s) of this class of compound in Trypanosoma brucei to understand its mode of action and aid further structural optimisation. We used compound 3, a diazirine- and alkyne-containing bi-functional photo-affinity probe analogue of our lead B-THP-T, compound 1, to identify potential targets of our lead compound in the procyclic form T. brucei. Bi-functional compound 3 was UV cross-linked to its target(s) in vivo and biotin affinity or Cy5.5 reporter tags were subsequently appended by Cu(II)-catalysed azide-alkyne cycloaddition. The biotinylated protein adducts were isolated with streptavidin affinity beads and subsequent LC-MSMS identified the FoF1-ATP synthase (mitochondrial complex V) as a potential target. This target identification was confirmed using various different approaches. We show that (i) compound 1 decreases cellular ATP levels (ii) by inhibiting oxidative phosphorylation (iii) at the FoF1-ATP synthase. Furthermore, the use of GFP-PTP-tagged subunits of the FoF1-ATP synthase, shows that our compounds bind specifically to both the α- and β-subunits of the ATP synthase. The FoF1-ATP synthase is a target of our simplified acetogenin-type analogues. This mitochondrial complex is essential in both procyclic and bloodstream forms of T. brucei and its identification as our target will enable further inhibitor optimisation towards future drug discovery. Furthermore, the photo-affinity labeling technique described here can be readily applied to other drugs of unknown targets to identify their modes of action and facilitate more broadly therapeutic drug design in any pathogen or

PRISM 3: expanded prediction of natural product chemical structures from microbial genomes

PubMed Central

Skinnider, Michael A.; Merwin, Nishanth J.; Johnston, Chad W.

2017-01-01

Abstract Microbial natural products represent a rich resource of pharmaceutically and industrially important compounds. Genome sequencing has revealed that the majority of natural products remain undiscovered, and computational methods to connect biosynthetic gene clusters to their corresponding natural products therefore have the potential to revitalize natural product discovery. Previously, we described PRediction Informatics for Secondary Metabolomes (PRISM), a combinatorial approach to chemical structure prediction for genetically encoded nonribosomal peptides and type I and II polyketides. Here, we present a ground-up rewrite of the PRISM structure prediction algorithm to derive prediction of natural products arising from non-modular biosynthetic paradigms. Within this new version, PRISM 3, natural product scaffolds are modeled as chemical graphs, permitting structure prediction for aminocoumarins, antimetabolites, bisindoles and phosphonate natural products, and building upon the addition of ribosomally synthesized and post-translationally modified peptides. Further, with the addition of cluster detection for 11 new cluster types, PRISM 3 expands to detect 22 distinct natural product cluster types. Other major modifications to PRISM include improved sequence input and ORF detection, user-friendliness and output. Distribution of PRISM 3 over a 300-core server grid improves the speed and capacity of the web application. PRISM 3 is available at http://magarveylab.ca/prism/. PMID:28460067

Microbial production of 1-octanol: A naturally excreted biofuel with diesel-like properties

PubMed Central

Akhtar, M. Kalim; Dandapani, Hariharan; Thiel, Kati; Jones, Patrik R.

2014-01-01

The development of sustainable, bio-based technologies to convert solar energy and carbon dioxide into fuels is a grand challenge. A core part of this challenge is to produce a fuel that is compatible with the existing transportation infrastructure. This task is further compounded by the commercial desire to separate the fuel from the biotechnological host. Based on its fuel characteristics, 1-octanol was identified as an attractive metabolic target with diesel-like properties. We therefore engineered a synthetic pathway specifically for the biosynthesis of 1-octanol in Escherichia coli BL21(DE3) by over-expression of three enzymes (thioesterase, carboxylic acid reductase and aldehyde reductase) and one maturation factor (phosphopantetheinyl transferase). Induction of this pathway in a shake flask resulted in 4.4 mg 1-octanol L−1 h−1 which exceeded the productivity of previously engineered strains. Furthermore, the majority (73%) of the fatty alcohol was localised within the media without the addition of detergent or solvent overlay. The deletion of acrA reduced the production and excretion of 1-octanol by 3-fold relative to the wild-type, suggesting that the AcrAB–TolC complex may be responsible for the majority of product efflux. This study presents 1-octanol as a potential fuel target that can be synthesised and naturally accumulated within the media using engineered microbes. PMID:27066394

Microbial production of 1-octanol: A naturally excreted biofuel with diesel-like properties.

PubMed

Akhtar, M Kalim; Dandapani, Hariharan; Thiel, Kati; Jones, Patrik R

2015-12-01

The development of sustainable, bio-based technologies to convert solar energy and carbon dioxide into fuels is a grand challenge. A core part of this challenge is to produce a fuel that is compatible with the existing transportation infrastructure. This task is further compounded by the commercial desire to separate the fuel from the biotechnological host. Based on its fuel characteristics, 1-octanol was identified as an attractive metabolic target with diesel-like properties. We therefore engineered a synthetic pathway specifically for the biosynthesis of 1-octanol in Escherichia coli BL21(DE3) by over-expression of three enzymes (thioesterase, carboxylic acid reductase and aldehyde reductase) and one maturation factor (phosphopantetheinyl transferase). Induction of this pathway in a shake flask resulted in 4.4 mg 1-octanol L -1  h -1 which exceeded the productivity of previously engineered strains. Furthermore, the majority (73%) of the fatty alcohol was localised within the media without the addition of detergent or solvent overlay. The deletion of acrA reduced the production and excretion of 1-octanol by 3-fold relative to the wild-type, suggesting that the AcrAB-TolC complex may be responsible for the majority of product efflux. This study presents 1-octanol as a potential fuel target that can be synthesised and naturally accumulated within the media using engineered microbes.

The value of nature's natural product library for the discovery of New Chemical Entities: the discovery of ingenol mebutate.

PubMed

Ogbourne, Steven M; Parsons, Peter G

2014-10-01

In recent decades, 'Big Pharma' has invested billions of dollars into ingenious and innovative strategies designed to develop drugs using high throughput screening of small molecule libraries generated on the laboratory bench. Within the same time frame, screening of natural products by pharmaceutical companies has suffered an equally significant reduction. This is despite the fact that the complexity, functional diversity and druggability of nature's natural product library are considered by many to be superior to any library any team of scientists can prepare. It is therefore no coincidence that the number of New Chemical Entities reaching the market has also suffered a substantial decrease, leading to a productivity crisis within the pharmaceutical sector. In fact, the current dearth of New Chemical Entities reaching the market in recent decades might be a direct consequence of the strategic decision to move away from screening of natural products. Nearly 700 novel drugs derived from natural product New Chemical Entities were approved between 1981 and 2010; more than 60% of all approved drugs over the same time. In this review, we use the example of ingenol mebutate, a natural product identified from Euphorbia peplus and later approved as a therapy for actinic keratosis, as why nature's natural product library remains the most valuable library for discovery of New Chemical Entities and of novel drug candidates. Copyright © 2014 Elsevier B.V. All rights reserved.

Neurobiology of autism gene products: towards pathogenesis and drug targets.

PubMed

Kleijer, Kristel T E; Schmeisser, Michael J; Krueger, Dilja D; Boeckers, Tobias M; Scheiffele, Peter; Bourgeron, Thomas; Brose, Nils; Burbach, J Peter H

2014-03-01

The genetic heterogeneity of autism spectrum disorders (ASDs) is enormous, and the neurobiology of proteins encoded by genes associated with ASD is very diverse. Revealing the mechanisms on which different neurobiological pathways in ASD pathogenesis converge may lead to the identification of drug targets. The main objective is firstly to outline the main molecular networks and neuronal mechanisms in which ASD gene products participate and secondly to answer the question how these converge. Finally, we aim to pinpoint drug targets within these mechanisms. Literature review of the neurobiological properties of ASD gene products with a special focus on the developmental consequences of genetic defects and the possibility to reverse these by genetic or pharmacological interventions. The regulation of activity-dependent protein synthesis appears central in the pathogenesis of ASD. Through sequential consequences for axodendritic function, neuronal disabilities arise expressed as behavioral abnormalities and autistic symptoms in ASD patients. Several known ASD gene products have their effect on this central process by affecting protein synthesis intrinsically, e.g., through enhancing the mammalian target of rapamycin (mTOR) signal transduction pathway or through impairing synaptic function in general. These are interrelated processes and can be targeted by compounds from various directions: inhibition of protein synthesis through Lovastatin, mTOR inhibition using rapamycin, or mGluR-related modulation of synaptic activity. ASD gene products may all feed into a central process of translational control that is important for adequate glutamatergic regulation of dendritic properties. This process can be modulated by available compounds but may also be targeted by yet unexplored routes.

Bioactive natural products from Chinese marine flora and fauna.

PubMed

Zhou, Zhen-Fang; Guo, Yue-Wei

2012-09-01

In recent decades, the pharmaceutical application potential of marine natural products has attracted much interest from both natural product chemists and pharmacologists. Our group has long been engaged in the search for bioactive natural products from Chinese marine flora (such as mangroves and algae) and fauna (including sponges, soft corals, and mollusks), resulting in the isolation and characterization of numerous novel secondary metabolites spanning a wide range of structural classes and various biosynthetic origins. Of particular interest is the fact that many of these compounds show promising biological activities, including cytotoxic, antibacterial, and enzyme inhibitory effects. By describing representative studies, this review presents a comprehensive summary regarding the achievements and progress made by our group in the past decade. Several interesting examples are discussed in detail.

Nature is the best source of anti-inflammatory drugs: indexing natural products for their anti-inflammatory bioactivity.

PubMed

Aswad, Miran; Rayan, Mahmoud; Abu-Lafi, Saleh; Falah, Mizied; Raiyn, Jamal; Abdallah, Ziyad; Rayan, Anwar

2018-01-01

The aim was to index natural products for less expensive preventive or curative anti-inflammatory therapeutic drugs. A set of 441 anti-inflammatory drugs representing the active domain and 2892 natural products representing the inactive domain was used to construct a predictive model for bioactivity-indexing purposes. The model for indexing the natural products for potential anti-inflammatory activity was constructed using the iterative stochastic elimination algorithm (ISE). ISE is capable of differentiating between active and inactive anti-inflammatory molecules. By applying the prediction model to a mix set of (active/inactive) substances, we managed to capture 38% of the anti-inflammatory drugs in the top 1% of the screened set of chemicals, yielding enrichment factor of 38. Ten natural products that scored highly as potential anti-inflammatory drug candidates are disclosed. Searching the PubMed revealed that only three molecules (Moupinamide, Capsaicin, and Hypaphorine) out of the ten were tested and reported as anti-inflammatory. The other seven phytochemicals await evaluation for their anti-inflammatory activity in wet lab. The proposed anti-inflammatory model can be utilized for the virtual screening of large chemical databases and for indexing natural products for potential anti-inflammatory activity.

PRISM 3: expanded prediction of natural product chemical structures from microbial genomes.

PubMed

Skinnider, Michael A; Merwin, Nishanth J; Johnston, Chad W; Magarvey, Nathan A

2017-07-03

Microbial natural products represent a rich resource of pharmaceutically and industrially important compounds. Genome sequencing has revealed that the majority of natural products remain undiscovered, and computational methods to connect biosynthetic gene clusters to their corresponding natural products therefore have the potential to revitalize natural product discovery. Previously, we described PRediction Informatics for Secondary Metabolomes (PRISM), a combinatorial approach to chemical structure prediction for genetically encoded nonribosomal peptides and type I and II polyketides. Here, we present a ground-up rewrite of the PRISM structure prediction algorithm to derive prediction of natural products arising from non-modular biosynthetic paradigms. Within this new version, PRISM 3, natural product scaffolds are modeled as chemical graphs, permitting structure prediction for aminocoumarins, antimetabolites, bisindoles and phosphonate natural products, and building upon the addition of ribosomally synthesized and post-translationally modified peptides. Further, with the addition of cluster detection for 11 new cluster types, PRISM 3 expands to detect 22 distinct natural product cluster types. Other major modifications to PRISM include improved sequence input and ORF detection, user-friendliness and output. Distribution of PRISM 3 over a 300-core server grid improves the speed and capacity of the web application. PRISM 3 is available at http://magarveylab.ca/prism/. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Metabolic engineering of microorganisms for the synthesis of plant natural products.

PubMed

Marienhagen, Jan; Bott, Michael

2013-01-20

Of more than 200,000 plant natural products known to date, many demonstrate important pharmacological activities or are of biotechnological significance. However, isolation from natural sources is usually limited by low abundance and environmental, seasonal as well as regional variation, whereas total chemical synthesis is typically commercially unfeasible considering the complex structures of most plant natural products. With advances in DNA sequencing and recombinant DNA technology many of the biosynthetic pathways responsible for the production of these valuable compounds have been elucidated, offering the opportunity of a functional integration of biosynthetic pathways in suitable microorganisms. This approach offers promise to provide sufficient quantities of the desired plant natural products from inexpensive renewable resources. This review covers recent advancements in the metabolic engineering of microorganisms for the production of plant natural products such as isoprenoids, phenylpropanoids and alkaloids, and highlights general approaches and strategies to gain access to the rich biochemical diversity of plants by employing the biosynthetic power of microorganisms. Copyright © 2012 Elsevier B.V. All rights reserved.

An Overview of Natural Gas Conversion Technologies for Co-Production of Hydrogen and Value-Added Solid Carbon Products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dagle, Robert A.; Dagle, Vanessa; Bearden, Mark D.

This report was prepared in response to the U.S. Department of Energy Fuel Cell Technologies Office Congressional Appropriation language to support research on carbon-free production of hydrogen using new chemical processes that utilize natural gas to produce solid carbon and hydrogen. The U.S. produces 9-10 million tons of hydrogen annually with more than 95% of the hydrogen produced by steam-methane reforming (SMR) of natural gas. SMR is attractive because of its high hydrogen yield; but it also converts the carbon to carbon dioxide. Non-oxidative thermal decomposition of methane to carbon and hydrogen is an alternative to SMR and produces COmore » 2-free hydrogen. The produced carbon can be sold as a co-product, thus providing economic credit that reduces the delivered net cost of hydrogen. The combination of producing hydrogen with potentially valuable carbon byproducts has market value in that this allows greater flexibility to match the market prices of hydrogen and carbon. That is, the higher value product can subsidize the other in pricing decisions. In this report we highlight the relevant technologies reported in the literature—primarily thermochemical and plasma conversion processes—and recent research progress and commercial activities. Longstanding technical challenges include the high energetic requirements (e.g., high temperatures and/or electricity requirements) necessary for methane activation and, for some catalytic processes, the separation of solid carbon product from the spent catalyst. We assess current and new carbon product markets that could be served given technological advances, and we discuss technical barriers and potential areas of research to address these needs. We provide preliminary economic analysis for these processes and compare to other emerging (e.g., electrolysis) and conventional (e.g., SMR) processes for hydrogen production. The overarching conclusion of this study is that the cost of hydrogen can be potentially

Natural health product use in Canada.

PubMed

Troppmann, Leticia; Johns, Timothy; Gray-Donald, Katherine

2002-01-01

To quantify patterns of Natural Health Product (NHP) use in Canada. The Food Habits of Canadians surveyed 1,543 Canadian adults using a 24-hour recall to record dietary supplements. Prevalence of use by user profile was examined. Forty-six percent of women and 33% of men reported taking at least one Natural Health Product with a mean of 2.3 among users. The highest prevalence of supplement use, 57%, occurred among women aged 50-65. Supplement users were older, less likely to smoke and perceived their health as better than non-users. Among supplement users, men had higher rates of use of garlic and vitamin C while women used iron, calcium, B complex, evening primrose oil and glucosamine sulfate. Supplement use by Canadians, at 38% for nutrients and 15% for herbal products, was similar to the rate of uses in the U.S., although differences in the reporting of types of supplements underline aspects of consumer behaviour as well as methodological issues specific to NHPs. Investigation of the use of NHPs in the healthcare setting is important given the widespread use and the potential health care consequences associated with supplement use.

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

Natural Products as Sources of New Drugs from 1981 to 2014.

PubMed

Newman, David J; Cragg, Gordon M

2016-03-25

This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions and the designation "natural product botanical", or "NB", to cover those botanical "defined mixtures" now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from around the 1940s to the end of 2014, of the 175 small molecules approved, 131, or 75%, are other than "S" (synthetic), with 85, or 49%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore it is considered that this area of natural product research should be expanded significantly.

[Strategies of elucidation of biosynthetic pathways of natural products].

PubMed

Zou, Li-Qiu; Kuang, Xue-Jun; Sun, Chao; Chen, Shi-Lin

2016-11-01

Elucidation of the biosynthetic pathways of natural products is not only the major goal of herb genomics, but also the solid foundation of synthetic biology of natural products. Here, this paper reviewed recent advance in this field and put forward strategies to elucidate the biosynthetic pathway of natural products. Firstly, a proposed biosynthetic pathway should be set up based on well-known knowledge about chemical reactions and information on the identified compounds, as well as studies with isotope tracer. Secondly, candidate genes possibly involved in the biosynthetic pathway were screened out by co-expression analysis and/or gene cluster mining. Lastly, all the candidate genes were heterologously expressed in the host and then the enzyme involved in the biosynthetic pathway was characterized by activity assay. Sometimes, the function of the enzyme in the original plant could be further studied by RNAi or VIGS technology. Understanding the biosynthetic pathways of natural products will contribute to supply of new leading compounds by synthetic biology and provide "functional marker" for herbal molecular breeding, thus but boosting the development of traditional Chinese medicine agriculture. Copyright© by the Chinese Pharmaceutical Association.

Large Scale Accelerator Production of 225Ac: Effective Cross sections for 78-192 MeV Protons Incident on 232Th Targets

DOE PAGES

Griswold, Justin R; Medvedev, Dmitri G.; Engle, Jonathan W.; ...

2016-09-28

Actinium-225 and 213Bi have been used successfully in targeted alpha therapy (TAT) in preclinical and clinical research. This paper is a continuation of research activities aiming to expand the availability of 225Ac. The high energy proton spallation reaction on natural thorium metal target has been utilized to produce millicurie quantities of 225Ac. The results of sixteen irradiation experiments of Th metal at beam energies between 78 and 200 MeV are summarized in this work. Irradiations have been conducted at Brookhaven National Laboratory (BNL) and Los Alamos National Laboratory (LANL), while target dissolution and processing was carried out at Oak Ridgemore » National Laboratory (ORNL). Excitation functions for actinium and thorium isotopes as well as for some of the fission products are presented. The cross sections for production of 225Ac range from 3.6 to 16.7 mb in the incident proton energy range of 78 to 192 MeV. Based on these data, production of Curie quantities of 225Ac is possible by irradiating a 5.0 g cm -2232Th target for 10 days in either BNL or LANL proton irradiation facilities.« less

Large scale accelerator production of 225Ac: Effective cross sections for 78-192MeV protons incident on 232Th targets.

PubMed

Griswold, J R; Medvedev, D G; Engle, J W; Copping, R; Fitzsimmons, J M; Radchenko, V; Cooley, J C; Fassbender, M E; Denton, D L; Murphy, K E; Owens, A C; Birnbaum, E R; John, K D; Nortier, F M; Stracener, D W; Heilbronn, L H; Mausner, L F; Mirzadeh, S

2016-12-01

Actinium-225 and 213 Bi have been used successfully in targeted alpha therapy (TAT) in preclinical and clinical research. This paper is a continuation of research activities aiming to expand the availability of 225 Ac. The high-energy proton spallation reaction on natural thorium metal targets has been utilized to produce millicurie quantities of 225 Ac. The results of sixteen irradiation experiments of thorium metal at beam energies between 78 and 192MeV are summarized in this work. Irradiations have been conducted at Brookhaven National Laboratory (BNL) and Los Alamos National Laboratory (LANL), while target dissolution and processing was carried out at Oak Ridge National Laboratory (ORNL). Excitation functions for actinium and thorium isotopes, as well as for some of the fission products, are presented. The cross sections for production of 225 Ac range from 3.6 to 16.7mb in the incident proton energy range of 78-192MeV. Based on these data, production of curie quantities of 225 Ac is possible by irradiating a 5.0gcm -2 232 Th target for 10 days in either BNL or LANL proton irradiation facilities. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Elaboration of Pseudo-natural Products Using Artificial In Vitro Biosynthesis Systems].

PubMed

Goto, Yuki

2018-01-01

 Peptidic natural products often consist of not only proteinogenic building blocks but also unique non-proteinogenic structures such as macrocyclic scaffolds and N-methylated backbones. Since such non-proteinogenic structures are important structural motifs that contribute to diverse bioactivity, we have proposed that peptides with non-proteinogenic structures should be attractive candidates as artificial bioactive peptides mimicking natural products, or so-called pseudo-natural products. We previously devised an engineered translation system for pseudo-natural peptides, referred to as the flexible in vitro translation (FIT) system. This system enabled "one-pot" synthesis of highly diverse pseudo-natural peptide libraries, which can be rapidly screened by mRNA display technology for the discovery of pseudo-natural peptides with diverse bioactivities.

One-Compound-Multi-Target: Combination Prospect of Natural Compounds with Thrombolytic Therapy in Acute Ischemic Stroke

PubMed Central

Chen, Han-Sen; Qi, Su-Hua; Shen, Jian-Gang

2017-01-01

Abstract: Tissue plasminogen activator (t-PA) is the only FDA-approved drug for acute ischemic stroke treatment, but its clinical use is limited due to the narrow therapeutic time window and severe adverse effects, including hemorrhagic transformation (HT) and neurotoxicity. One of the potential resolutions is to use adjunct therapies to reduce the side effects and extend t-PA's therapeutic time window. However, therapies modulating single target seem not to be satisfied, and a multi-target strategy is warranted to resolve such complex disease. Recently, large amount of efforts have been made to explore the active compounds from herbal supplements to treat ischemic stroke. Some natural compounds revealed both neuro- and blood-brain-barrier (BBB)-protective effects by concurrently targeting multiple cellular signaling pathways in cerebral ischemia-reperfusion injury. Thus, those compounds are potential to be one-drug-multi-target agents as combined therapy with t-PA for ischemic stroke. In this review article, we summarize current progress about molecular targets involving in t-PA-mediated HT and neurotoxicity in ischemic brain injury. Based on these targets, we select 23 promising compounds from currently available literature with the bioactivities simultaneously targeting several important molecular targets. We propose that those compounds merit further investigation as combined therapy with t-PA. Finally, we discuss the potential drawbacks of the natural compounds' studies and raise several important issues to be addressed in the future for the development of natural compound as an adjunct therapy. PMID:27334020

Synthesis and Biological Investigation of Antioxidant Pyrrolomorpholine Spiroketal Natural Products

NASA Astrophysics Data System (ADS)

Verano, Alyssa Leigh

The pyrrolomorpholine spiroketal natural product family is comprised of epimeric furanose and pyranose isomers. These compounds were isolated from diverse plant species, all of which are used as traditional Chinese medicines for the treatment of a variety of diseases. Notably, the spiroketal natural products acortatarins A and B exhibit antioxidant activity in a diabetic renal cell model, significantly attenuating hyperglycemia-induced production of reactive oxygen species (ROS), a hallmark of diabetic nephropathy. The xylapyrrosides, additional members of the family, also inhibit t-butyl hydroperoxide-induced cytotoxicity in rat vascular smooth muscle cells. Accordingly, these natural products have therapeutic potential for the treatment of oxidative stress-related pathologies, and synthetic access would provide an exciting opportunity to investigate bioactivity and mechanism of action. Herein, we report the stereoselective synthesis of acortatarins A and B, furanose members of the pyrrolomorpholine spiroketal family. Our synthetic route was expanded to synthesize the pyranose congeners, thus completing entire D-enantiomeric family of natural products. Efficient access towards these scaffolds enabled systematic analogue synthesis, investigation of mechanism-of-action, and the discovery of novel antioxidants.

University of Texas Southwestern Medical Center (UTSW): U01 Natural Products Screening | Office of Cancer Genomics

Cancer.gov

The goal of this project was to enlarge the chemical space probed by Project 1 (High-Throughput siRNA Screening of a Non-Small Cell Lung Cancer Cell Line Panel) by screening an expanded natural products library (~40,000) in an effort to further define vulnerabilities and therapeutic targets in non-small cell lung cancer. This new library is derived from a diverse collection of marine bacteria (prepared by Dr. John MacMillan, University of Texas Southwestern).

Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection.

PubMed

De Clercq, E

2000-09-01

A large variety of natural products have been described as anti-HIV agents, and for a portion thereof the target of interaction has been identified. Cyanovirin-N, a 11-kDa protein from Cyanobacterium (blue-green alga) irreversibly inactivates HIV and also aborts cell-to-cell fusion and transmission of HIV, due to its high-affinity interaction with gp120. Various sulfated polysaccharides extracted from seaweeds (i.e., Nothogenia fastigiata, Aghardhiella tenera) inhibit the virus adsorption process. Ingenol derivatives may inhibit virus adsorption at least in part through down-regulation of CD4 molecules on the host cells. Inhibition of virus adsorption by flavanoids such as (-)epicatechin and its 3-O-gallate has been attributed to an irreversible interaction with gp120 (although these compounds are also known as reverse transcriptase inhibitors). For the triterpene glycyrrhizin (extracted from the licorice root Glycyrrhiza radix) the mode of anti-HIV action may at least in part be attributed to interference with virus-cell binding. The mannose-specific plant lectins from Galanthus, Hippeastrum, Narcissus, Epipac tis helleborine, and Listera ovata, and the N-acetylgl ucosamine-specific lectin from Urtica dioica would primarily be targeted at the virus-cell fusion process. Various other natural products seem to qualify as HIV-cell fusion inhibitors: the siamycins [siamycin I (BMY-29304), siamycin II (RP 71955, BMY 29303), and NP-06 (FR901724)] which are tricyclic 21-amino-acid peptides isolated from Streptomyces spp that differ from one another only at position 4 or 17 (valine or isoleucine in each case); the betulinic acid derivative RPR 103611, and the peptides tachyplesin and polyphemusin which are highly abundant in hemocyte debris of the horseshoe crabs Tachypleus tridentatus and Limulus polyphemus, i.e., the 18-amino-acid peptide T22 from which T134 has been derived. Both T22 and T134 have been shown to block T-tropic X4 HIV-1 strains through a specific

Novel Artificial Natural Products Against Breast Cancer Through Combinatorial Biosynthesis

DTIC Science & Technology

2002-07-01

compounds normally produced by a certain strain. Our investigations on the discovery of novel natural metabolites using type II polyketide synthase ...limitations, shall be included on any reproduction hereof which includes any part of the portions subject to such limitations. THIS TECHNICAL REPORT HAS... polyketides remain the central group of natural products in this research area, since this class of natural products form one of the largest and most

Flow chemistry syntheses of natural products.

PubMed

Pastre, Julio C; Browne, Duncan L; Ley, Steven V

2013-12-07

The development and application of continuous flow chemistry methods for synthesis is a rapidly growing area of research. In particular, natural products provide demanding challenges to this developing technology. This review highlights successes in the area with an emphasis on new opportunities and technological advances.

Label-free pharmacological profiling based on dynamic mass redistribution for characterization and authentication of hazardous natural products.

PubMed

Song, Hui-Peng; Wang, Hong; Zhao, Xiaoai; He, Ling; Zhong, Huailing; Wu, Si-Qi; Li, Ping; Yang, Hua

2017-07-05

Natural products are becoming increasingly popular in multiple fields involving medicines, foods and beverages. However, due to the frequent occurrence of poisoning incidents, their toxicity and safety have caused a serious concern. Here we report a method of biosensor-based two-phase pharmacological profiling (BTPP) for discovery, monitor and control of receptor-targeted natural products. BTPP uses a resonant waveguide grating biosensor for label-free and non-invasive detection of intracellular dynamic mass redistribution (DMR), a phenomenon caused by protein relocalization after receptors receiving stimulation from toxicants. The method can not only facilitate the identification of hazardous materials but also quantify their bioactivity by EC 50 . As a proof of concept, the method was successfully applied to recognize Daturae Flos (DF), an herb that can antagonize muscarinic acetylcholine M 2 receptor and further cause poisoning, from other easily confused species. BTPP combined with high performance liquid chromatography revealed that scopolamine and hyoscyamine in DF were the key marker compounds. Moreover, the method accurately picked out 2 M 2 receptor antagonists from 25 natural compounds, displaying its potential in high-throughput screening. This study provides a systematic illustration about the establishment, applicability and advantages of BTPP, which contributes to the safety assessment of natural products in related fields. Copyright © 2017 Elsevier B.V. All rights reserved.

Transporter-mediated natural product-drug interactions for the treatment of cardiovascular diseases.

PubMed

Zha, Weibin