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Bannerman-Akwei, Laude. "Synthesis of Marine Chemicals and Derivatives as Potential Anti-Cancer Drugs." Digital Commons @ East Tennessee State University, 2008. https://dc.etsu.edu/etd/1990.
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Two natural marine compounds, 3-bromo-4,5-dihydroxybenzaldehyde 2 and 2,3-dibromo-4,5-dihydroxybenzaldehyde 5 together with two novel derivatives, 3-bromo-5-(tert-butyl-dimethyl-silanyloxy)-4-hydroxybenzaldehyde 3 and 1-bromo-2,3-dimethoxy-5-nitrooxy-methylbenzene 9, were synthesized. Compounds 2, 3, and 5 were evaluated for their biological activity towards the inhibition of prostate cancer cell growth using staurosporine a a positive control. All three compounds have shown significant inhibition of prostate cancer cell growth. Compound 9 is yet to be evaluated.
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Lane, Amy L. "Marine natural products as antimicrobial chemical defenses and sources of potential drugs." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/26556.
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Thesis (Ph. D.)--Chemistry and Biochemistry, Georgia Institute of Technology, 2009.Committee Chair: Kubanek, Julia; Committee Member: Fernandez, Facundo M.; Committee Member: Harvey, Stephen C.; Committee Member: Hay, Mark E.; Committee Member: Hud, Nicholas V. Part of the SMARTech Electronic Thesis and Dissertation Collection.
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Sunkel, Vanessa Ann. "The investigation of novel marine microorganisms for the production of biologically active metabolites." Thesis, Rhodes University, 2009. http://hdl.handle.net/10962/d1004579.
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New drugs, particularly antibiotics, are urgently required to combat the increasing problem of antibiotic resistant human pathogens. Due to the scarcity of products available today, the pharmaceutical industry is now under pressure to reassess compounds derived from plants, soil and marine organisms. Pharmaceutical companies are showing renewed interest in marine biotechnology as the oceans represent a rich source of both biological and chemical diversity of novel molecular structures with anti-cancer, anti-inflammatory and antibiotic properties. Formerly unexplored locations, such as deep ocean sediments, show great potential as a source of genetically novel microorganisms producing structurally unique secondary metabolites. In this research, a metabolite producing marine Pseudoalteromonas strain, known as AP5, was initially used to develop methods for the detection, optimisation of production and extraction of bioactive metabolites from other potentially novel marine isolates. Two hundred and seventy six (276) marine isolates from water and sediment samples from the Antarctic Ocean and Marion Island were isolated. Ten visually different isolates were screened for bioactivity against Gram-positive and -negative bacteria, fungi and yeast. Three out of the 10 isolates, WL61 , WL 114 and WL 136, appeared to be novel Streptomyces spp. showing activity against different test organisms. Many of these marine microorganisms are difficult to culture in the laboratory, particularly when they are cultivated continuously in shake flasks as they can stop producing bioactive compounds. The cultivation of marine isolates in bioreactors may be a more beneficial process for the optimisation of metabolite production compared to conventional liquid fermentation techniques whereby the solid-liquid-air interface of membrane bioreactors can imitate the natural environment of microbes. The membrane bioreactor system is a stable growth environment with low shear that supports steady-state biofilm growth consisting of a high cell density due to a high mass transfer of nutrients and oxygen to the cells. This approach was employed and isolates WL61, WL114 and WL136 were immobilised onto ceramic membranes using Quorus single fibre bioreactors (SFR). The SFRs were used to establish the most suitable growth medium for continuous secondary metabolite production. The best growth conditions were applied to the Quorus multifibre bioreactor (MFR) for scale up of biologically active metabolites, highlighting the potential of bioreactor technology for use in bioprospecting for isolating and screening novel and known organisms for new and interesting natural products. Furthermore, the Quorus MFR was shown to be suitable for the production of high yields of antimicrobial metabolites and is an efficient new fermentation production system. Purification by HPLC fractionation was used to characterise four major compounds from isolate WL 114 extracts. NMR structure elucidation identified one of the two primary compounds as Bisphenol A. The complete chemical structure for the second potent bioactive compound could not be determined due to the low concentration and volume of material.KMBT_363
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Watson, Daniel John. "Studies directed towards the total asymmetric synthesis of Altohyrtin A." Thesis, University of Liverpool, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364263.
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Llorach, Parés Laura. "Computer-Aided Drug Design applied to marine drug discovery = Disseny de fàrmacs assistit per ordinador aplicat a la cerca de possibles fàrmacs marins." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668298.
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The potential of natural products in general, and marine natural products in particular, as pharmacological entities has been widely demonstrated in recent years. Marine benthic ecosystems contain an extraordinary range of diverse organisms that possess bioactive natural compounds, which are commonly used as defensive or protective chemical mechanisms. These effective defensive strategies are based on secondary metabolites that are crucial for the species survival. The pharmacological properties of these unique chemical compounds constitute an interesting and emerging hot research line, based upon exploiting them for the development of new drugs. The evolution, biodiversity, and specific environmental conditions found in marine ecosystems, such as Antarctica and the Mediterranean Sea, make them an amazing source of potential therapeutic agents. Interestingly, some of these natural products are capable to modulate protein functions in pathogenesis-related pathways. The process of discovery and development of new drugs, for instance small molecules, with the aforementioned capacity to modulate protein functions, is a tedious procedure that requires economic resources and time. To reduce these drawbacks, computer-aided drug design (CADD) has emerged as one of the most effective methods. A rapid exploration of the chemical space can be done with computational methods, and they are very interesting and useful complementary approaches to experimental methods. CADD techniques can be applied in different steps of the drug discovery pipeline, and also, can cover several phases of this pipeline. To that end, several objectives have been set and reached in this thesis: 1. To find possible therapeutic activities and to establish the capability to modulate protein functions in pathogenesis-related pathways from marine molecules by using different CADD tools and techniques: I. Improve the drug discovery pipeline by the elucidation of the possible therapeutic potential of a set of marine molecules against a list of targets related to different pathologies. II. Elucidation of different pharmacophoric features of marine compounds and a precise in silico binding study, highlighting the power of CADD techniques, and reporting the inhibitory activity of different natural products and indole scaffold derivatives as GSK3β, CK1δ, DYRK1A, and CLK1 inhibitors. III. Computational study and an experimental validation of meridianins and lignarenones as possible ATP and/or substrate inhibitors of GSK3β. The main conclusions of this thesis are that marine molecules can be used as therapeutic agents against protein kinases related to the AD, and the exemplification of CADD potential applied to marine drug discovery.El potencial dels productes naturals en general, i els productes naturals marins en particular, com a entitats farmacològiques ha quedat demostrat al llarg dels últims anys. Els ecosistemes bentònics marins contenen una extraordinària diversitat d'organismes que posseeixen compostos naturals bioactius, que utilitzen com mecanismes químics defensius i de protecció. Aquestes efectives estratègies defensives es basen en metabòlits secundaris, crucials per a la supervivència de les espècies. Tenint en compte les propietats farmacològiques d'aquests compostos químics únics, utilitzar-los per al desenvolupament de nous fàrmacs constitueix una línia interessant de recerca emergent. L'evolució, la biodiversitat i les condicions específiques que es troben en els ecosistemes marins, com ara l'Antàrtida i el mar Mediterrani, els converteixen en una font increïble de possibles agents terapèutics, capaços de modular funcions de proteïnes involucrades en determinades patologies. El procés de descobriment i desenvolupament de nous fàrmacs, per exemple, molècules petites, és un procediment tediós que requereix de recursos econòmics i de temps. Per reduir aquests inconvenients, el disseny de fàrmacs assistit per ordinador (DFAO) ha sorgit com un dels mètodes principals i més eficaços. Es pot fer una exploració ràpida de l'espai químic amb mètodes computacionals i a més, són aproximacions complementàries als mètodes experimentals molt interessants i útils. Les tècniques de DFAO es poden aplicar en diferents passos del procés de descobriment de fàrmacs, i també, poden cobrir diverses fases d'aquest pipeline. Amb aquesta finalitat, es varen establir diversos objectius en aquesta tesi: 1. Dilucidar la possible activitat terapèutica i la capacitat per modular les funcions de proteïnes que estan relacionades amb una determinada patologia de les molècules marines mitjançant l'ús de diferents eines i tècniques de DFAO: I. millorar el pipeline de descobriment de fàrmacs mitjançant l'elucidació del possible potencial terapèutic d'un conjunt de molècules marines enfront d'una llista de dianes relacionades amb diferents patologies. II. Dilucidació de les diferents característiques farmacofóriques dels compostos marins i en un precís estudi d’unió in silico, destacant el poder de les tècniques de DFAO, i avaluar l'activitat inhibidora de diferents productes naturals i derivats d’esquelets indòlics com inhibidors de GSK3β, CK1δ, DYRK1A i CLK1. III. Estudi computacional i validació experimental de meridianines i lignarenones com a possibles inhibidors de GSK3β mitjançant la unió a la cavitat de l'ATP i/o del substrat. En relació amb aquests objectius, les conclusions principals d'aquesta tesi són, que les molècules marines poden ser utilitzades com a agents terapèutics contra proteïnes quinases relacionades amb la malaltia d’Alzheimer, i l'exemplificació del potencial de les tècniques de DFAO aplicat al descobriment de fàrmacs marins.
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Mezzelani, Marica. "Ecotoxicological potential of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in marine organisms: bioavailability, biomarkers and natural occurrence in Mytilus galloprovincialis." Doctoral thesis, Università Politecnica delle Marche, 2016. http://hdl.handle.net/11566/243116.
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I residui dei composti farmaceutici presenti in ambiente rappresentano una problematica emergente dato che le informazioni riguardo la loro presenza, distribuzione e potenziale ecotossicologico sono molto limitate, specialmente per le aree costiere. In questa tesi è stata valutata la sensibilità del mitilo Mediterraneo Mytilus galloprovincialis nei confronti di diversi farmaci anti infiammatori non steroidei (FANS), applicando un approccio integrato che ha previsto sia attività di laboratorio che indagini di campo. In condizioni di laboratorio i mitili sono stati esposti a diverse concentrazioni ambientalmente realistiche (25, 2.5 e 0.5 μg/L) di acetaminofene AMP, diclofenac DIC, ibuprofene IBU, ketoprofene KET e nimesulide NIM, per diversi tempi di esposizione (da 14 a 60 giorni). Il potenziale ecotossicologico dei FANS è stato valutato combinando le analisi chimiche del bioaccumulo dei farmaci con un approccio multi-biomarker, basato sullo studio di un ampio numero di risposte subcellulari che rappresentano dei segnali di allerta precoce di alterazione cellulare e di tossicità. Per alcune condizioni sperimentali, le alterazioni funzionali misurate a livello cellulare sono state integrate con modificazioni trascrittomiche a livello molecolare attraverso la tecnica di microarray a DNA. I risultati ottenuti hanno dimostrato che i mitili sono in grado di bioaccumulare DIC, IBU e NIM non seguendo, tuttavia, una cinetica dose dipendente, mentre AMP e KET non sono mai stati misurati indipendentemente dalla dose e dal tempo di esposizione. Ciononostante, tutte le molecole testate e tutte le condizioni sperimentali hanno determinato l’insorgenza di alterazioni a carico dei parametri immunitari, modulazione del metabolismo lipidico e danno genotossico. Le analisi trascrittomiche hanno rivelato modificazioni a carico degli organismi esposti alle dosi più basse, sia nel breve (KET e NIM) che nel lungo termine (KET). I risultati ottenuti a livello molecolare supportano le alterazioni misurate a livello cellulare e suggeriscono che il meccanismo di azione dei FANS negli invertebrati risulta essere molto simile a quello ampiamente documentato nei mammiferi. Le indagini a lungo termine hanno permesso di comprendere che l’effetto dei FANS si mantiene costantemente per 60 giorni. Le indagini in campo hanno rivelato, per la prima volta, la presenza di DIC, IBU e NIM nei mitili naturali campionati in primavera e in estate da tipiche aree turistiche del Mare Adriatico centrale. Complessivamente tutti i risultati hanno dimostrato che il M. galloprovincialis è una buona specie sentinella per i FANS, e il reale pericolo ecotossicologico dei farmaci nel Mediterraneo.Pharmaceuticals represent a major environmental concern since the knowledge on their occurrence, distribution and ecotoxicological potential is still limited particularly in coastal areas. In this thesis the sensitivity of the Mediterranean mussels Mytilus galloprovincialis toward different Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) was assessed, applying an integrated approach which combined laboratory studies with field investigation. In laboratory conditions mussels were exposed to different environmental realistic concentrations (25, 2.5 and 0.5 μg/L) of acetaminophen AMP, diclofenac DIC, ibuprofen IBU, ketoprofen KET and nimesulide NIM, for different periods (from 14 to 60 days). The ecotoxicological potential of NSAIDs was evaluated combining chemical analyses on pharmaceuticals bioaccumulation with a multi-biomarker approach, based on a wide array of molecular and subcellular responses reflecting early warning signals of biological disturbance, modulation of specific cellular pathways, onset of various typologies of cellular damages and toxicity. For some experimental condition, functional alteration at cellular level were further integrated with transcriptomic changes at molecular level using DNA microarray. Obtained results demonstrated that mussels are able to bioconcentrate DIC, IBU and NIM without dose dependent response, while AMP and KET are never detected independently from the doses and the exposure period. Nonetheless, for all tested NSAIDs and in all experimental conditions, measurement of a large panel of ecotoxicological biomarkers highlighted impairment of immunological parameters, modulation of lipid metabolism and genotoxic effects. The analyses on transcriptomic profile highlighted changes at molecular level for organisms exposed to lower doses, both in short (for KET and NIM) and long-term condition (for KET). Molecular results supported changes obtained at cellular level and suggest similar mechanisms of action of NSAIDs in mammals and vertebrates. Long-term responses allowed to determine that the effects of anti-inflammatory pharmaceuticals were constantly maintained over 60 days. Field studies provided the first evidence on the occurrence of DIC, IBU and NIM in tissues of wild mussels sampled during summer and spring periods from typical, touristic areas of Central Adriatic Sea. Overall results demonstrated M. galloprovincialis as a good sentinel species toward anti inflammatory pharmaceuticals and the actual ecotoxicological hazard of pharmaceuticals in the Mediterranean.
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Noor, Humaira. "Immunological Effects of Haliotis Rubra Hemolymph and Hemolymph Components." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17063.
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Marine derived drugs are emerging with promises to positively intervene in a range of diseases including viral, bacterial, fungal, and to even some forms of cancers. Hemolymph of several molluscs are of particular interest for their immunomodulatory properties that enhance their anti-microbial and anti-cancerous mechanisms. Our research aims to uncover the immunological effects of Haliotis rubra hemolymph, purified hemocyanin and hemolymph permeate. Their immunomodulatory properties can be key to treating Herpes Simplex Virus -1, HSV-1, infected patients and prostate cancer patients. In this study, we cultured HaCat cells and Human oral primary and prostate cancer cell line (PC-3) to observe immunomodulatory effects of the extracts on such form of cancer. Treatment with variable concentrations of abalone sera, purified hemocyanin and the sera/hemolymph were carried out. Results show a 50% inhibition in Interleukin-6 (IL-6) expression, 21% inhibition in Interleukin-8 (IL-8) . There is an observed inhibition of IL-6 expression in permeate, AH and sera treated PC-3. Additionally, the effects also extend to IL-8. The most significant results were obtained for primary oral keratinocytes treatment with the abalone sera yielding a sharp 35 fold increase in IL-8 concentration and 23 fold increase in IL-6 concentration as compared to the untreated control. To summarize: hemolymph, purified hemocyanin and hemolymph permeate targets IL-6 and IL-8 , that will potentially help HSV-1 infected and prostrate cancer patients. Whole hemolymph permeate induces highest degree of cytokine modulation in all cell types. The permeate is found to predominantly consist of hemocyanin fragments of various sizes . Therefore, broken hemocyanin fragments, rather than whole hemocyanin molecule, has greater immunomodulatory properties. HaCat cells do not fit as a model for IL-6 and IL-8 modulation studies, although targeted modulation of these cytokines are also exhibited here on hemolymph treatments.
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Bovio, Elena. "Champignons marins d'éponges marines : biodiversité, chimiodiversité et applications biotechnologiques." Thesis, Université Côte d'Azur (ComUE), 2019. http://theses.univ-cotedazur.fr/2019AZUR4009.
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L'environnement marin est doté d’une diversité fongique encore trop faiblement explorée puisqu’on estime qu’environ 10% des champignons marins ont fait l’objet d’une étude. Dans ce contexte, le projet de thèse décrit dans ce manuscrit est focalisé sur le potentiel biotechnologique des champignons marins isolés d’éponges marines. Ces champignons sont caractérisés par une importante biodiversité et chimiodiversité susceptible de conduire à de nouvelles molécules bioactives. Il s’agit d’un projet pluridisciplinaire qui joint la mycologie, la chimie, la biochimie et les biotechnologies. Il couvre la stratégie complète de découverte de nouveaux produits naturels avec l'isolement et l'identification des souches fongiques à l’extraction et l'isolement des molécules ainsi que l’évaluation des propriétés biologiques. Le manuscrit est divisé en trois parties principales : - La première partie est dédiée à l’isolement des communautés fongiques cultivables associées à quatre éponges de l’océan Atlantique et trois éponges de Méditerranée. Nous avons obtenu au total 129 taxons parmi lesquels 84,5% ont pu être identifiées jusqu’au niveau de l’espèce via une approche polyphasique basée sur des techniques morphologiques, moléculaires et phylogénétiques. Parmi ces derniers, nous avons décrit pour la première fois deux espèces : Thelebolus balaustiformis et Thelebolus spongiae. Nos travaux ont permis de souligner la spécificité des communautés fongiques hébergées par chaque éponge ce qui laisse à penser que les éponges sont capables de recruter leur propre mycobiote. - La seconde partie est consacrée à l'étude de la diversité chimique des champignons marins associés à l'éponge Grantia compressa en utilisant l'approche OSMAC (une souche – de nombreux composés). Les résultats obtenus ont révélé les difficultés à obtenir des conditions de culture optimales. De façon générale et pour tous les champignons, les milieux riches en nutriments favorisent à la fois le développement du mycélium et la production de métabolites secondaires. Parmi les champignons isolés, Eurotium chevalieri MUT 2316 produits de nombreux métabolites, comparativement aux autres champignons. Dans ce contexte, nous avons pu isoler et caractériser dix composés. - La troisième partie est dédiée à l’évaluation des propriétés biologiques (pharmacologiques et environnementales) des différentes molécules isolées. Six composés ont montré des propriétés antibactériennes notamment l'isodihydroauroglaucine qui s’est avérée active vis-à-vis de la plupart des bactéries à Gram-positif testées et pour laquelle une activité bactéricide a pu également être décelée. La dihydroauroglaucine et le physcion inhibent complètement la réplication du virus de la grippe A tandis que la neoechinuline inhibe le virus de l'herpès simplex 1. Enfin, les différentes molécules ont été évaluées pour leurs propriétés antifoulings susceptibles de rentrer dans la composition de peintures plus respectueuses de l’environnement. Les molécules inhibent à de très faibles concentrations l'adhésion et la croissance de bactéries et de microalgues impliquées dans le biofouling. Par ailleurs, la combinaison de molécules isolées d’E. chevalieri MUT 2316 inhibe la totalité des bactéries et microalgues testées. Les travaux menés ont permis de mettre en avant l’importante biodiversité et chimiodiversité de champignons marins hébergés par les éponges. Les molécules isolées d’E. chevalieri MUT 2316 sont susceptibles de valorisation dans différents domaines de recherche tels que le développement de nouveaux médicaments ou de peintures antifoulings plus respectueuses de l’environnementMarine environment represents an untapped source of fungal diversity, where it has been estimated that about 10% of fungi have been explored until now. Due to the lack of knowledge on marine fungi and their incredible biotechnological potential, this Ph.D. thesis focuses on a highly promising group of fungi: those associated with marine sponges. These fungi are both characterized by high biodiversity and chemodiversity, being the most successful producers of new bioactive molecules. On these premises, the main goal of the research was to cover the firsts and fundamentals aspects of the natural products discovery pipeline: from the isolation and identification of fungi from sponges to the isolation of molecules and the evaluation of their biological activity. This resulted in a multidisciplinary Ph.D. project that enclosed mycology, chemistry, biochemistry and biotechnology. In a “funnel-like” perspective, using multidisciplinary experimental approaches three main parts were developed: - The first aim was to isolate the fungal communities associated with sponges using several isolation techniques to increase the number of cultivable fungi. Four and three sponges were respectively collected in the Atlantic Ocean and in the Mediterranean Sea. Overall, 129 taxa were obtained; thanks to a polyphasic approach based on morphological, molecular and phylogenetic techniques, 84.5% of them were identified at the species level. Two fungal species Thelebolus balaustiformis and Thelebolus spongiae were here first described, updating the knowledge on marine fungal diversity. This work underlined the specificity of the fungal community for each sponge, leading to think that these animals are able to recruit their own mycobiota. - The second part was based on the investigation of the chemical diversity of marine fungi associated with the sponge Grantia compressa, using the OSMAC approach (One Strain – Many Compounds). Not surprisingly, it has been difficult to define a condition that promotes both the development of the mycelium and the secondary metabolites production for all fungi; generally, rich nutrients media are the best candidates to achieve the above-mentioned results. Among the tested fungi, Eurotium chevalieri MUT 2316 produce more metabolites than any other fungus and ten pure compounds were isolated. - The third part of this Ph.D. project aimed to test the biological activity of the ten fungal molecules. Two main research fields, pharmaceutical and environmental, were chosen as potential targets. Six compounds showed antibacterial activity, with isodihydroauroglaucin active against most of the Grampositive bacteria tested also with bactericidal activity. Dihydroauroglaucin and physcion were able to completely inhibit the replication of Influenza A virus, while neoechinulin completely inhibited Herpes Simplex Virus 1. Finally, the last series of bioassays aimed to face the urgent need of environmentally friendly antifouling and highlighted several molecules already active at extremely low concentrations, inhibiting the adhesion and growth of both bacteria and microalgae. As result, a mix of few compounds produced by E. chevalieri MUT 2316 would inhibit all the bacteria and microalgae tested. In conclusion, this Ph.D. project highlighted the outstanding biodiversity and chemodiveristy of marine fungi inhabiting sponges. The molecules isolated from E. chevalieri MUT 2316 found applications in different research fields and represent promising candidates for the development of new drugs and antifouling paints
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Hagos, Selam. "Chemical Investigation of Bioactive Marine Extracts." Scholar Commons, 2018. https://scholarcommons.usf.edu/etd/7301.
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Natural products have been a fundamental source of medicinal scaffolds for decades; with sixty percent of marketed drugs. Many synthetic chemists are focused on synthesizing potent and nontoxic compounds for pharmaceutical targets, however, nature is still proving to be a source of new bioactive compounds. Produced by the host organism for defense, reproduction and communication, secondary metabolites also demonstrate promising bioactivity against human pathogens. Hence, natural product chemists continue their quest for new leads.
As a continuation of these efforts, this thesis attempts to explore fungi and sponges for new chemistry, and ultimately, new drug candidates. Antarctica is largely untapped; hence herein two Antarctic sponges were chemically investigated. This resulted in isolation and characterization of two metabolites. Concurrently, chemical investigation of fungus, from Floridian mangrove species, resulted in the isolation of two structurally diverse metabolites. Further, a dereplication process was applied to MPLC fractions, which lead to the identification of known metabolites and mycotoxins. This enabled prioritization of fractions for future studies.
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Houssen, Wael E. "Chemical, biological and molecular approaches toward drug discovery from marine organisms." Thesis, University of Aberdeen, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439971.
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The first chapter provides a comprehensive review on the current status of drug discovery from the sea, the hurdles encountered and the future trends. The second chapter describes the use of biologically guided fractionation to isolate cytotoxic compounds from the marine ascidian Sigillina signifera. The main outcome was the isolation and identification of four known compounds identified as 4-methoxy-2,2’-bipyrrole-5-carboxaldehyde, tambjamine C, tambjamine F and phenyl ethylamine. The first three compounds were shown to be responsible for the cytotoxicity shown by the crude extract. The third chapter describes the isolation and identification of a new 4-hydroxybenzoyl derivative from the aqueous extract of the marine hydroid Campanularia sp. using NMR-guided fractionation. In spite of its structural resemblance to some potent histone deacetylase inhibitors, the new compound has proved to completely lack such activity. The fourth and fifth chapters describe the use of electrophysiological techniques and Ca2+ imaging to investigate the effects of two compounds on the behaviour of different ion channels expressed on cultured DRG neurones. The first compound, latrunculin A, was shown to alter channels behaviour through disruption of the actin cytoskeleton. This study offers a new biological screen for compounds that act through the same mechanism of action. The second compound, trigonelline, was shown to induce neuronal excitability in cultured DRG neurones by suppressing the outward voltage-activated potassium current. The last chapter describes the cloning of patE gene as part of the efforts toward cloning of the gene cluster encoding the biosynthesis of the cyclic octapeptides patellamides, ascidiacyclamide and ulithiacyclamides from Prochloron didemni, the cyanobacterial symbiont of the tropical ascidian Lissoclinum patella. The aim of the project is to get a sustainable supply of such biologically active compounds.
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Carloni, Riccardo. "Electron paramagnetic resonance applications: from drug discovery to marine biology studies." Doctoral thesis, Urbino, 2021. http://hdl.handle.net/11576/2682203.
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Hatala, John W. "The feasibility of testing hair for illicit drug use in the United States Marine Corps." Thesis, Monterey, Calif. : Springfield, Va. : Naval Postgraduate School ; Available from National Technical Information Service, 2003. http://library.nps.navy.mil/uhtbin/hyperion-image/03Jun%5FHatala.pdf.
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Thesis (M.S. in Leadership and Human Resource Development)--Naval Postgraduate School, June 2003.Thesis advisor(s): Walter E. Owen, Armando X. Estrada. Includes bibliographical references (p. 75). Also available online.
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Holland, Darren C. "Marine Natural Products Biodiscovery and Meta-analysis of their Bioactivities to Improve their Potential for Drug Discovery." Thesis, Griffith University, 2022. http://hdl.handle.net/10072/416310.
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Marine natural products biodiscovery continues to evolve into an increasingly more sophisticated and multidisciplinary field. Since the first reported marine compound in the 1970’s, there have been more than 33,000 marine natural products reported in the literature with seventeen marine-derived drugs currently approved for therapeutic use worldwide. Despite this, how much do we really know about marine natural product chemical space with respect to biological activity, and are we examining these precious resources against suitable disease targets that aim to maximise their potentials for drug discovery? Currently, most marine drugs are approved for the treatment of cancer, however, because most marine natural products are inactive in these assays, should this continue to be the main emphasis for exploration of their potential bioactivity? Instead, should we be placing a larger emphasis on leveraging these precious natural resources against more suitable disease and infection targets? This thesis attempts to answer the aforementioned questions using multidisciplinary approaches toward marine natural products biodiscovery that aim to maximise the bioactivity ascribed to marine derived and/or inspired compounds for drug discovery.
The introduction to the thesis presented in Chapter 1.0 provides an informative overview focused on the history of marine natural products and their roles in modern drug discovery and development. Chapter 2.0 explores a meta-analysis of the biological activities reported for marine indole alkaloids, a diverse and increasing sub-class of marine natural products represented across most marine phyla. Our analyses found that the biological potentials for 85% of marine indole alkaloid chemical space is unexplored or undefined. Further, most marine indoles are continuing to be examined for cytotoxicity and antimicrobial activities despite the fact that they are unlikely to display meaningful activities in these assays. Using cheminformatics analyses, we have clustered the chemical diversity of marine indoles based on both, the potency of their activities in specific disease areas, and with a dataset of indole drugs and drug-leads from non-natural sources, to predict underexplored areas of potential new activity for future testing. Our findings clearly suggest that the testing of marine indoles, and marine natural products in general, continue to be conducted on a narrow breadth of bioassays and we recommend the diversification of their future testing to include non-toxic disease targets to maximise the potential of these precious resources for future drug discovery.
Using the findings from our meta-analysis of marine indole bioactivities presented in Chapter 2.0 to direct biological testing, we undertook the chemical investigation of two Australian marine invertebrates for new marine natural products. Chapter 3.0 describes the chemical re-investigation of the colonial Australian ascidian Synoicum prunum for minor components, including indole alkaloids, that remained unidentified. This resulted in the isolation and structure elucidation of eight new marine natural products, including seven prunolides and a β-carboline sulfamate, alongside the previously reported prunolides A-C. The prunolides were found to bind and inhibit the aggregation of the Parkinson’s disease implicated amyloid protein, α-synuclein. Further, prunolide B was found to contain significant inhibition of pSyn aggregate formation in a primary embryonic mouse midbrain dopamine neuron model at 0.5 μM, suggesting the prunolides, and perhaps other butenolide natural products, provide interesting scaffolds for the potential treatment of amyloidosis.
Chapter 4.0 reports six new thiazole-homologated cyclic peptides, the cyclotheonellazoles D-I, isolated and identified from a Theonella sponge species collected from the Coral Sea, Northern Australia. The type 2 azole-homologated peptides reported herein each contained up to five non-proteinogenic amino acids including the α-keto-β-amino acid protease transition state mimic, 3-amino-4-methyl-2-oxohexanoic acid (Amoha). Further, the known cyclic anabaenopeptins, the keramamides A and L, were also reisolated in this investigation affording further investigation of their biological activities. The marine peptides were examined for inhibition of SARS-CoV-2 3CL protease, an attractive antiviral therapeutic target for COVID-19. The keramamides A and L displayed the highest inhibition of the protease (IC50 1.1 and 4.6 μM, respectively), with the leucine containing cyclotheonellazoles D and H the most potent of the new peptides tested (IC50 16.1 and 6.1 μM, respectively). All of the peptides examined for cytotoxicity against human breast, ovarian, and prostate cancer cell lines were inactive up to 20 μM.
Chapter 5.0 describes the synthesis of 32 ascidian-inspired brominated indol-3-yl-glyoxylamide analogues and the exploration of their potential bioactivities against SARS-CoV-2 3CL protease, inhibition of the amyloid protein implicated in Parkinson’s disease, α-synuclein, and their effect on the cell viability of 3 human cancer cell lines (breast, prostate and ovarian cancer). Consistent with our findings in Chapter 2.0, the marine-inspired synthetic indoles had no effect on the cell viability of three cancer cell lines, but displayed interesting non-toxic activities, including promising inhibition of SARS-CoV-2 3CLpro and α-synuclein aggregation.
Chapter 6.0 reports the structure revision of a series of sponge-derived bis-indole sulfamates, echinosulfone A and the echinosulfonic acids A-D. The total synthesis of echinosulfone A, alongside reanalysis of the reported NMR spectroscopic and MS spectrometric data for the echinosulfonic acids A-D, resulted in the reassignment of their structures from sulfone and α-sulfonic acid carbamates to carbon-bridged bis-indole sulfamates.
In Chapter 7.0 we report the synthesis of the non-sulfonated scaffolds of the echinosulfonic acids C and D, alongside a series of echinosulfonic acid D and echinosulfone A inspired bis-indoles. The synthesis of the non-sulfonated echinosulfonic acids C and D, in tandem with comparative DFT NMR analysis, confirms undoubtedly our recent structure revisions published for this series of bis-indoles. The potential biological activities of the synthesised bis-indoles reported herein were explored by predictive cheminformatic cluster analyses using the results of our meta-analysis of marine indole alkaloids in Chapter 2.0. Findings from our cheminformatic analysis suggest that an interesting starting point for their future biological evaluation should examine their potential antibacterial activities, alongside unexplored areas of non-toxic activity associated with mode of action disease targets.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Environment and Sc
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Peters, Joseph Richard. "Pharmaceutical Contaminants as Stressors on Rocky Intertidal and Estuarine Organisms: a Case Study of Fluoxetine." PDXScholar, 2016. https://pdxscholar.library.pdx.edu/open_access_etds/2729.
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Contaminants such as pharmaceuticals are of increasing concern due to their ubiquitous use and persistence in surface waters worldwide. Limited attention has been paid to the effects of pharmaceuticals on marine life, despite widespread detection of these contaminants in the marine environment. Of the existing studies, the majority assess the negative effects of pharmaceuticals over an exposure period of 30 days or less and focus on cellular and subcellular biomarkers. Longer studies are required to determine if chronic contaminant exposure poses risks to marine life at environmentally relevant concentrations. Also scarce in the literature is examination of whole organism effects to identify potential community-level consequences. Two long-term studies with the antidepressant pharmaceutical, fluoxetine (the active constituent in Prozac®) were conducted to determine whether nominal concentrations detected in estuarine and coastal environments affect organism health and interactions.
First, we measured whole organism metrics in the California mussel, Mytilus californianus over a period of 107 days. Specifically, we measured algal clearance rates, growth, and condition indices for both reproductive and overall health. We found that fluoxetine negatively affects all measured characteristics, however many effects are mediated by length of exposure. Perhaps the most notable result was that mussels spiked with fluoxetine cleared less algae after 30 days of exposure. Reduced growth and condition indices likely are a consequence of improper nutrition among fluoxetine-treated mussels. Any level of fluoxetine significantly affected the gonadosomatic index after 47 days. The results from this study on mussels fill an important data gap, highlighting organism-level effects of chronic exposure periods; such data more explicitly identify the impacts of pharmaceuticals and other contaminants on marine communities and ecosystems.
Fluoxetine has also been documented to affect the behavior of fish and invertebrates, including freshwater and marine bivalves, crustaceans, and fish. Given that other crustaceans exhibited increased activity levels under fluoxetine exposure, we hypothesized that this would subject them to greater predation risk. In our second exposure study, we assessed whether a similar range of fluoxetine concentrations used in the mussel study altered the risk behavior of the Oregon mud crab, Hemigrapsus oregonensis, in response to a common predator, the red rock crab, Cancer productus. We conducted this study for 60 days, conducting day and night behavioral trials (with and without predators) four times a week. We found that crabs exposed to any amount of fluoxetine (3 or 30 ng/L) had increased activity levels relative to controls; however behaviors of 3 ng/L-spiked crabs were not always significantly different from controls. Among control crabs, day and night trials yielded similar results, where a clear response to the addition of the predator was observed. Crabs dosed with fluoxetine exhibited more foraging and active behaviors in the presence of the predator. Additionally, crabs spiked with fluoxetine at 30 ng/L had the greatest risk of mortality either by predation by red rock crabs or due to more aggressive behaviors among conspecifics. The results of this study shed light on a particularly unexplored area of contaminants research: how do psychoactive pharmaceuticals affect animal behavior when exposed to the low concentrations persisting in the aquatic environment for a prolonged period of time?
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Adendorff, Matthew Ralph. "Marine anti-malarial isonitriles : a synthetic and computational study." Thesis, Rhodes University, 2010. http://hdl.handle.net/10962/d1006674.
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The development of Plasmodium falciparum malarial resistance to the current armoury of anti-malarial drugs requires the development of new treatments to help combat this disease. The marine environment is a well established source of potential pharmaceuticals. Of interest to us are isonitrile, isocyanate and isothiocyanate compounds isolated from marine sponges and molluscs which have exhibited nano-molar anti-plasmodial activities. Through quantitative structure-activity relation studies (QSAR), a literature precedent exists for a pseudoreceptor model from which a pharmacophore for the design of novel anti-malarial agents was proposed. The current theory suggests that these marine compounds exert their inhibitory action through interfering with the heme detoxification pathway in P. falciparum. We propose that the computational methods used to draw detailed conclusions about the mode of action of these marine compounds were inadequate. This thesis addresses this problem using contemporary computational methodologies and seeks to propose a more robust method for the rational design of new anti-malarial drug compounds that inhibit heme polymerization to hemozoin. In order to investigate the interactions of the marine compounds with their heme targets, a series of modern computational procedures were formulated, validated and then applied to theoretical systems. The validations of these algorithms, before their application to the marine compound-heme systems, were achieved through two case studies. The first was used to investigate the applicability of the statistical docking algorithm AutoDock to be used for the exploration of conformational space around the heme target. A theoretical P. falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR) enzyme model, constructed by the Biochemistry Department at Rhodes University, provided the ideal model to validate the AutoDock program. The protein model was accordingly subjected to rigorous docking simulations with over 30 different ligand molecules using the AutoDock algorithm which allowed for the docking algorithm’s limitations to be ascertained and improved upon. This investigation facilitated the successful validation of the protein model, which can now be used for the rational design of new PfDXR-inhibiting anti-plasmodial compounds, as well as enabling us to propose an improvement of the docking algorithm for application to the heme systems. The second case study was used to investigate the applicability of an ab initio molecular dynamics algorithm for simulation of bond breaking/forming events between the marine compounds and their heme target. This validation involved the exploration of intermolecular interactions in a naturally occurring nonoligomeric zipper using the Car-Parrinello Molecular Dynamics (CPMD) method. This study allowed us to propose a model for the intermolecular forces responsible for zipper self-assembly and showcased the CPMD method’s abilities to simulate and predict bond forming/breaking events. Data from the computational analyses suggested that the interactions between marine isonitriles, isocyanates and isothiocyanates occur through bond-less electrostatic attractions rather than through formal intermolecular bonds as had been previously suggested. Accordingly, a simple bicyclic tertiary isonitrile (5.14) was synthesized using Kitano et al’s relatively underutilized isonitrile synthetic method for the conversion of tertiary alcohols to their corresponding isonitriles. This compound’s potential for heme detoxification inhibition was then explored in vitro via the pyridine-hemochrome assay. The assay data suggested that the synthesized isonitrile was capable of inhibiting heme polymerization in a similar fashion to the known inhibitor chloroquine. Attempts to synthesize tricyclic analogues of 5.14 were unsuccessful and highlighted the limitation of Kitano et al’s isonitrile synthetic methodology.
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Fries, Jacqueline Lee. "Chemical Investigation of Antarctic Marine Organisms & Their Role in Modern Drug Discovery." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6084.
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The chemicals produced by biological systems, whether proteins, peptides, or terpenes, will always provide an intriguing topic for researchers. Invisibly controlling every aspect of nature, these molecules are responsible for life, evolution, and death. Specifically, here is described the secondary metabolites produced by Antarctic marine organisms as well as others, and how they are used to defend or attract other animals while potentially providing health benefits to mankind. This is done through collection, extraction, and separation of individual specimens. The respective mixtures of compounds after isolation are then analyzed via spectroscopic methods such as nuclear magnetic resonance spectroscopy, mass spectrometry, and X-ray crystallography. Once identified, these compounds are tested in biological assays to provide a hypothesis for their use in nature or evidence that there may be a use for them in medicine.
For this thesis, the Antarctic organisms described are an alga, Pocamium cartilagineum, an amphipod, Paradexamine fissicauda, a sponge, Dendrilla membranosa, and one undescribed and two known deep sea coral species, Briareopsis aegeon and Plumarella delicatissima. Beyond these specific specimens, their chemistry as well as natural products from other origins were combined to create a diverse compound library for biological screening against human pathogens. This was done using computational modeling and statistical analysis of the compound library and its comparison to other known chemical libraries. The diversity and impact of these molecules are assessed.
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Hatton, Christopher Martin. "Exploring marine sponges as a source of novel chemical entities for drug development." Thesis, Cardiff University, 2015. http://orca.cf.ac.uk/74792/.
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Antibacterial resistant infections are one of the most challenging problems affecting healthcare and have developed through the overuse of antibiotics and a shortage of new treatments progressing to market. Natural products are the initial source of most antibiotics currently available and marine sponges are a known resource of novel antibacterial compounds; although well-‐studied marine sponges found in UK waters have been scarcely explored. An examination of the chemical research on sponges identified previously unstudied species for collection in both Greece and Wales. Sequential solvent gradient extraction was optimised, to best exploit the material collected, providing three crude extracts for each sponge collected. A significant difference was observed between the chemical composition of sponges collected from Greece and Wales. An efficient antimicrobial assay was developed to screen each extract against clinically relevant organisms; allowing the direct identification of activity on an eluted thin layer chromatography plate. This overlay data was used for detailed chemical analysis using high performance counter current chromatography, with some separated fractions displaying greater activity towards the bacterium methicillin resistant Staphylococcus aureus (MRSA) than vancomycin. The parent masses of compounds responsible for activity were identified by directly coupling the overlay assay data to mass spectrometry, identifying multiple novel parent masses. Dereplication of samples was completed using the database MarinLit and the construction of a molecular network to compare fragmentation patterns in mass spectra. Bacterial cultivation from Welsh sponge samples isolated 18 antibacterial strains, which were identified using 16S rRNA analysis. Four of these strains were previously uncultured. Chemical analysis was also completed, on two unstudied strains, identifying further active novel parent masses, with no parent mass crossover to the host sponge. Overall, this investigation concluded that marine sponges are excellent source of novel antibacterial compounds, which can display activity against clinically relevant bacteria equivalent to current treatments.
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Quan-Le, Diana Huynh. "Natural Products as Novel Therapies for Tuberculosis." Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18464.
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Tuberculosis (TB) continues to devastate the global population as the leading cause of death from an infectious disease. TB infects over 10 million people annually and is estimated to cost the world’s economy over US$984 billion in healthcare and productivity over the next 15 years. The current TB vaccine is only partially effective in preventing infection and any protection afforded wanes over time as the recipients reach adolescence. Furthermore, current treatment programs for TB are lengthy, complex and problematic with regards to patient non-adherence and drug misuse. As TB is endemic in areas of low socioeconomic status, these issues have led to a global pandemic of multiple drug-resistant TB. There is an urgent need for a more effective vaccine and new drugs to combat the burden of TB disease. Throughout history, natural products have been the richest source of bioactive compounds as novel vaccines and therapies. In this study, samples from a library of marine organisms and extracts from sponge-associated microflora were screened for antimycobacterial activity against Mycobacterium tuberculosis, the causative agent of TB. Samples displaying inhibitory activity were then further assessed for potency, cytotoxicity, selectivity and efficacy against drug-resistant strains of M. tuberculosis. One species of marine sponge of the Tedania genus was found to yield samples with exceptionally potent antimycobacterial activity against drug-susceptible and drug-resistant strains of M. tuberculosis. These samples were found to be non-toxic against four human cell lines and yielded twelve antimycobacterial fractions upon purification via high performance liquid chromatography. Mass spectroscopy and nuclear magnetic resonance analysis of one of these fractions identified bengamide B as a potential compound for novel TB drug lead development, being highly potent, able to work in synergy with existing TB drugs, and able to inhibit intracellular and drug-resistant M. tuberculosis. Additional screening of extracts from sponge-associated microflora resulted in the identification of two chemical classes, the mycalazals and oroidins, as potent antimycobacterial compounds. They were found to be non-cytotoxic against three human cell lines and retained antimycobacterial activity at micromolar concentrations. Overall this study has identified three chemical scaffolds from the marine biosphere, the bengamides, mycalazals and oroidins, with potential for further development as novel antimycobacterial agents. Similarly, natural products such as tree bark saponin extracts and microbial components have long been used as adjuvants to boost the immunogenicity of protein subunit vaccines. The plant-derived polysaccharide, Advax™, is an immunomodulating δ-inulin formulation which was found to enhance the protective effect of the novel CysVac2 multistage fusion protein vaccine when administered in conjunction with CpG7909 oligonucleotide and murabutide. This vaccine, termed Advax4/CysVac2, was able to induce potent antigen-specific IFNγ+/TNF+/IL-2+ triple positive polyfunctional CD4+ T cell responses and significantly reduce bacterial burden in the lungs of M. tuberculosis-infected mice at both short- and long-term timepoints post-infection. The protective efficacy of Advax4/CysVac2 also correlated with the rapid influx of neutrophils, macrophages and monocytes to the site of vaccination and the expansion of CD44+ CD8+ T cells in the lungs. When dimethyldioctadecylammonium bromide (DDA) was added to Advax4/CysVac2, it significantly increased the frequency of antigen-specific IFNγ+/TNF+/IL-2+ triple positive polyfunctional CD4+ T cell responses, and resulted in lung and splenic protection at a level on par with that conferred by BCG. Both Advax4/CysVac2 and Advax4-DDA/CysVac2 are strong candidates for further preclinical evaluation as potential lead TB vaccines.
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Carbonell, Abigail. "Identification of potential lead antimalarial compounds from marine microbial extracts." Honors in the Major Thesis, University of Central Florida, 2013. http://digital.library.ucf.edu/cdm/ref/collection/ETH/id/829.
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Malaria, caused by the parasite Plasmodium falciparum, has a long history as a global health threat. The vector-borne disease causes millions of deaths yearly, especially in developing countries with tropical climates that facilitate transmission. Compounding the problem is the emergence of drug-resistant strains due to overuse of outdated treatments. New compounds with antiplasmodial activity are needed to be developed as effective drugs against malaria. The hypothesis for this project is that marine microorganisms have a high likelihood of yielding novel antiplasmodial chemotypes because of their high diversity, which has not yet been explored for antimalarial development. In this project, microbes harvested and fermented by the Harbor Branch Oceanographic Institute in Fort Pierce, Florida were explored as sources for antiplasmodial natural products. Using a SYBR Green I fluorescence-based assay, 1,000 microbial extracts were screened for inhibition of the multidrug-resistant Plasmodium falciparum strain Dd2. Dose-response analysis was performed on 46 fractions from isolates whose extracts demonstrated greater-than or equal to] 70% inhibition of Dd2 at 1 micro]g/mL. To evaluate cytotoxicity, the MTS cell viability assay was used to calculate IC50 of extracts from active isolates in NIH/3T3 embryonic mouse fibroblasts. Several extracts demonstrated low IC50 in Dd2 and high IC50 in 3T3, suggesting that they contain potential lead antimalarial compounds. Extracts with high selectivity indices (potent plasmodial inhibition with low mammalian toxicity) have been prioritized for dereplication, with the goal of identifying novel active components that can be developed as antimalarial drugs.B.S.
Bachelors
Burnett School of Biomedical Sciences
Molecular Biology and Microbiology
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Klein, Timothy Matsiko Ninsiima. "The isolation and characterisation of novel natural products from marine bacterial symbionts." University of the Western Cape, 2015. http://hdl.handle.net/11394/4747.
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>Magister Scientiae - MScDrug-resistant infections are a global health crisis and drastically hinder the treatment options to effectively combat disease. Today, natural products remain an important source of novel drug candidates. Micro-organisms, in addition to being a source of bioactive natural products, represent a sustainable source of these compounds. As the marine environment is largely underexplored, the oceans represent a potential source of novel NPs. This study aimed at the discovery of novel NPs from bacteria associated with novel marine invertebrate species endemic to the South African coast, including a sponge Spongia (Spongia) sp. 001RSASPN and a tunicate, Pseudodistoma africanum Millar, 1954. The methodology comprised of culture-dependent and culture-independent strategies. The former involved the isolation of bacteria associated with the invertebrate species and subsequent screening for anti-microbial activity against a panel of indicator strains including a multi-drug resistant E. coli strain. Anti-bacterial activity was detected in 6.1% and 4% of bacterial isolates from the sponge and tunicate isolates respectively. The culture-independent strategy involved the use of PCR to select bioactive strains likely to contain novel NRPS or PKS secondary metabolite pathways. An NRPS A- domain exhibiting low sequence identity (65%) to reference sequences in the NCBI database was amplified from isolate PE8-15, a strain belonging to the genus Bacillus. This predicted a novel NRPS pathway within this strain. In addition, this isolate exhibited the most diverse anti-microbial profile including anti-bacterial and anti-fungal activity (A.fumigatus ATCC 46645). Therefore, as the most promising candidate, the genome of PE8-15 was sequenced following which 10 secondary metabolite pathways including bacteriocins (5), NRPS (3), siderophore (1) and a terpene pathway were identified. The A-domain amplified from PE8-15 originated from Cluster 4, and NRPS pathway predicted to encode a lipopeptide. Lipopeptides are an important class of compounds with a range of industrial applications in the pharmaceutical, cosmetic as well as food industry. The identification of potentially novel secondary metabolite pathways from even well- studied groups of organisms demonstrates the importance of sequence-based methods in natural product discovery. Furthermore, this study highlights the South African coast as a rich source of microbial natural products and should be exploited further for drug discovery.
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Knestrick, Matthew A. "From Florida to Antarctica: Dereplication Strategies and Chemical Investigations of Marine Organisms." Scholar Commons, 2018. https://scholarcommons.usf.edu/etd/7635.
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In the fight against disease and illness, nature has provided mankind some of our best therapeutics in the form of secondary metabolites. The plant, fungi and animal phyla inhabiting the Earth produce diverse and unique chemistry that can be used in our fight against disease. In the growing threat of drug resistance and pathogen evolution, the field of natural products chemistry strives to explore new biological and chemical diversity sources, and develop innovative methodology to identify and isolate new chemistry faster than ever.
The dissertation herein presented is one such effort to find new, bioactive chemistry from the marine environments. New biodiversity sources, from the tropical Floridian mangrove forests to the cold waters of the Antarctic oceans, were evaluated for the new, unique chemistry they produce. A large-scale screening of epigenetically modulated mangrove fungi was undertaken, producing a large, biologically and chemically diverse extract library. New methodology was developed in order to evaluate these extracts, leading to rapid identification and isolation of known and new bioactive metabolites. From the Southern Oceans, a collection of sponges was studied, and a new, highly unique peptide was isolated and characterized. These efforts were undertaken in the continued effort to isolate new, unique lead compounds.
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Hislop, Ewan. "Marine microbial co-cultivation and the production of novel bioactive secondary metabolites for drug discovery." Thesis, University of Strathclyde, 2017. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=28738.
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Bruß, Christina [Verfasser], and Marina [Akademischer Betreuer] Kreutz. "Impact of drugs targeting tumor metabolism on CD8 T cell effector function / Christina Bruß ; Betreuer: Marina Kreutz." Regensburg : Universitätsbibliothek Regensburg, 2020. http://d-nb.info/1210702029/34.
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Ogunmwonyi, Isoken Nekpen Henrietta. "Assessment of antibiotic production by some marine Streptomyces isolated from the Nahoon Beach." Thesis, University of Fort Hare, 2010. http://hdl.handle.net/10353/264.
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Rapidly emerging strains of bacteria resistant to most advanced antibiotics have become issues of very important public health concern. Research currently directed towards marine actinomycetes presents a vast potential for new compounds that could be able to safely and effectively target resistant species. In this regard, ten putative Streptomyces strains isolated from the Nahoon beach were selected and assessed for antibiotic production and activity against a wide range of bacteria including reference strains, environmental strain and clinical isolates. The ethyl acetate extracts of the putative Streptomyces isolates showed activities against at least 6 and up to 26 of the 32 test bacteria. Inhibition zones were found to range between 9-32 mm diameters at a concentration of 10 mg/ml. The minimum inhibitory concentrations (MICs) of the crude extracts ranged from 0.039 - 10 mg/ml and the least minimum bactericidal concentration (MBC) demonstrated was 0.625 mg/ml against a reference strain Staphylococcus aureus ATCC 6538. Time kill kinetics of all extracts revealed bacteristatic and bactericidal activities. Average Log reductions in viable cell counts for all the extracts ranged from 0.86 Log10 and 3.99 Log10 cfu/ml after 3 h interaction and 0.01 Log10 and 4.86 Log10 after 6 h interaction at MIC, 2 × MIC, 3 × MIC and 4 × MIC concentrations. Most of the extracts were speedily bactericidal at 3 × MIC and 4 × MIC resulting in over 50 % elimination of most of the test bacteria within 3 h and 6 h interaction. The partial characterization of the crude extracts by IR spectral analysis revealed possibility of terpenoid, long chain fatty acids and secondary amine derivatives compounds in the extracts. It is therefore recommended that further investigation should address the relationship between the structure of the active component of the extracts and the broad spectrum activity, as well as a rapid method for large scale production and purification and whether this group of antibiotics has any application in managing human infectious disease.
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Voser, Tanja M. "Marine Biodiscovery - An Exploration of Chemical Diversity, Antibiotic Discovery, and Invertebrate Natural Product Chemistry." Thesis, Griffith University, 2022. http://hdl.handle.net/10072/414294.
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This thesis covers a wide range of research on marine natural products with a focus on their role in drug discovery. Chapter 1 starts with a general introduction to marine natural product chemistry, describing current trends and problems. It gives an insight into the importance of the discovery of new antibiotics in this pressing time where multidrug-resistant bacteria are on the rise. Chapter 2 is a meta-analysis of current trends in marine microbial natural product research and an analysis of how much of their chemistry overlaps with the chemistry of terrestrial microbial natural products. Over the past decade, research has greatly shifted to focus on marine microbial natural products, at the expense of marine macro-organism studies. An assessment of the structural overlap between 55,817 published marine and terrestrial microbe and marine macroorganism natural products, using structural fingerprints and scaffold clustering, was enlightening. The results showed that currently 76.7% of the chemistry found in marine microbes is vastly similar to the chemistry isolated from terrestrial microbes. This overlap is mainly due to the use of terrestrial isolation and culturing methods that select for the growth of terrestrial-like bacteria instead of unique marine bacteria. As a result, the unique chemistry associated with truly marine microbe species that are in close symbiotic relationships with marine macro-organisms is being missed. Chapter 3 describes the antimicrobial assay development and screening of a large collection of Australian marine invertebrate specimens for activity against four different strains of bacteria. It resulted in 12.5% of all the specimens tested, showing activity against the drugresistant strain of Staphylococcus aureus (MRSA) but lower bioactivity rates against Pseudomonas aeruginosa (0.76%) and Escherichia coli (0.76%). This illustrates how much harder it is to find activity against Gram-negative bacteria such as P. aeruginosa and E. coli. To investigate this challenge further, drug combination screening was undertaken to assess the potential of resurrecting antibiotics, for the use against bacterial strains that have developed resistance, by combining the antibiotic with marine invertebrate extracts. The combinatorial assays were unsuccessful, thus for further investigations I concentrated on the specimens that exhibited activity in the main assay. Analysis of the sponge specimen Aaptos aaptos that showed activity against S. aureus resulted in the isolation of demethylaaptamine as the bioactive component. Small quantities of a series of peptides with molecular weights in the range of 3,000- 4,000 Da were also isolated from the sponge. Unfortunately, a detailed structure determination could not be undertaken due to COVID-19 state border restrictions, which prevented recollection of the sponge. The subsequent two chapters report on the chemistry of antimicrobial bioactive marine invertebrate extracts. Chapter 4 describes the structures of two new betaine molecules isolated from the bryozoan Amathia lamourouxi. Their structures were determined through analysis of 1D and 2D NMR and mass spectrometric data. Crude extracts of the specimen showed antimicrobial activity at 2.5 mg/mL. Although the yield of active compounds was too small to be completely isolated and identified they were associated with brominated alkaloids. Unfortunately, recollection of this species was also hindered by state border closure due to the COVID-19 pandemic. Chapter 5 describes the isolation and identification of two new amphiphilic polyamines that together with a mixture of relatives were extracted from the marine sponge Aaptos lobata. The two pure compounds and the mixture of amphiphilic compounds showed moderate bioactivity against both drug sensitive and resistant S. aureus, and P. aeruginosa. Chapter 6 describes a multiplatform investigation of the chemistry of the ascidian B. leachii. This species was targeted because it had a similar chemical profile to Aaptos aaptos, small alkaloid and large (>3500 Da) peptide and was more accessible after the COVID-19 state border closures. The investigation used different analytical tools like LC-MS and advanced NMR techniques, including DOSY to characterise the diversity of compounds found in the mixture, while MALDITOF imaging was used to identify the specific locations of these metabolites within the ascidian tissue. This study demonstrated the power of MALDI imaging to provide an insight into the chemical ecology of marine species and helped to establish relationships between marine invertebrates and their associated microorganisms. This finding will aid future specific targeting of tissue regions within marine invertebrates for symbiotic microbe isolation and identification of natural products. Finally, Chapter 7 combines and discusses all the findings of this thesis and examines the future of marine drug discovery. The research reported here has explored the chemical diversity of microbial natural products, discovered new compounds, some with antimicrobial activity, and investigated the chemistry of marine invertebrates and their interesting symbiotic relationship with microorganisms.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Environment and Sc
Science, Environment, Engineering and Technology
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Afolayan, Anthonia Folake. "Isolation and characterization of antiplasmodial metabolites from South African marine alga." Thesis, Rhodes University, 2008. http://hdl.handle.net/10962/d1003063.
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Malaria is one of the three most deadly diseases in Africa. Although there are available treatments, their efficacy has been greatly reduced over the past two decades due to the development of resistance to currently available drugs. This has necessitated the search for new and effective antimalarial agents. This project approached the search for new antimalarial compounds in two ways: (i) by screening natural products isolated from marine algae against the Plasmodium parasite and (ii) by modification of selected isolated active compounds to target 1-deoxY-đ-xylulose 5-phosphate reductoisomerase (DXR), an enzyme found in the nonmevalonate isoprenoid biosynthetic pathway of Plasmodium Jalciparum. It was envisaged that such a compound would exhibit dual action on the Plasmodium parasite. Extracts obtained from 22 marine algae were prefractionated by solvent partitioning and were screened for anti plasmodial activity against the chloroquine sensitive (CQS) P. Jalciparum D 10 strain. Overall, 50% of the algae screened produced at least one crude fraction with activity against P. Jalciparum. Extracts of the algae Sargassum heterophyllum, Plocamium cornutum, Amphiroa ephedrea and Pterosiphonia cloiophylla gave the most promising results. Fractionation of S. heterophyllum afforded three tetraprenyltoluquinols (3.1, 3.2 and 3.5) and an all-trans-fucoxanthin (3.6). Three new compounds (4.5, 4.6 and 4.7) and two known halogenated monoterpenes (4.1 and 4.4) were isolated from P. cornutum. Each of the isolated compounds from both S. heterophyllum and P. cornutum showed antiplasmodial activity with IC₅₀ values ranging from 2.0 - 15.3 μM for S. heterophyllum and 13 - 230 μM for P. cornutum. Attempts to synthetically modify halogenated monoterpene 4.4 by dihydroxylation and phosphorylation in order to inhibit the DXR enzyme was unsuccessful. However, the hemiterpene analogue (5.42) of the halogenated monoterpenes was successfully phosphorylated and dihydroxylated to give compound 5.45 which showed promising activity against DXR. The result obtained indicated that the proposed phosphorylation and dihydroxylation of the halogenated monoterpene 4.4 would result in the synthesis of a potent DXR inhibitor and therefore a potential antimalarial agent with dual mode of action on the Plasmodium parasite.
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Prinz, Eva-Marie [Verfasser], and Rolf [Akademischer Betreuer] Hempelmann. "Multifunktionalisierte magnetische Nanopartikel als Drug-Delivery Systeme / Eva-Marie Prinz. Betreuer: Rolf Hempelmann." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2012. http://d-nb.info/1051586682/34.
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Johnston, Heather Jennifer. "Development of novel analogues of the anti-proliferative marine natural product bisebromoamide : synthesis and structure activity relationship studies." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/17617.
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The linear peptide bisebromoamide was isolated by the Suenaga group in 2009 from the marine cyanobacterium Lyngbya sp. It exhibits antiproliferative activity at nanomolar levels against a wide range of cell lines. Current SAR data indicates that there is some flexibility in the structure with respect to stereochemistry, but the range of modifications that have been biologically tested is limited, as reviewed in Chapter 1. Bisebromoamide contains a number of non-commercial amino acids and an oxopropyl pyrrolidine moiety which had not been found in a natural product previously. Several new synthetic routes towards the non-commercial amino acid fragments have been developed, as described in Chapter 2, including two ring-closure-based approaches to the substituted proline derivative 4-methyl proline (4-MePro). While the presence of six amide bonds makes solid phase peptide synthesis (SPPS) an appealing approach to the synthesis of bisebromoamide, the 4-MePro moiety is attached to a thiazoline and it is well documented that the α-position of an amino acid will racemise, under both acidic and basic conditions, when attached to a thiazoline or oxazoline. Previous reports indicated that the methyl group of the thiazoline was not essential for biological activity and so to increase stability it was replaced with a thiazole. The total synthesis of a series of novel bisebromoamide analogues, via an SPPS approach which enables facile modification of the final structure, is described in Chapter 3. The simple and adaptable SPPS route developed lends itself to SAR studies and allows modifications such as an alanine scan, truncations and incorporation of modified proline derivatives to be achieved rapidly. The promising anticancer activity of bisebromoamide makes the biological activity of these analogues of particular interest and the results of current biological testing are reported in Chapter 4.
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May, Megan Katherine. "Characterizing bacterial antibiotic resistance, prevalence, and persistence in the marine environment." Thesis, Massachusetts Institute of Technology, 2019. https://hdl.handle.net/1721.1/122524.
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Thesis: Ph. D., Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Department of Biology; and the Woods Hole Oceanographic Institution), 2019Cataloged from PDF version of thesis.
Includes bibliographical references.
Antibiotics are naturally occurring chemicals in bacteria that were recently discovered and utilized by humans. Despite a relatively short time of use, anthropogenic use of antibiotics has increased natural levels of antibiotic resistance, which has caused a looming antibiotic resistance crisis, where antibiotics may not work. Understanding resistance patterns is critical to allow for continued therapeutic use of antibiotics. While resistance is often thought of in hospitals, antibiotics and antibiotic resistance genes from human activity are disposed of into nature where they are able to interact with naturally occurring antibiotics and resistance. In this dissertation, I examine the ocean as an understudied region of the environment for antibiotic resistance. The ocean represents an area of human activity with recreation and food consumption and it is an enormous region of the planet that is affected by both land and sea activities.
In Chapter 2, I explore the policies that have contributed to the antibiotic resistance crisis. I offer explanations of market and political failures that contributed to the situation, areas for growth in terms of assessing scientific knowledge, and finally, recommendations for mitigating antibiotic resistance. In Chapters 3 and 4, I collected individual bacterial cultures from Cape Cod, MA beaches to assess the phenotypic response to antibiotic resistance. I show that 73% of Vibrio-like bacteria and 95% of heterotrophic bacteria (both groups operationally defined) are resistant to at least one antibiotic. These results indicate that antibiotic resistance is prevalent and persistent on beaches over both spatial and temporal scales. In Chapter 5, I used metagenomics to assess the abundance and types of resistance genes at coastal impacted Massachusetts sites. I found that, even in sites that seem distinct in terms of anthropogenic impact, prevalence of resistance remained the same.
Finally, in Appendix A, I examined part of the TARA Ocean dataset for prevalence of antibiotic resistance genes across the world's ocean. Here, I found that there are distinctions between different ocean biomes based upon antibiotic, metal, and mobile genetic elements. This dissertation has increased the understanding of temporal and spatial dynamics of antibiotic resistance in the coastal and open ocean.
"This work has be funded by the National Science Foundation Graduate Research Fellowship under Grant No. 1122374 and a Martin Fellows for Sustainability Fellowship (both to MKM). Grants from Woods Hole Oceanographic Institution from the Coastal Ocean Institute, Grassle Family Foundation, Hill Family Foundation, and Biology Department also supported this work"--Page 6
by Megan Katherine May.
Ph. D.
Ph.D. Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Department of Biology; and the Woods Hole Oceanographic Institution)
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Desbois, Andrew P. "Antibacterial free fatty acids from the marine diatom, Phaeodactylum tricornutum." Thesis, St Andrews, 2008. http://hdl.handle.net/10023/568.
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Hayton, Joshua Blake. "Northern New South Wales Marine Invertebrate-Derived Natural Products; A Source of Bioactive S. aureus Drug-like Molecules." Thesis, Griffith University, 2017. http://hdl.handle.net/10072/365380.
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This thesis describes the development of a rapid antistaphylococcal bioassay and chemical investigation of antistaphylococcal extracts derived from marine invertebrates collected from northern New South Wales. This thesis is divided into three sections. Chapter 2 describes the development of a novel HTS antistaphylococcal bioassay and the subsequent screening of a marine invertebrate extract collection using the developed assay. Chapters 3-7 report on the isolation and structure elucidation of natural products from antistaphylococcal extracts derived from three sponges and two bryozoans. Finally, in chapter 8, the isolated natural products were investigated to determine if they were active against Staphylococcus aureus. The MIC80 of active compounds were reported as was the bacteriostatic or bactericidal mode of action of these bioactive compounds.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
Griffith School of Environment
Science, Environment, Engineering and Technology
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Mardal, Marie [Verfasser]. "Studies on the biotransformation/degradation pathways of drugs of abuse and their main human metabolites in wastewater / Marie Mardal." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2017. http://d-nb.info/1227925484/34.
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Battaglia, Dax C. "An activity-based cost analysis of the Substance Abuse Counseling Center, Marine Corps Base Hawaii." Thesis, Monterey, Calif. : Springfield, Va. : Naval Postgraduate School ; Available from National Technical Information Service, 2003. http://library.nps.navy.mil/uhtbin/hyperion-image/03Mar%5FBattaglia.pdf.
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Frevert, Marie Louise [Verfasser], and Günter Karl [Akademischer Betreuer] Stalla. "24 drugs as potential SKP2 Inhibitors : a novel approach to finding new antidepressants / Marie Louise Frevert ; Betreuer: Günter Karl Stalla." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1136270582/34.
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Gil, Escolano Alejandro. "Studies toward the synthesis of marine natural products Phormidolides B-D." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/544128.
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Marine natural products (MNPs) are, undoubtedly, highly valuable starting points for drug-development programs. Generally, MNPs show a well-defined spatial orientation that have evolved for thousands of years to interact with their biological target and the special and unique conditions present in seas, lakes, oceans and rivers allow the biosynthesis of highly potent compunds. Nowadays, the processes to discover a new drug from MNPs are bio-assay guided, giving more importance to the biological results rather than to the molecular structure. After a molecular entity has shown to be biologically relevant the next step is to determine the structural and stereochemical information of such molecule. It is at this step where the project described in this doctoral thesis started.
Phormidolides B, C and D (PM B-D) is a family of complex molecules that were isolated in 2010 by the pharmaceutical company Pharmamar S.A. during an expedition to collect samples in the Pemba Island (Madagascar). The extracts rendered a mixture of PM B-D that, once purified, were tested on an IC50 assay against three tumour cell lines. The results showed activity in the low micromolar range with a still unknown mechanism of action. After extensive HRMS, 1D-NMR and 2D-NMR techniques a possible structure was proposed.
Following previous UB doctoral theses (Dr. Adriana Lorente and Dr. Janire Lamariano) this doctoral thesis describes, as a compendium of publications, several synthetic studies with the final objective of achieving a robust total synthesis to confirm the structural information of PM B-D by chemical synthesis. After a general introduction (Chapter 1), Chapter 2 (Org. Lett. 2015, 17, 6246.) describes an optimization for the synthesis of the macrocyclic core present in PM B-D. Chapter 3 (Chem. Eur. J. 2016, 21, 7033.) deals, for the first time, with the synthesis and introduction of the most challenging part of the molecule: the bromo-methoxy-diene (BMD) moiety present at the end of the polyhydroxylated chain. After this finding, Chapter 4 (Org. Lett., 2016, 18, 4485.) illustrates the enantioselective synthesis of the polyol chain present in Oscillariolide and Phormidolides, including the previously mentioned BMD moiety. Chapter 5 reports the preparation of the fatty acids present in PM C and D. Finally, after the previous synthetic optimizations, Chapter 6 describes the first synthetic approach for the construction of this large family of natural products using a highly convergent approach.
Finally, as an annex a review article entitled “Role of the Nozaki-Hiayama-Kishi-Takai coupling in the synthesis of natural products” (Chem. Rev., 2017, 117, 8420.) is included to deeply explain the uses of this reaction used, as well, for the synthesis of phormidolide B-D. A section with the general conclusions extracted from this thesis is also included.Los productos naturales marítimos (MNPs) son puntos de partida muy válidos para programas de desarrollo de fármacos. Generalmente, los MNPs muestran una orientación espacial bien definida que ha evolucionado durante miles de años para interaccionar con su diana terapéutica y las condiciones especiales presentes en mares, lagos, océanos y ríos permiten la biosíntesis de compuestos de gran potencia. Las Formidolidas B, C y D (PM B-D) son una familia de policétidos que fue aislada en 2010 por la compañía farmacéutica Pharmamar S.A. durante una expedición para recoger muestras en Madagascar. Los extractos dieron una mezcla de PM B-D que, una vez purificadas, se ensayaron (IC50) contra tres líneas celulares de cáncer. Los resultados mostraron actividad en el rango micromolar con un mecanismo de acción desconocido. Utilizando técnicas de HRMS, 1D-NMR y 2D-NMR se determinó una posible estructura para esta familia de MNPs. Siguiendo el trabajo de tesis doctorales anteriores (el Dr. Adriana Lorente y el Dr. Janire Lamariano) esta tesis describe, como un compendio de publicaciones, varios estudios sintéticos para conseguir una síntesis total robusta que confirme la información estructural de las PM B-D. Después de una introducción general (Capítulo 1), en el Capítulo 2 (Org. Lett. 2015, 17, 6246.) se describe una optimización para la síntesis del núcleo macrocíclico presente en las PM B-D. En el Capítulo 3 (Chem. Eur. J. 2016, 21, 7033.) se explica, por primera vez, la síntesis e introducción de la parte más compleja de la molécula: el dominio bromo-metoxi-dieno (BMD) presente al final de cadena polihidroxilada. Después de este avance, el Capítulo 4 (Org. Lett. 2016, 18, 4485.) ilustra la síntesis enantioselectiva de la cadena poliólica presente en la Oscillariolida y en las Formidolidas. El capítulo 5 relata la preparación de los ácidos grasos presentes en las PM C y D. Finalmente, después de las optimizaciones sintéticas anteriores, el Capítulo 6 describe el primer enfoque sintético para la construcción de esta compleja familia de productos naturales usando una estrategia muy convergente. Finalmente, se incluye, como un anexo, una revisión titulada “Role of the Nozaki-Hiayama-Kishi-Takai coupling in the synthesis of natural products” (Chem. Rev, 2017, 117, 8420.) para explicar profundamente los usos de esta reacción usada, también, para la síntesis de las formidolidas B-D. Las conclusiones generales de este trabajo están comentadas al final de la presente tesis.
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Pinto, Alexandre. "Common scaffolds for the enantioselective synthesis of marine, plant, and amphibian cis-decahydroquinoline alkaloids." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/457969.
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Chiral amino alcohol derived lactams are a valuable scaffold for the enantioselective synthesis of alkaloids. In the present thesis the potential of this methodology was expanded and to demonstrate the synthetic utility of chiral tricyclic lactams obtainedthe enantioselective total synthesis complex cis-decahydroquinoline alkaloids was carried out. The alkaloids that were targeted for synthesis using the developed methodology were the lepadin alkaloids (marine alkaloids) and tricyclic cis-decahydroquinoline alkaloids such as cermizine B (Lycopodium alkaloids). To accomplish these objectives further studies on the functionalization of the decahydroquinoline system were required in order to install the appropriate substituents and functionalities for the synthesis of each target. During the present PhD thesis it was possible to complete the total synthesis of (+)-gephyrotoxin 287C, (−)-cermizine B, (−)-lepadin B and (+)-lepadin D and the formal total synthesis of (−)-lepadins A and C.
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Lesobre-Romiée, Cécile. "Le drug master file et son évolution." Paris 5, 2001. http://www.theses.fr/2001PA05P005.
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Bräuer, Marie-Luise [Verfasser], Jürgen [Akademischer Betreuer] Brockmöller, Michael [Gutachter] Oellerich, and Rainer [Gutachter] Mausberg. "Therapeutisches Drug Monitoring von Immunsuppressiva: Vergleich intrazellulärer Konzentrationsmessungen mit Messungen in Vollblut / Marie-Luise Bräuer ; Gutachter: Michael Oellerich, Rainer Mausberg ; Betreuer: Jürgen Brockmöller." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2018. http://d-nb.info/1172071829/34.
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Nair, Vimal [Verfasser], Hartmut [Akademischer Betreuer] Laatsch, Ulf [Akademischer Betreuer] Diederichsen, and Birger [Akademischer Betreuer] Dittrich. "Indole Alkaloids as Potential Leads in Drug Discovery and Further Secondary Metabolites from Terrestrial and Marine Bacteria / Vimal Nair. Gutachter: Ulf Diederichsen ; Ulf Diederichsen ; Birger Dittrich. Betreuer: Hartmut Laatsch." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2012. http://d-nb.info/1043779175/34.
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Rúbies, Prat Antoni. "Noves propostes per a l’anàlisi de medicaments d’ús veterinari i de toxines marines en aliments destinats al consum humà." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/403882.
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El sector de la producció ramadera i de l’aqüicultura són pilars fonamentals de la indústria alimentària, que té plantejats grans reptes, com el de poder posar a l’abast de la població quantitat suficient d’aliments i que aquests siguin saludables als consumidors.
La indústria alimentària ha anat optimitzant els seus mecanismes de producció d’aliments, i a dia d’avui són molt esteses les pràctiques de producció intensiva, que es caracteritzen per una productivitat molt elevada amb un cost econòmic relativament baix. Aquests tipus d’enfocament utilitza medicaments veterinaris per tractar els animals malalts, però també amb finalitats profilàctiques, per minimitzar el risc de contagi. L’ús de medicaments pot comportar la presència de residus dels fàrmacs en els productes alimentaris destinats a consum humà, i el risc associat és un tema que preocupa la societat.
Amb l’objectiu d’oferir a la població l’accés a aliments segurs i saludables, s’han establert límits màxims de residu (LMR) per a medicaments d’us veterinari o bé prohibició per d’altres, atenent a la seva toxicitat.
No és aquest l’únic àmbit on es regula la presència als aliments de compostos que poden suposar un risc per als consumidors; podem citar els pesticides, els contaminants ambientals, les toxines d’origen natural, etc.
El repte pels laboratoris de control és el de poder disposar de mètodes d’anàlisi prou sensibles i selectius com per poder donar compliment a la legislació. A la vegada aquests mètodes convé que siguin suficientment transversals com per poder ser aplicats a diferents matrius alimentàries, les quals poden ser de naturalesa molt diversa pel que fa a la seva composició.
Els mètodes han de ser d’elevada fiabilitat, però també ràpids i senzills.
En aquesta tesi, s’han posat a punt mètodes per l’anàlisi de residus de 3 famílies de medicaments veterinaris (avermectines, nitroimidazols i antiinflamatoris no estereoideus); moltes de les substàncies considerades tenen establerts LMR, però algunes són prohibides. Per altra banda, s’ha posat a punt un mètode d’anàlisi de toxines marines lipofíliques en mol·luscs bivalves. Les toxines estudiades tenen nivells màxims admissibles legislats.Livestock plays an important role in food industry. In the last decades, the mechanisms for food production have been optimized, based mainly in an intensive livestock farming and, as a consequence an increasing use of veterinary drugs to raise the animals. As a result of the use of veterinary drugs in livestock raising, residues can be present in foodstuff for human consumption. Nowadays, this issue is currently becoming more and more important. Also some natural processes occurring in oceans and seas (red tides) may produce natural toxins that contaminate foodstuff, such as the bivalves. Food safety laboratories need to control the presence of such residues in food of animal origin. Therefore, reliable, easy and fast analytical methods should be used in order to control an increasing amount of samples. In this thesis, simple analytical methods for the analysis of avermectins, nitroimidazoles, non- steroidal anti-inflammatory drugs (NSAIDs) and lipophilic marine biotoxins (MBTXs) have been set up and validated. These methods are base in the QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) strategy, a method that was first published for pesticide residue analysis and nowadays becoming widely used. Some of the compounds have a published MRL (Maximum Residue Limit) in some matrices of animal origin, but because of their mutagenic and carcinogenic properties, some nitroimidazoles are included in the list of prohibited substances of Regulation (EU) No 37/2010, namely dimetridazole, metronidazole and ronidazole. The instrumentation involved in the present analytical methods is UHPLC-MS/MS, (triple quadrupole, QqQ) using an electrospray ionization (ESI) interface in Multiple Reaction Monitoring (MRM) mode. The use of high resolution mass spectrometry (HRMS), with Q-Orbitrap mass analyzer, has been tested as well. The use of HRMS has permitted to resolve coeluting isobaric interferences which did not permit confirmation of analytical results by QqQ. Also due to its excellent selectivity, very low regulated limits could be achieved. This is the case of diclofenac, a NSAIDs with a very low MRL in milk (0.1 µg·kg-1). Different working modes of the Q-Orbitrap mass analyzer have been tested, among them, t-SIM-ddpp (target-sim-data-dependent) and t-MS/MS (target- MS/MS). Validation of the methods included in this thesis has been performed following European legislation rules included in the 657/2002/CE Decision with excellent results. CCα (decision limit) and CCβ (detection capability) have been calculated as well. Limits of quantification (LQ) of the analytical methods for veterinary drugs residues range between 0.5- 2.5 µg·kg-1. For MBTX, LQ has been set up at 25 µg·kg-1. The validated matrices are muscle, milk and mussel, but all methods have been tested in alternatives matrices with successful results. Avermectin analysis has been tested in liver and milk; nitroimidazole analysis in kidney and liver, NSAIDs analysis in kidney and MBTXs analysis in canned and processed bivalves. The methods have been implemented in the Laboratori de l’Agència de Salut Pública de Barcelona for control analysis and are used for routine analysis.
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Anzicek, Nika. "Studies towards a second-generation synthesis of the aplyronines." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/267831.
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The aplyronines are a family of 24-membered macrolides of polyketide origin, isolated from the Japanese sea hare Aplysia kurodai. They exhibit an exceptional biological activity profile, acting through an actin and tubulin dual-targeting mechanism, with subnanomolar growth inhibitory potency against a diverse range of cancer cell lines. These characteristics render the aplyronines ideal payloads for antibody-drug conjugates but their prohibitively low natural abundance calls for an efficient total synthesis to overcome the supply issue. This dissertation describes the efforts towards developing a second-generation Paterson synthesis of the macrocyclic core of the aplyronines, focused on improving the scalability and selectivity of key transformations. Chapter 1 details the isolation, biological background and previous synthetic efforts towards the aplyronines to illustrate their therapeutic potential and the challenges associated with material sourcing by chemical synthesis. Chapter 2 presents the existing body of work on the aplyronine project within the Paterson group, highlighting the lessons learned over the past two decades and shortcomings to be addressed. Chapter 3 discusses a revised protecting group strategy towards the C1-C27 macrocyclic alcohol 159 with fewer manipulation steps. A refined reaction sequence featuring titanium aldol methodology and an enzymatic desymmetrisation process delivered multigram stocks of the C15-C27 aldehyde 161 upon scale- up, testifying to the robustness of the devised route. Synthesis of the C1-C14 northern fragment 253 closely followed the existing boron aldol approach with optimisation of the C11-C12 alkylation step, geared towards enhancing the regioselectivity. Chapter 4 describes the coupling of the two major fragments using an Horner-Wadsworth-Emmons reaction to assemble the C1-C27 backbone of the cyclic aplyronine core and suitably adjusted endgame steps to enable a one-step oxidative unmasking of the macrolactonisation sites. The first-generation intermediate 159 was accessed via site-specific Yamaguchi esterification and orthogonal deprotection of the C27 allyl carbonate. Discussion in Chapter 5 includes the appendage of the C28-C34 side chain 118, prepared by the known sequence, and suggestions for the future direction of the second-generation route with the outlook of linker appendage for the purposes of antibody-drug conjugate development.
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Sleigh, James Nicholas. "Model systems for exploring new therapeutic interventions and disease mechanisms in spinal muscular atrophies (SMAs)." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:378416c5-a586-4a2a-980c-81dfff6803df.
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Spinal muscular atrophy (SMA) and Charcot-Marie-Tooth disease type 2D (CMT2D)/distal SMA type V (dSMAV) are two incurable neuromuscular disorders that predominantly manifest during childhood and adolescence. Both conditions are caused by mutations in widely and constitutively expressed genes that encode proteins with essential housekeeping functions, yet display specific lower motor neuron pathology. SMA results from recessive inactivating mutations in the survival motor neuron 1 (SMN1) gene, while CMT2D/dSMAV manifests due to dominant point mutations in the glycyl-tRNA synthetase (GlyRS) gene, GARS. Using a number of different model systems, ranging from Caenorhabditis elegans to the mouse, this thesis aimed to identify potential novel therapeutic compounds for SMA, and to increase our understanding of the mechanisms underlying both diseases. I characterised a novel C. elegans allele, which possesses a point mutation in the worm SMN1 orthologue, smn-1, and showed its potential for large-scale screening by highlighting 4-aminopyridine in a screen for compounds able to improve the mutant motility defect. Previously, the gene encoding three isoforms of chondrolectin (Chodl) was shown to be alternatively spliced in the spinal cord of SMA mice before disease onset. I performed functional analyses of the three isoforms in neuronal cells with experimentally reduced Smn levels, and determined that the dysregulation of Chodl likely reflects a combination of compensatory mechanism and contributor to pathology, rather than mis-splicing. Finally, working with two Gars mutant mice and a new Drosophila model, I have implicated semaphorin-plexin pathways and axonal guidance in the GlyRS toxic gain-of-function disease mechanism of CMT2D/dSMAV.
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Kamberovic, Farah. "Searching for innovative antitumoral drugs in marine microalgae." Master's thesis, 2019. http://hdl.handle.net/10400.1/13994.
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Cancer is one of the leading causes of death globally. Current available chemotherapeutics are aggressive and not specific to cancer cells, causing damage and death of healthy cells as well. As a consequence, the number of side-effects in patients arise. Another important therapeutic issue is the development of resistance and/or development of secondary malignancies. In some types of cancer, such as hepatocellular carcinoma (HCC) and acute monocytic leukaemia (AML), chemotherapy is associated with high mortality rate. This points out to the need to search and identify new sources of anti-cancer drugs with high selectivity and toxicity only for malignant cells, while conserving healthy cells.
Marine microalgae are a rich source of different bioactive metabolites (e.g. poly-unsaturated fatty acids, carotenoids, polysaccharides, phenols, sterols, vitamins) with anti-inflammatory, anti-bacterial, anti-diabetic and anti-hypertensive properties, among others. During the past few years, marine microalgae have been featured in cancer research. In this research, we studied the cytotoxic effect of six selected microalgae species against adherent (HepG2) and suspended (THP-1) human cancer cell lines.
The ethanolic extract of Phaeodactylum tricornutum was the most bioactive with an IC50 of 19.4±2.2 μg/mL for HepG2 cells. In addition, this extract was highly selective for HepG2 cells (SI=4.40) in comparison with a non-tumoural derived cell line (S17). The active extract was further subjected to bio-guided fractionation process to obtain four fractions: hexane, dichloromethane, ethyl-acetate and water with ethanol. Among these fractions, the dichloromethane fraction displayed high cytotoxicity towards both HepG2 and THP-1 cell lines with IC50 of 27.5±1.6 and 22.3±1.8 μg/mL, and selectivity of SI>4.54 and SI>5.60, respectively.
In order to tentatively identify compounds responsible for the observable cytotoxic effect, the dichloromethane fraction was analysed by gas chromatography – mass spectrometry (GC/MS). Thirteen molecules with potential anti-cancer properties were identified, belonging to six different classes of metabolites: saturated fatty acids (SFA), polyunsaturated fatty acids (PUFAs), sterols, vitamins (dl-α-Tocopherol), phenols and terpenoid alcohols. The most abundant compounds detected were hexadecanoic acid, 9-hexadecenoic acid and 5,8,11,14,17-Eicosapentaenoic acid (EPA).
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Lin, Chun-kuang, and 林俊光. "Development of antiviral drugs from marine natural products and investigation of drug target against virus." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/9s549w.
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博士國立中山大學
海洋生物科技博士學位學程
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Hepatitis C virus (HCV) infection causes chronic inflammation of liver, leading to the development of cirrhosis and hepatocellular carcinoma (HCC). Infection of dengue virus (DENV) caused diseases ranging from acute self-limiting febrile illness to life-threatening dengue hemorrhagic fever and dengue shock syndrome. The purposes of present dissertation are to discover the anti-viral agents from marine natural products and to investigate the impact of cellular factors on DENV replication. For finding the potential antivirals, we found that betulinic acid (BA) and acteoside (AM-4) extracted from Avicennia marina could reduce HCV replication. The mechanism study demonstrated that BA reduced HCV replication through decreasing the NF-κB- and ERK1/2-mediated cyclooxygenase-2 (COX-2) expression. The AM-4 suppressed HCV infection by blocking viral entry into cells and cell-to-cell spread of HCV. In addition, we identified that lobohedleolide extracted from soft coral exhibited anti-HCV activity by suppression of HCV-induced COX-2 expression. Using various COX-2 promoter deletion constructs linked to luciferase reporter gene, we first identified CCAAT/enhancer-binding protein (C/EBP) as a key transcription factor for the down-regulation of COX-2 by lobohedleolide, and then demonstrated that the HCV-induced C/EBP expression could be suppressed by lobohedleolide through inhibiting the phosphorylation of JNK and c-Jun. Notably, combination treatment of BA, AM-4 and lobohedleolide with several clinically used HCV drugs synergistically inhibited HCV RNA replication, indicating that these three natural products exhibited a high biomedical potential to be used as a supplementary agent for control of HCV infection. Besides, BA and lobohedleolide also exhibited anti-DENV activity. For finding the therapeutic targets from cellular gene against DENV, we observed an increased level of COX-2 in patients with dengue fever compared with healthy individuals. Then, an elevated level of COX-2 expression was also observed in DENV-infected ICR suckling mice. COX-2 gene silencing and catalytic inhibition sufficiently suppressed DENV-2 replication. Using ICR suckling mouse model, we identified that the COX-2 inhibitor NS398 protected mice from succumbing to life-threatening DENV-2 infection, revealing targeting COX-2 is a promising strategy to control DENV infection. In addition, we found that the expression of prostasin, a serine protease, is lower in patients with dengue fever than in healthy individuals. Exogenous expression of prostasin could protect ICR suckling mice from life-threatening DENV-2 infection and reduce DENV-2 propagation in Huh-7 cells. We further revealed that prostasin reduced DENV replication through proteolytic cleavage of epithelial growth factor receptor (EGFR). The activity of proteolytic cleavage of prostasin is dependent on the expression of matriptase and hepatocyte growth factor activator inhibitor type 2 (HAI-2). Collectively, COX-2 and prostasin exhibited highly potential to serve as therapeutic targets against DENV replication.
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"Synthesis of Marine Chemicals and Derivatives as Potential AntiâCancer Drugs." East Tennessee State University, 2008. http://etd-submit.etsu.edu/etd/theses/available/etd-0821108-120401/.
Full text
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"The anticlastogenic study of selected Chinese medicinal herbs and marine algae." 2001. http://library.cuhk.edu.hk/record=b5890796.
Full textAbstract:
Chan Wai-Lung, William.Thesis submitted in: December 2000.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2001.
Includes bibliographical references (leaves 124-131).
Abstracts in English and Chinese.
Abstract --- p.i
Abstract (Chinese Version) --- p.iii
Acknowledgements --- p.v
Table of Contents --- p.vi
List of Tables --- p.ix
List of Figures --- p.xii
List of Abbreviations --- p.xvi
Chapter 1 --- Introduction --- p.1
Literature Review --- p.4
Chapter 1.1 --- A Brief Introduction of Cancer --- p.4
Chapter 1.2 --- Natural Products as a Drug --- p.5
Chapter 1.2.1 --- Development of terrestrial plants as a drug --- p.6
Chapter 1.2.1.1 --- Anticancer drugs from terrestrial plants and Chinese medicinal herbs --- p.7
Chapter 1.2.2 --- Development of marine organisms as a drug --- p.8
Chapter 1.2.2.1 --- Anticancer drugs from marine organisms --- p.9
Chapter 1.3 --- Anticlastogenic Study - an Anticancer Study --- p.10
Chapter 1.3.1 --- Anticlastogenesis mechanisms study --- p.11
Chapter 1.3.2 --- In vivo anticlastogenic study --- p.13
Chapter 1.4 --- Anticlastogenic Study of Chinese Medicinal Herbs and Marine Algae --- p.17
Chapter 1.4.1 --- Selection of nine Chinese medicinal herbs and three marine algae for anticlastogenic screening --- p.18
Chapter 1.5 --- Methods of Investigation --- p.20
Chapter 1.5.1 --- Extraction methods --- p.20
Chapter 1.5.2 --- Single cell gel electrophoresis (Comet assay) --- p.21
Chapter 2 --- Materials and Methods --- p.27
Chapter 2.1 --- Materials --- p.27
Chapter 2.1.1 --- Chinese medicinal herbs --- p.27
Chapter 2.1.2 --- Marine algae --- p.27
Chapter 2.1.3 --- Animals --- p.27
Chapter 2.1.4 --- Chemicals and solutions --- p.28
Chapter 2.2 --- Methods --- p.31
Chapter 2.2.1 --- Crude extraction of natural products --- p.31
Chapter 2.2.1.1 --- Water extraction of Chinese herbs --- p.31
Chapter 2.2.1.2 --- Water extraction of marine algae --- p.31
Chapter 2.2.2 --- Test for the effective dosage of clastogen ethyl methanesulfonate (EMS) to BALB/c mice --- p.31
Chapter 2.2.2.1 --- In vitro test --- p.32
Chapter 2.2.2.2 --- In vivo test --- p.32
Chapter 2.2.3 --- Anticlastogenic bioassays --- p.33
Chapter 2.2.3.1 --- In vitro anticlastogenic screening --- p.33
Chapter 2.2.3.2 --- In vitro anticlastogenic mechanisms investigation --- p.33
Chapter 2.2.3.3 --- In vivo anticlastogenic screening --- p.34
Chapter 2.2.3.4 --- Different in vivo anticlastogenic treatment schedules --- p.35
Chapter 2.2.4 --- Single cell gel electrophoresis assay (Comet assay) --- p.36
Chapter 2.2.5 --- White blood cell viability determination --- p.37
Chapter 2.2.6 --- Statistical analysis --- p.38
Chapter 3 --- Results --- p.40
Chapter 3.1 --- Extraction amount of different natural products and cell viability checking --- p.40
Chapter 3.1.1 --- Chinese medicinal herbs --- p.40
Chapter 3.1.2 --- Seaweeds --- p.40
Chapter 3.1.3 --- Cell viability --- p.42
Chapter 3.2 --- Effective dosage of clastogen EMS to BALB/c mice peripheral white blood cells --- p.42
Chapter 3.2.1 --- In vitro --- p.42
Chapter 3.2.2 --- In vivo --- p.42
Chapter 3.3 --- In vitro anticlastogenic screen test and mechanisms investigation --- p.44
Chapter 3.3.1 --- In vitro anticlastogenic screen test --- p.44
Chapter 3.3.1.1 --- Chinese herbs --- p.44
Chapter 3.3.1.2 --- Seaweeds --- p.53
Chapter 3.3.2 --- In vitro anticlastogenic mechanisms investigation --- p.55
Chapter 3.3.2.1 --- H. dilatata --- p.56
Chapter 3.3.2.2 --- S. angustifolium --- p.56
Chapter 3.3.2.3 --- S. siliquastrum --- p.63
Chapter 3.4 --- In vivo anticlastogenic screen test and mechanisms investigation --- p.66
Chapter 3.4.1 --- In vivo anticlastogenic screen test --- p.66
Chapter 3.4.1.1 --- Chinese herbs --- p.66
Chapter 3.4.1.2 --- Seaweeds --- p.73
Chapter 3.4.2 --- Different treatment methods in in vivo anticlastogenic test --- p.86
Chapter 3.4.2.1 --- Simultaneous application method --- p.86
Chapter 3.4.2.2 --- Pre-drug treatment method --- p.91
Chapter 3.4.2.3 --- Post drug treatment method --- p.91
Chapter 4 --- Discussion --- p.94
Chapter 4.1 --- Cell viability and water extracts in Chinese medicinal herbs and marine algae --- p.94
Chapter 4.2 --- Clastogenic effect of EMS to pWBCs of BALB/c mice --- p.94
Chapter 4.3 --- In vitro anticlastogenic screen test of nine water extracts of Chinese medicinal herbs and three water extracts of marine algae --- p.99
Chapter 4.4 --- In vitro anticlastogenic mechanisms investigation of three \03 marine algae extracts --- p.103
Chapter 4.5 --- In vivo anticlastogenic screen test of Chinese herbs extracts and seaweeds extracts --- p.108
Chapter 4.6 --- Different administration methods in in vivo anticlastogenic test --- p.115
Chapter 4.6.1 --- Intraperitoneal route of administration --- p.115
Chapter 4.6.2 --- In vivo pre- and post-treatment methods --- p.116
Chapter 5 --- Summary and Conclusion --- p.120
References --- p.124
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Zaleta-Pinet, Diana A. "Drugs from nature: 1. dynamin I inhibitors from Mexican marine algae; 2. chemical investigation of an Australian Aboriginal traditional remedy." Thesis, 2014. http://hdl.handle.net/1959.13/1041664.
Full textAbstract:
Research Doctorate - Doctor of Philosophy (PhD)The biological activity of 45 crude ethanolic extracts obtained from Mexican algae collected in the Baja California Peninsula were assessed. Extracts were tested for their antibacterial activity against the human pathogenic bacteria Staphylococcus epidermidis, Enterococcus faecalis and Moraxella catarrhalis and also for their inhibition towards dynamin I enzyme using a colourimetric assay. From the initial 45 extracts, 18 extracts were deemed suitable for further investigation because they showed significant activity in either one or both bioassays, representing a 40% hit rate. From the active extracts, 4 were selected for further fractionation. The ethanolic extract of the brown alga Dictyopteris delicatula was selected based on its antibacterial activity. Fractionation of the crude extract resulted in different active fractions which suffered loss of its activity in the last separation step. This activity loss suggested the presence of synergy within the compounds present in the fractions. A compound was isolated from an active fraction but due to its volatile nature it evaporated while 13C NMR data was being acquired and no structure elucidation was possible. Comparison of the 1H NMR obtained from the isolated compound with previous compounds isolated within the genus Dictyopteris suggested the prences of structures similar to the dictyopterenes. Fractionation of the crude extract obtained from brown alga Colpomenia tuberculata led to 3 fractions that presented inhibition against dynamin I. The 1H NMR spectrum of the fractions were similar but did not show any signs of a compound responsible for the activity. Further fractionation of this compound was impossible due to the rapid decomposition of the extract as well as the fractions. Chemical investigation of the crude extract of Laurencia pacifica was done based on its antibacterial activity as well as its activation of dynamin I. Fractionation of the extract resulted in the isolation of five pure compounds that were identified as isolaurenisol, isoaplysin, debromoisolaurinterol, debromoaplysinol, laur-11-en-10-ol and a 1:1 mixture of compounds 3α hydroxydebromoaplysin and 10-bromo-1,7-dien-3-ol, the latter one being reported for the first time. Antibacterially active compounds were found to be compounds isoaplysin, isolaurenisol, debromoisolaurinterol and debromoaplysionol, as previously reported; none of the isolated compounds presented dynamin I or dynamin II inhibition. Compounds were also tested against 11 cancer cell lines and 1 normal cell line. In this assay isoaplysin, isolaurenisol and debromoaplysionol presented higher activity and were selected for a second round of cancer biological testing where isoaplysin was shown to be the most active. Fractionation of the crude extract of Codium simulans that was selected for its inhibition towards dynaimin I led us to the isolation of a sterol, that was the main constituent of the crude extract. Based on the 1H and 13C data it was identified as clerosterol, which has been previously reported as the major sterol constituent of other Codium species. Clerosterol was found to be biologically inactive in inhibiting the enzymatic activity of dynamin I and dynamin II. In a second study, the medicinal potential of an Australian Aboriginal remedy, given to us by the Ngarrabul people, was evaluated. The traditional medicine is prepared as a tea with a native plant that was identified as Myoporum montanum. The acetone extract of the plant yielded six different furanosesquiterpenes: (+)myoporone, (–)-10,11-dehydromyoporone, (–) 10,11-dehydroisomyodesmone, (–)-10,11-dehydromyodesmone and the myoporum ketols as well as the constituent phytol. These furanosesquiterpenes have been previously isolated from Myoporum spp. and have been reported as being toxic. In addition to the furanosesquiterpenes, 14 carbocyclic sesquiterpenes were identified by GCMS as constituents of the acetone extract, which had antibacterial activity. Subsequently, the chemical investigation of the medicinal tea revealed the presence of three of the furanosesquiterpenes: myoporone, dehydromyoprone, and a new furanosesquiterpenes named 11 hydroxymyoporone. These compounds were assessed in the antibacterial assay, as well as a cytotoxic assay, where they showed high antibacterial activity but low cytotoxicity versus cancer cells.
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Kamat, Siya. "Investigation of anticancer compounds in the natural productome of marine algae associated-endophytic fungi." Thesis, 2022. https://etd.iisc.ac.in/handle/2005/6032.
Full textAbstract:
Cancer is one of the leading causes of death worldwide. Owing to the complex ways in which this disease develops, there is a constant demand for new drugs. Natural products have delivered great promise in inspiring chemotherapy, for example, Taxol, Trabectedin, Plinabulin, Marizomib, Midostaurin, etc. Endophytic fungi have potentiated this promise by producing potent bioactive compounds. They live symbiotically in the internal tissues of higher organisms. Marine endophytic fungi offer a diverse chemical space for the discovery of novel anticancer compounds, sustainably. Marine endophytes demonstrate a higher chemical diversity, possibly due to immense competition and abiotic and biotic stress. These secondary metabolites are highly potent at minuscule concentrations because they act in dilute environments over larger distances.
In this study, 26 endophytic fungi were isolated and identified from 10 marine algal samples collected from the Konkan coast, India. This work led to the first diversity study of marine algae-associated endophytic fungi of the Konkan coast. All the fungal extracts were screened for cytotoxicity on several human cancer cell lines, A431, HeLa, A549 and MCH-7. Three endophytic fungi, Aspergillus unguis AG 1.1 (G), Chaetomium globosum PG 1.6, and Aspergillus unguis AG 1.2, were chosen for further study as their IC50 values were < 10 μg/mL.
Chrysin, a dihydroxyflavone was purified and reported for the first time from a marine endophyte C. globosum. It was so far known to be found in honey and passionflower. It induced apoptosis, G1 phase cell cycle arrest, MMP loss, and ROS production in MCF-7 cells. Further, using metabolic profiling of C. globosum, several key intermediates of the chrysin biosynthesis pathway were identified, thus, proving the presence of flavonoid biosynthetic machinery in the marine fungus. The yield of chrysin was enhanced using optimization of several media and fermentation parameters, inducing abiotic and biotic stresses and elicitation. The free use of chrysin in clinical scenarios is disadvantaged due to poor solubility at physiological pH, rapid metabolism, and low bioavailability. In this study, chrysin nanoparticles (NChr) were prepared by optimization of several physico-chemical parameters using response surface methodology. The apoptotic effect of NChr was studied in HeLa cells by Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy.
This work also reports the isolation and characterization of a novel isoquinoline derivative from A. unguis AG 1.1 (G). It had a N-heterocyclic steroid-like structure with a lactone moiety. The compound demonstrated maximum cytotoxicity in A549 cells with an IC50 of 18.8 μM after 48 h. It induced G1 phase cell cycle arrest, disruption of mitochondrial membrane potential, production of reactive oxygen species and caspase 3/7 activation, leading to apoptosis.
This work highlights the immense potential of marine natural products that can introduce highly impactful drugs into the pharmaceutical market.
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Nair, Vimal. "Indole Alkaloids as Potential Leads in Drug Discovery and Further Secondary Metabolites from Terrestrial and Marine Bacteria." Doctoral thesis, 2010. http://hdl.handle.net/11858/00-1735-0000-0006-B084-F.
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Thornburg, Christopher C. "Investigation of unique marine environments for microbial natural products." Thesis, 2013. http://hdl.handle.net/1957/37941.
Full textAbstract:
Metagenomics has revealed that the marine microbial biosphere is immensely more diverse than originally considered, and is an almost untapped reservoir for the potential discovery of microbial natural products. Despite numerous advances in culturing, biosynthetic engineering and genomic-based screening efforts to uncover much of this diversity in relatively accessible environments, a high rediscovery rate has resulted in the investigation of unique, relatively unexplored ecosystems harboring phylogenetically diverse communities of marine organisms. The focus of this research was to establish a culture repository of microorganisms collected from the Red Sea and from deep-sea hydrothermal vents, and to assess their biosynthetic potential for the production of new chemical scaffolds. Cultivation of marine cyanobacteria from the Red Sea has led to the identification of five new cyclic depsipeptides, apratoxin H, grassypeptolides D and E, Ibu-epidemethoxylyngbyastin 3 and leptochelin, the latter possessing a unique chemical scaffold capable of binding metals. A collection of deep-sea hydrothermal vent sediment and microbial mat samples led to the isolation of 64 unique bacterial strains, with eight assigned as members of the order Actinomycetales. Importantly, these isolates, along with a collection of deep-vent invertebrates and microbes, have led to the development of methods for the collection, culturing and biological screening of organisms from this extreme environment for future natural products research.Graduation date: 2013