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1
Stacey, N. A. "An approach to avermectin and milbemycin synthesis." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379897.
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Dewi, Ariyanti Suhita. "Biologically active secondary metabolites from tropical marine invertebrates." Thesis, University of British Columbia, 2009. http://hdl.handle.net/2429/15299.
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In our effort to discover promising anticancer agents, we have screened a series of
compounds for their activities as indoleamine-2,3-dioxygenase (IDO) inhibitor and SHcontaining
inositol 5-phosphatase (SHIP1) activator. In comparison to aaptamine (2.1) and
demethylaaptamine (2.2), isoaaptamine (2.4) from Aaptos cf. suberitoides appears to be the most
promising IDO inhibitor with an IC₅₀ of 0.00215 mg/mL, owing to the presence of hydroxyl
group at C9 position and the methylation at N1 position. A study on the sponge extract of RJA
55275 for its SHIP activator yielded theonellapeptolide Id (3.4), the first peptide that enhanced
the SHIP with 25% activity at concentration 124 μM, thus makes it the most potent SHIP
activator known to date. The third project studied the crystals of a novel eunicellin-based
diterpenoid (4.39) with a modest SHIP activity from an unidentified Micronesian soft coral RJA
47686. The X-ray analysis illustrated that the crystals are monoclinic, space group P21/b, with a
= 9.3711(14) A; α = 90⁰; b = 13.5349(17) A; β = 99.142(7)⁰; c = 10.9891(17) A; γ = 90⁰; V =
1376.1 (3) ų; Z value = 2; Dcalc 1.189. 10-³ g/cm³; F₀₀₀ 536.00; Cu (MoKα) 0.84 cm-¹.
Based on the NMR and x–ray data 4.39 was shown to possess (1R*, 2R*, 3R*, 6R*, 7S*, 10R*,
14R*, 18R*)-configuration with an ether linkage connecting C2 and C6.
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Chapman, Robert Laurence. "Biologically active secondary metabolites of the fungus, Aspergillus flavipes /." The Ohio State University, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487843314694226.
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Vinayavekhin, Nawaporn. "Metabolomics Strategies for Discovery of Biologically Active or Novel Metabolites." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10150.
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Along with genes and proteins, metabolites play important roles in sustaining life. There remains much to be learned about the in vivo roles of metabolites. Metabolomics is a comparative tool to study global metabolite levels in samples under various conditions. This dissertation describes the development and application of metabolomics strategies for discovery of biologically active or novel metabolites with priori knowledge about genes, proteins, or phenotypes. The power of metabolomics for discovery of novel metabolites from genes is demonstrated through the work with the pyochelin (pch) gene cluster. Comparison of the extracellular metabolomes of pch gene cluster mutants to the wild-type Pseudomonas aeruginosa (strain PA14) identified 198 ions regulated by the pch genes. In addition to known metabolites, a pair of novel metabolites were characterized as 2-alkyl-4,5-dihydrothiazole-4-carboxylates (ATCs). Subsequent assays revealed that ATCs bind iron and that their production is regulated by iron levels and dependent on pchE gene in the pch gene cluster. Metabolomics can also facilitate discovery of active metabolites from proteins, as shown in the work with orphan nuclear receptor Nur77. We applied a metabolomics platform for detected protein-metabolite interactions to identify lipids that bind to Nur77. Using this approach, we discovered that the Nur77 ligand-binding domain (Nur77LBD) enriched unsaturated fatty acids (UFAs) in tissue lipid mixtures. Subsequent biophysical and biochemical assays indicate that UFAs bind to Nur77LBD to cause changes in the conformation and oligomerization of the receptor. Last, analogous to classic fractionation experiments, metabolomics can also be applied to discover active metabolites from phenotypes. Using combination of genetics, biochemistry, and metabolomics, we identified three phenazine compounds produced by Pseudomonas aeruginosa that are toxic to the nematode Caenorhabditis elegans. 1-hydroxyphenazine, phenazine-1-carboxylic acid (PCA), and pyocyanin are capable of killing nematodes in a matter of hours. 1-hydroxyphenazine is toxic over a wide pH range, whereas the toxicities of PCA and pyocyanin are strictly pH-dependent at non-overlapping pH ranges. The diversity within a class of metabolites can be used to modulate bacterial toxicity in different environmental niches.Chemistry and Chemical Biology
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Kottakota, Suresh Kumar. "The synthesis of novel biologically active marine sponge secondary metabolites." Thesis, University of Sunderland, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.592881.
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Bromotyrosine-derived secondary metabolites from marine sponges of the order Verongida provide unique diversity in chemical structure and a wide range of biological activities. With a decline in the number of novel antibiotic scaffolds which are emerging and the on-going search for more effective antibacterial and anticancer drugs, these brominated metabolites are attractive candidates for further total synthesis and biological evaluation. An Efficient total synthesis of bromotyrosine alkaloids purpurealdin E (92), aplyzanzine A (122), suberedamine A (123) and B (124), iso-Anomoian A (121a) and aplysamine-2 (104) were achieved through the carbodiimide coupling of appropriate tyrosine/tyramine units in excellent yields. Their structures have been confirmed through direct comparison with spectroscopic data of isolated natural products. The key step was the one-pot Bocdeprotection, dimethylation and hydrolysis of desired intermediate, which was achieved in 88% yield. A new synthetic route was developed for the preparation of diverse analogues for biological assessment. This route utilized cheap and commercially available starting materials, and allowed access to various analogues inaccessible via currently reported methods. By utilising this route, the total syntheses of 5- bromoverongamine (207), 20-N-methylpu rpuramine E (208) , psammaplin A (150), psammaplin C (156), spermatinamine (50) and tokaradine A (209) were successfully carried out and are reported herein. These new syntheses of spermatinamine and psammaplin A are more efficient than previously reported sequences. In addition, we explored a method for the selective removal of benzyl protecting groups in the presence of both oxime and disulphide moieties. Aplyzanzine A (122) was found to be the most active product against a Grampositive bacterial and fungal screen demonstrating MIC values 2-4 times lower than the other compounds. All compounds, except purpurealdin E and psammaplin C, exhibit modest inhibition against M. bovis BCG and M. tuberculosis H37Rv. 20-N-methylpurpuramine-E (208) was most active with an MIC (5 μg/mL) towards M. bovis BCG. iso-Anomoian A (1 21a) and suberedamine B (124) showed antitumor activity in the NCI-DTP60 cell line screen at single micromolar concentrations, with iso-anomoian A (121 a) inhibiting 53 cell lines. These molecules present novel scaffolds for further optimization.
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Alenazi, Mohrah. "Extraction and Purification of Biologically Active Metabolites from Rhodococcus sp. MTM3W5.2." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/etd/3507.
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Rhodococcushas been recognized as a potential antibiotic producer. Recently, a strain of Rhodococcussp. MTM3W5.2 was isolated from a soil sample collected in Morristown, Tennessee and was found to produce an inhibitory compound which is active against other related species. The purpose of this research is to extract, purify and analyze the active metabolite. The compound was extracted from RM broth cultures and purified by preliminary fractionation of crude extract through a Sephadex LH-20 column. Further purification was completed using semi-preparative reversed phase column chromatography. Final purification was obtained using multiple rounds of an analytical C18 HPLC column. Based on the results achieved in the UV-Vis spectroscopy and high-resolution mass spectroscopy, the two desired compounds at a retention time of at 57 and 72 min could be polyketides with the molecular formulas C52H78O13 and C19H32O1N1/C13H34O1N1, respectively.
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Dajana, Kovač. "Biotehnološki potencijal filamentoznih sojeva cijanobakterija sa područja Vojvodine." Phd thesis, Univerzitet u Novom Sadu, Prirodno-matematički fakultet u Novom Sadu, 2017. https://www.cris.uns.ac.rs/record.jsf?recordId=104930&source=NDLTD&language=en.
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S obzirom da su cijanobakterije (modrozelene alge) identifikovane kao jedna odnajperspektivnijih grupa organizama za izolaciju novih i biološki aktivnih prirodnihprodukata, cilj ove teze bio je utvrđivanje biotehnološkog potencijala autohtonihfilamentoznih sojeva cijanobakterija izolovanih sa područja Vojvodine koji pripadajuazotofiksirajućim rodovima Nostoc i Anabaena i neazotofiksirajućem rodu Spirulina. Biotehnološki potencijal testiranih sojeva je određen u smislu produkcije biomase, fikobiliproteinskih pigmenata, masnih kiselina, fenolnih jedinjenja, antioksidanata, antibakterijskih i antikancerogenih agenasa. Dobijeni rezultati su pokazali da su produkcija biomase i sadržaj fikobiliproteinskih pigmenata kod svih testiranih sojeva zavisili od primenjenih uslova kultivacije, pri čemu je kod sojeva roda Spirulina produkcija biomase bila jače stimulisana primenom kontinualnog osvetljenja, a kod azotofiksirajućih sojeva rodova Nostoc i Anabaena organskim izvorima ugljenika (glicerolom i glukozom). Kao soj sa najvećim potencijalom za proizvodnju biomase izdvaja se soj Spirulina S1, a za produkciju fikobiliproteina sojevi Spirulina S1, Nostoc 2S1, Anabaena Č2 i Spirulina S2. Određivanjem sadržaja masnih kiselina GC-FID metodom utvrđeno je da su kod svih sojeva najzastupljenije bile palmitinska, palmitoleinska, oleinska i linolna kiselina, pri čemu su sojevi roda Spirulina produkovali i γ-linolensku kiselinu, dok su svi sojevi rodova Nostoc i Anabaena produkovali -linoleinsku kiselinu. Najzastupljenije fenolne komponente testiranih etanolnih ekstrakata određene HPLC-MS/MS metodom bile su hinska kiselina i katehin, pri čemu je najveći sadržaj fenolnih jedinjenja registrovan kod soja Nostoc 2S7B. Hemijskom karakterizacijom ekstrakata kod testiranih sojeva takođe je utvrđen značaj azotnih uslova kultivacije u cilju povećanja produkcije fenolnih jedinjenja, kao i -linoleinske kiseline. Poređenjem rezultata antioksidantne aktivnosti u korišćenim testovima DPPH i FRAP, kao sojevi sa najvećim antioksidantnim potencijalom izdvajaju se Spirulina S1 i Spirulina S2. Antibakterijska aktivnost metanolnih ekstrakata registrovana je kod sojeva Nostoc 2S7B, Nostoc 2S1, Anabaena Č2, Anabaena Č5, Spirulina S1 i Spirulina S2, koji su ispoljili efekat na Gram-pozitivne i Gram-negativne bakterije, pri čemu su sojevi Anabaena Č2, Nostoc 2S7B i Nostoc 2S1 delovali na najviše bakterijskih sojeva. Kod svih testiranih sojeva je primenom MTT testa uočena antikancerogena tj. citotoksična aktivnost dimetil sulfoksidnih (DMSO) ekstrakata prema HepG2 ćelijskoj liniji, među kojima su najveću aktivnost ispoljili sojevi Nostoc LC1B i Nostoc 2S7B. Primenom bioeseja Artemia salina, Daphnia magna i Danio rerio konstatovan je mali broj sojeva koji su ispoljili toksičnost na test organizme, dok na ćelijsku liniju RTL-W1 testirani sojevi nisu ispoljili citotoksičnost in vitro, što sa aspekta potencijalne biotehnološke primene sojeva ima veliki značaj. Kao najtoksičniji izdvojili su se sojevi Nostoc LC1B i Nostoc S8 koji su ispoljili toksičnost u sva tri bioeseja. Ispitivanjem toksičnosti in vitro u enzimskim esejima konstatovano je da je manji broj sojeva inhibirao aktivnost enzimaprotein fosfataze 1 (PP1) u odnosu na aktivnost enzima acetilholinesteraze (AChE). Primenom Analitičkog hijerarhijskog procesa u grupnom kontekstu, najveću težinu su dobili kriterijumi antikancerogena ativnost, produkcija biomase i sadržaj fikocijanina, navedenim redom. Konačno, u višekriterijumskom kontekstu najbolje rangiran soj jeSpirulina S1, na drugom mestu je soj Spirulina S2, dok je na trećem soj Nostoc LC1B.Cyanobacteria (blue-green algae) have been identified as one of the most promising groups of organisms for the isolation of new and biologically active natural products, therefore, the aim of this thesis was to determine the biotechnological potential of autochthonous filamentous cyanobacterial strains isolated from Vojvodina region, which belong to the N 2-fixing genera Nostoc and Anabaena and non-N2-fixing genus Spirulina. Biotechnological potential of tested strains was determined using the production of biomass, phycobiliprotein pigments, fatty acids, phenolic co mpounds, antioxidants, antibacterial and anticancer agents. The obtained results showed that the production of biomass and phycobiliprotein pigments, in all tested strains, depended on the cultivationconditions, whereas biomass production was strongly stimulated by continuous light in Spirulina strains, and by organic carbon sources (glycerol and glucose) in N2-fixingstrains. The highest potential for biomass production was shown in Spirulina S1 strain.On the other hand, the highest potential for the production of phycobiliproteins wasshown in strains Spirulina S1, Nostoc 2S1, Anabaena C2 and Spirulina S2. By determination of the content of fatty acids using GC-FID method it was found that in allthe tested strains the most common fatty acids were palmit ic, palmitoleic, oleic andlinoleic acid, whereby the strains of the genus Spirulina produced γ-linolenic acid as well,while all strains of the Nostoc and Anabaena genera produced y-linolenic acid. The most frequent phenolic compounds of tested strains determined by using the HPLC-MS/MSmethod were quinic acid and catechin, with the highest content of phenolic compounds registered in Nostoc strain 2S7B. By chemical characterization of the extracts in the tested strains it was also stated a significance of the nitrogen cultivation conditions in order toincrease the production of phenolic compounds, as well as y-linolenic acid. Comparing the results of the antioxidant activity in the DPPH and FRAP tests, it was shown that strains Spirulina S1 and Spirulina S2 had the highest antioxidant potential. The antibacterial activity of the intracellular methanolic extracts was registered in strains Nostoc 2S7B, Nostoc 2S1, Anabaena C2, Anabaena C5, Spirulina S1 and Spirulina S2, that inhibited the growth of Gram-positive and Gram -negative bacteria. Using MTT test, anti-cancer ie. cytotoxic activity of dimethyl sulfoxide (DMSO) extracts to the HepG2 cell line was detected in all tested strains, however, the highest activity was exhibited in strains Nostoc LC1B and Nostoc 2S7B . In bioassays Artemia salina, Daphnia magna and Danio rerio a small number of strains exhibited toxicity to the test organisms, while in case of cell line RTL-W1 tested strains did not show in vitro cytotoxicity, which is of great importance from the aspect of the potential biotechnological application of thestrains. Nostoc LC1B and Nostoc S8 strains induced toxicity in all three bioassays, and therefore considered as the most toxic strains. By testing in vitro toxicity in enzyme assays, it was found that few strains inhibited the activity of protein phosphatase (PP1) enzyme in relation to acetylcholinesterase enzyme (AChE) activity. Using the Analytical hierarchical process in the group context, the highest weight was given to the criteria of anticancer activity, biomass production, and the phycocyanin content, respectively. Finally, in the multi-criteria context, the best-ranked strain is Spirulina S1, Spirulina strain S2 is on the second place, while Nostoc strain LC1B is the third one.
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Alenazi, Mohrah, Jaimin kapadia, Patrick South, Abbas Shilabin, and Bert Lampson. "Extraction and purification of biologically active metabolites from the Rhodococcus sp. MTM3W5.2." Digital Commons @ East Tennessee State University, 2018. https://dc.etsu.edu/asrf/2018/schedule/71.
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Due to an increasing prevalence of bacterial resistance to antibiotic drugs and the overuse of commercial antibiotics, the need to discover novel antibacterial compounds is becoming more urgent. There is one promising avenue of novel drug discovery which has begun to be explored; the analysis of secondary metabolites. Rhodococcus is a genus of gram-positive bacterium known for their ability to catabolize a wide range of compounds, and more notably for its ability to produce bioactive secondary metabolites. Rhodococcus belongs to the class actinobacteria. A species of Rhodococcus, MTM3W5.2, has been discovered in Morristown, Tennessee and was found to produce a metabolite with inhibitory activity against closely related species. The aim of this study is to elucidate the structure of the inhibitory metabolite by first isolating and purifying it, and then characterizing it using spectroscopic techniques. The compound was isolated from MTM3W5.2 RM broth cultures using n-butanol extraction, which yielded an active crude extract. The crude extract was then subjected to fractionation using a Sephedex LH-20 column with a 100% methanol solvent. The inhibitory activity of the fractions was tested through disk diffusion assay using Rhodococcus erythropolis as an indicator of inhibitory activity. Further preparation was completed using preparative reverse-phase high-performance liquid chromatography. Advanced purification was conducted using multiple rounds of analytical reverse-phase HPLC and activity was tested at each subsequent step using disk diffusion assay. Throughout the study, the HPLC fractions were characterized and the stability was monitored using UV-Visible spectroscopy. Two pure samples at 58.63 and 72.72 minutes from HPLC (High-performance liquid chromatography) collections were selected for further structural identification and are currently being studied using spectroscopic techniques, most notably 2D NMR spectroscopy (two-dimensional nuclear magnetic resonance).
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Hooper, Gregory John. "Biologically active natural products from South African marine invertebrates." Thesis, Rhodes University, 1997. http://hdl.handle.net/10962/d1003239.
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This thesis describes the chemical and biological investigation of the extracts of six different marine invertebrate organisms collected along the South African coastline. The work on these extracts has resulted in the isolation and structural elucidation of twenty-one previously undescribed secondary metabolites; The history of marine natural product chemistry in South Africa has not previously been reviewed and so a comprehensive review covering the literature from the 1940's up until the end of 1995 is presented here. The marine ascidian Pseudodistoma species collected in the Tsitsikamma Marine Reserve was shown to contain four new unsaturated amino alcohols [47], [48], [49] and [50] which were isolated as their acetyl derivatives. These compounds exhibited strong antimicrobial activity. Four new pyrroloiminoquinone alkaloids, the tsitsikammamines A [90] to D [93],were isolated from a new genus of Latrunculid sponge collected in the Tsitsikamma Marine Reserve. These highly pigmented compounds also possessed strong antimicrobial activity. An investigation of two phenotypic colour variants of the soft coral Capnella thyrsoidea resulted in the isolation of the known steroid 5α-pregna-1, 20-dien-3-one [97] and an additional six new metabolites, 16β-hydroxy-5α-pregna-1 ,20-dien-3-one 16-acetate [98], 3α,16β-dihydroxy-5α-pregna-1, 20-diene 3,16-diacetate [99] and four xenicane diterpenes, the tsitsixenicins A [100] to D [103]. This is the first reported isolation of xenicane diterpenes from the soft coral family Nephtheiidae. Tsitsixenicin A and B showed good anti-inflammatory activity by inhibiting superoxide production in both rabbit and human cell neutrophils. A further four new metabolites were isolated from two soft corals which could only be identified to the genus level and were designated Alcyonium species A and species B. Alcyonium species A was collected in the Tsitsikamma Marine Reserve and yielded two new polyhydroxysterols, cholest-5-ene-3β, 7β, 19-triol 19-acetate [121] and cholest-5,24-diene-3β, 7β, 19-triol 19-acetate [122]. The soft coral Alcyonium species B was collected off Aliwal Shoal and was found to contain two known xenicane diterpenes, 9-deacetoxy-14, 15-deepoxyxeniculin [110] and zahavin A [16], and two new xenicane diterpenes, 7 -epoxyzahavin A [123] and xeniolide C [124]. Compounds [110], [16] and [123] exhibited strong anti-inflammatory activity and compounds [110] and [16] showed good antithrombotic activity. The endemic soft coral A/cyanium fauri collected at Riet Point near Port Alfred yielded the new sesquiterpene hydroquinone rietone [141] in high yierd, fogether with the minor compounds 8'-acetoxyrietone [142] and 8'-desoxyrietone [143]. Rietone exhibited moderate activity in the NCl's in-vitro anti-HIV bioassays.
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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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Benedetti, Brad. "Drug Design, Biological Activity, and Metabolic Consequences of Cytotoxic Platinum Compounds: Utilizing Fluorescent Tagging to Understand Drug Action and Metabolism." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/195.
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Platinum drugs are among the most commonly used chemotherapeutics for the treatment of testicular, head and neck, ovarian, small cell lung, and colorectal carcinomas. Although the current set of platinum chemotherapeutics has proven somewhat successful, the overall success of platinum based drugs is limited due to acquired drug resistance and a limited range of tumor types that are treatable with the current regime. The development of novel cytotoxic platinum based compounds, both trans- and polynuclear, provides for the promising treatment of clinical platinum drug resistant tumors. While the cytotoxic activity of platinum drugs provides for a hopeful outlook, the ultimate factors that affect the success of chemotherapeutics are the fine balance between cytotoxic activity and metabolic deactivation. In general, this work reports the drug design/drug action, and pharmacokinetic consequences of anticancer compounds aimed to fight mechanisms of cisplatin resistance. In the first project, we report the biological and biophysical studies aimed at understanding and improving upon the pharmacokinetic properties of chemotherapeutics; specifically, understanding their interactions with serum proteins. This work resulted in the discovery of using carboxylate ligands to modulate the reactivity of trans-platinum based compounds towards sulfur containing proteins with consequent effects on drug efficacy. In addition, we report an in depth look into the biological consequences of non-covalent platinum drug-protein interactions on drug efficacy, and introduce the use of novel Platinum-NBD fluorescent conjugates as probes for drug metabolism. In the second project we report the design, synthesis, and biological consequences of fluorescent drug derivatives based on the NBD fluorophore, for use in understanding drug action and drug metabolism. As a result of this fluorescent drug labeling, TriplatinNC, a non-covalent platinum based chemotherapeutic, was found to specifically target nucleolar DNA/RNA, due to its high charge, and inhibit ribosomal RNA production in cancer cells. The use of fluorescent derivatization also resulted in the development of a series of novel water-soluble trans-platinum complexes, with greater cytotoxicity than cisplatin. Therefore, these data resulted in the understanding of, and improvement upon the pharmacokinetic profile of platinum chemotherapeutics, as well as the development of novel fluorescent platinum conjugates with novel metabolic and cytotoxic profiles.
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Xu, Zhengshuang, and 許正雙. "Studies toward the total synthesis of biologically active agents I: yanucamide a and apratoxin a from marinecyanobacteria, II: nonpeptide endothelin receptor antagonist SB-209670." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B31244981.
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Gebhard, Susanne, and n/a. "The Phn and Pst systems of Mycobacterium smegmatis : phosphate transport and gene regulation." University of Otago. Department of Microbiology & Immunology, 2006. http://adt.otago.ac.nz./public/adt-NZDU20070502.112113.
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Phosphate is an essential but often growth-limiting nutrient for bacteria. At low concentrations of phosphate in the growth medium, bacteria induce high-affinity uptake systems for phosphate, and this is usually the ABC-type phosphate specific transport system Pst. In the fully sequenced genomes of pathogenic species of mycobacteria, several copies of the genes encoding for the Pst system (pstSCAB) have been identified and some of these genes have been shown to be virulence factors. The reasons for the presence of multiple copies of pst genes in pathogenic mycobacteria are not understood, and phosphate transport by these bacteria, as well as the gene regulation involved, is poorly characterised. The fast-growing M. smegmatis contains only a single copy of the pst operon, but we recently identified a gene locus containing three genes, phnDCE, which encode for a putative ABC-type phosphate/phosphonate transport system, and a gene, phnF, which encodes for a putative transcriptional regulator of the HutC subfamily of GntR like regulators.
To identify a function for the PhnDCE transport system and to characterise high-affinity phosphate transport in M. smegmatis, we created allelic exchange mutants in phnD and pstS, as well as a phnD pstS double deletion mutant. All three mutants failed to grow in minimal medium containing 10 mM phosphate, while the wildtype was able to grow in the presence of micromolar phosphate concentrations. No differences were observed in complex growth medium. Steady-state levels of [��P]-phosphate uptake were approximately 25% lower in all mutant strains as compared to the wildtype. Kinetics of phosphate uptake in the wildtype strain when grown at low phosphate concentrations (50 [mu]M P[i]) were biphasic, suggesting the presence of two inducible transport systems with apparent K[m] values of 16 [mu]M P[i] and 64 [mu]M P[i], respectively. Analysis of the kinetics of phosphate transport in the mutant strains led us to the proposition that the Pst system has an apparent Km value of ca. 16 [mu]M P[i], and the Phn system has an apparent Km of ca. 60 [mu]M P[i]. A third inducible phosphate transport system, which was active in the double mutant strain, had an apparent K[m] of ca. 90 [mu]M P[i]. Uptake of phosphate in all strains was not inhibited by the presence of excess phosphonates or phosphite, suggesting that all three transport systems were specific for phosphate. The study of phosphate transport in the presence of various metabolic inhibitors revealed that uptake by the Phn and Pst systems is driven by ATP-hydrolysis, consistent with ABC-type transport, while the third, unidentified transport system may be driven by the proton motive force.
We showed that phnDCE formed an operon, and that the promoter area of the operon lies within 200 bp of the start of phnD. To investigate the regulation of the phn and pst genes, β-galacosidase activities of strains carrying transcriptional lacZ-fusions of the pstSCAB, phnDCE and phnF promoter areas, and levels of mRNA of the phn and pst genes were studied. All genes were induced when phosphate concentrations fell below a threshold value of 30 [mu]M, which coincided with a shift in the growth characteristics of M. smegmatis. Expression of the pst operon appeared to be controlled directly by the PhoPR two-component regulatory system, while the phn operon may be under direct or indirect control by PhoPR.
To identify a role for PhnF in the regulation of phn gene expression, we created a phnF deletion mutant. PhnF appeared to repress transcription of phnDCE and phnF under phosphate-replete conditions. We identified two putative binding sequences for PhnF in the intergenic region between phnD and phnF with the sequence TGGTATAGACCA, which is similar to the proposed recognition consensus for HutC-like transcriptional regulators. Using site-directed mutagenesis of these sequences, we demonstrated that they are required for the repression of phnDCE and phnF. To prove PhnF binding to these potential binding sites, we attempted to express the M. smegmatis PhnF protein in E. coli, but could not obtain soluble recombinant protein. Electrophoretic mobility shift assays of the phnDCE promoter fragment using cell-free crude extracts of M. smegmatis were not successful.
We propose that Pst and Phn both constitute high-affinity phosphate specific transport systems of M. smegmatis, and that a third inducible phosphate transport system is present in this bacterium. PhnF is required for repression of phnDCE and phnF transcription under phosphate-replete conditions, while induction of the pst operon, and possibly the phn operon, under phosphate-limited conditions involves the PhoPR system.
14
Pham, Huy Dien. "Effets de differents anti-inflammatoires sur la migration et le metabolisme oxydatif des polynucleaires neutrophiles de rat." Paris 6, 1987. http://www.theses.fr/1987PA066194.
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Panji, Sumir. "Identification of bacterial pathogenic gene classes subject to diversifying selection." Thesis, University of the Western Cape, 2009. http://etd.uwc.ac.za/index.php?module=etd&action=viewtitle&id=gen8Srv25Nme4_5842_1297942831.
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Availability of genome sequences for numerous bacterial species comprising of different bacterial strains allows elucidation of species and strain specific adaptations that facilitate their survival in widely fluctuating micro-environments and enhance their pathogenic potential. Different bacterial species use different strategies in their pathogenesis and the pathogenic potential of a bacterial species is dependent on its genomic complement of virulence factors. A bacterial virulence factor, within the context of this study, is defined as any endogenous protein product encoded by a gene that aids in the adhesion, invasion, colonization, persistence and pathogenesis of a bacterium within a host. Anecdotal evidence suggests that bacterial virulence genes are undergoing diversifying evolution to counteract the rapid adaptability of its host&rsquo
s immune defences. Genome sequences of pathogenic bacterial species and strains provide unique opportunities to study the action of diversifying selection operating on different classes of bacterial genes.
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Lemoine, Clément. "Culture in vitro de plantes halophiles du littoral breton et orientation de leur métabolisme vers la production de principes actifs pour la nutrition et la cosmétique." Thesis, Brest, 2018. http://www.theses.fr/2018BRES0113.
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Les plantes halophiles sont des plantes résistantes au stress salin, qui subissent une grande variété de stress dans leur environnement naturel. Ces conditions les ont menées à synthétiser des molécules de défense, qui peuvent présenter des activités biologiques intéressantes de par leur structure et diversité. Dans le cadre d’une collaboration avec la PME Salipouss, trois espèces ont été choisies sur la base de tests antioxydants préliminaires, avec pour objectif d’optimiser (i) la multiplication de plants in vitro pour des cultures industrielles en serre et (ii) d’améliorer le niveau d’activité de leurs extraits. La diversité des composés potentiellement actifs présents dans ces extraits est ensuite analysée par fractionnement bioguidé, afin d’isoler des molécules valorisables. Ce fractionnement est appuyé par des analyses de composés par RMN, permettant d’obtenir des informations sur la structure des composés bio-actifs. Les résultats obtenus montrent le fort potentiel de valorisation de ces trois espèces dans l’industrie, et plus particulièrement dans la nutrition et la cosmétiqueHalophytes are salt tolerant or salt-resistant plants which undergo high stress in their natural habitat. As a consequence of environmental stresses, they produce a number of active defense molecules which display interesting biological activities because of their diverse actions or structures. For the present study, three halophytic species were selected from preliminary antioxidant screening. In collaboration with Salipouss SME, objectives of the work were (i) to optimize in vitro halophyte multiplication in order to produce biomass under greenhouse and (ii) to elicit particular metabolic pathways in order to improve extract activities. To attempt to isolate molecules with potentially valuable activities, the variety of compounds from these extracts is reduced by successive fractionations. In addition, NMR analyzes allow to obtain indications on the nature and on the structure of the active compounds. First results highlight the strong activities of the selected halophytes, making them promising candidates for industrial uses, especially in nutrition and cosmetics
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Betbeder, Didier. "Synthese et etude du mode d'action d'inhibiteurs de voies metaboliques du trypanosome." Toulouse 3, 1988. http://www.theses.fr/1988TOU30029.
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Etude d'inhibiteurs de voies metaboliques du trypanosome. Synthese et action d'inhibiteurs possibles d'enzymes de replication. Etude d'enzymes de la glycolyse, cible cle dans le trypanosome, celui-ci utilisant le glucose comme seule source d'energie. Puis caracterisation d'une proteine qui presente les proprietes de recepteur vis-a-vis d'une nouvelle famille de trypanocides derives du diphenyl methane
18
Diawara, Bréhima. "Conservation de riz-paddy sous atmospheres controlees : aspects microbiologiques et consequences technologiques." Nantes, 1988. http://www.theses.fr/1988NANT2016.
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Des experiences realisees sur grains stockes en cellules etanches a differentes activites d'eau ont permis de montrer qu'il est inutile de creer une atmosphere anoxique artificielle pour stabiliser les populations microbiennes naturelles. Une relation quantitative directe existe entre croissance, sporulation et quantite d'oxygene disponible dans l'ecosysteme. Aux tres faibles pressions partielles d'oxygene, la perte de viabilite des propagules fongiques est fonction de l'activite d'eau des grains. Les qualites technologiques des grains restent stables pour les activites d'eau inferieures a 0. 95. Seules les levures de stockage sont capables de se developper dans ces conditions gazeuses, des lors que l'activite d'eau est superieure ou egale a 0. 86. Le developpement particulier d'hyphopichia burtonii (boidin) en presence de traces d'oxygene et l'arret de sa croissance en anaerobiose stricte montrent que c'est une espece "microaerotolerante". En presence de traces d'oxygene, le dioxyde de carbone a un effet stabilisant sur les populations fongiques (aspergillus, penicillium). Cependant, le dioxyde de carbone employe seul ne saurait assurer la stabilite microbiologique des grains conserves en structures insuffisamment etanches
19
Batcho, Elie. "Proprietes physiologiques de l'acide usnique et applications a la regulation de la transpiration vegetale." Paris 7, 1988. http://www.theses.fr/1988PA077008.
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Ce travail est consacre a la recherche d'un antitranspirant vegetal non synthetique. Les investigations menees du laboratoire au champ (agriculture et sylviculture) ont pour objectif l'augmentation de l'efficience de l'eau en zone sub-aride. Le principe d'action recherche est la reduction de l'etr par action sur la transpiration stomatique. L'importance du role de la pompe h**(+)/k**(+) sur le mouvement stomatique a oriente ce travail vers les chelateurs naturels. L'acide usnique extrait de divers lichens valide l'hypothese de travail. La purification du produit et l'etude de son activite sur la regulation du mouvement stomatique (sur plantes entieres et sur feuilles isolees) en constituent la demonstration
20
Noé-Galewski, Lydie. "Lipoprotéine lipase de plasma humain post-héparine, purification et anticorps : Récepteurs des LDL et régulation du métabolisme du cholésterol." Paris 6, 1986. http://www.theses.fr/1986PA066089.
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Etude bibliographique de la lipoprotéine lipase (LPL): structure et propriétés physicochimiques; propriétés enzymatiques; propriétés immunologiques. Biosynthèse de la LPL; rôle de la LPL. Isolement et purification à partir du tissu adipeux de plasma post-héparine et de lait de femme: chromatographie d'affinité sur sépharose-héparine, focalisation isoélectrique préparative; résultats. Préparation d'anticorps anti-LPL, par injection au lapin de l'enzyme hautement purifiée.
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Bourdier, Gilles. "Composition biochimique du materiel particulaire lacustre : interets pour l'etude de l'activite metabolique des microorganismes, de la dynamique des populations phytoplanctoniques et des relations trophiques phyto-zooplancton." Clermont-Ferrand 2, 1989. http://www.theses.fr/1989CLF21119.
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Dans le but de preciser l'interet que presente la determination de la composition biochimique du materiel particulaire lacustre, pour l'etude de l'activite metabolique des microorganismes, la dynamique des populations phytoplanctoniques et les relations trophiques phyto-zooplanctoniques, une etude a court terme puis a long terme de la composition en acide gras des lipides phytoplanctoniques est menee. Ces acides gras sont ensuite utilises comme marqueurs organiques, pour suivre le transfert de matiere organique au sein du reseau trophique. Une demarche nouvelle est proposee par l'etude des relations trophiques phyto-zooplancton
22
Mona, Sobhi. "Mode d'action cellulaire de séries de phenylcarbamates herbicides." Grenoble 1, 1987. http://www.theses.fr/1987GRE10105.
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Un groupe de 45 derives appartenant a la famille des carbamates a ete etudie, pour ses effets herbicides. Ce groupe contient des n-phenylcarbamates d'isopropyle, d'ethyle substitue, de phenyle et des biscarbamates. Dans une premiere partie ont ete analyses les effets de tous ces composes sur le transfert electronique associe a l'activite photosynthetique. . .
23
Landron, Dorothée. "Interactions de l'hormone de croissance humaine avec les adipocytes de rats zucker genetiquement obeses : relations entre la liaison et les effets biologiques." Paris 6, 1988. http://www.theses.fr/1988PA066344.
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L'objectif de ce travail est de comparer la liaison et les effets biologiques de l'hormone de croissance (gh) 1) dans les adipocytes du tissu inguinal de jeunes rats zucker obeses fa/fa et minces fa/fa; 2) dans les preadipocytes de rats zucker en culture primaire au cours de la differenciation adipocytaire. 1. Les etudes de liaison de la gh et les courbes dose-reponse pour le transport et le metabolisme du glucose sont realisees avec des adipocytes soit fraichement isoles (f) soit preincubes 3 h (p)
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Marlas, Guy. "A la recherche du facteur omega ou evolution de la structure moleculaire de glycoproteines activatrices des plaquettes sanguines (gap) isolees de venins de serpents crotalinae." Paris 7, 1988. http://www.theses.fr/1988PA077111.
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Massicot, France. "Etudes pharmacologiques et toxicologiques d'un régulateur métabolique : le chlorhydrate de chloro-4 phénoxyacétate d'hydroxyméthyl-3 N-méthyl pipéridine (PM 170)." Paris 7, 1986. http://www.theses.fr/1986PA077090.
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Burger, Alain. "Inhibiteurs irreversibles de la biosynthese de l'ecdysone." Université Louis Pasteur (Strasbourg) (1971-2008), 1988. http://www.theses.fr/1988STR13081.
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Mouton, Olivier. "Étude du comportement biologique de bis (N-ethoxy, N-ethyldithiocarbamato) nitruro 99mTc(V), 99mTcN-NOET, un nouveau marqueur de la perfusion myocardique." Université Joseph Fourier (Grenoble ; 1971-2015), 1997. http://www.theses.fr/1997GRE10296.
Full textAbstract:
Les traceurs radioactifs emetteurs de rayonnements sont les seuls outils disponibles permettant, par simple injection intraveineuse, l'analyse in vivo de la repartition regionale du debit sanguin coronaire. A l'heure actuelle, le radioelement utilise en medecine nucleaire est le thallium-201, un cation monovalent, considere comme un analogue du potassium. Cependant, le thallium-201 presente certains inconvenients (dosimetre et cout de production eleves). C'est pourquoi les recherches se sont orientees vers la synthese de molecules originales marquees au technetium-99m, les complexes techneties. Bis (n-ethoxy, n-ethyldithiocarbamato- nitrido #9#9#mtc (v), #9#9#mtcn-noet, un nouveau marqueur de la perfusion myocardique tres prometteur : du fait de sa redistribution, #9#9#mtcn-noet se presente comme un remplacant potentiel du thallium-201. Il est indispensable de connaitre les mecanismes de captation cellulaire de #9#9#mtcn-noet afin d'interpreter correctement les informations donnees par la tomoscintigraphie de perfusion myocardique. C'est pourquoi notre travail a consiste en etude du comportement biologique de #9#9#mtcn-noet. Comme ce marqueur lipophile et neutre est une molecule originale, nous avons choisi d'adopter une demarche systematique en considerant comme envisageable toute entree ou toute fixation par ou sur une structure membranaire. Des inhibitions specifiques de divers transports ioniques membranaires ont ete effectuees pour conclure en leur participation directe ou indirecte dans la fixation cellulaire de #9#9#mtcn-noet. Deux modeles experimentaux ont ete choisis : la culture primaire de cardiomyocytes de rats nouveau-nes (in vitro) et le cur isole et perfuse de rat (ex vivo). Les resultats obtenus in vitro ont montre que la fixation cellulaire de #9#9#mtcn-noet ne necessite pas d'atp et que parmi l'ensemble des transports ioniques inhibes, seuls les canaux calciques voltage-dependants de type l se sont reveles directement impliques dans les mecanismes de fixation cellulaire de #9#9#mtcn-noet. Le comportement biologique de #9#9#mtcn-noet est similaire sur les deux modeles biologiques. Ces resultats nous permettent d'envisager une interaction de #9#9#mtcn-noet avec les canaux calciques voltage-dependants de type l. Des etudes supplementaires seront necessaires pour mieux caracteriser la nature de cette interaction.
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Koci, Buleza. "Biologically active metabolites of plants.7.Alkaloids from Corydalis yanhusuo and their biological activity." Master's thesis, 2011. http://www.nusl.cz/ntk/nusl-298054.
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Bulëza Koci: Biological Activity of Plant Metabolites 7. Alkaloids from Corydalis yanhusuo W.T. Wang and their inhibitory activity on acetylcholinesterase. In the process of screening for plants containing alkaloids potentially inhibiting human erythrocytic AChE and human BuChE, Corydalis yanhusuo was studied. 10.8 kg of dry tuber was percolated with 120 liters of 95% ethanol. From the primary extract, extracts with individual types of alkaloids were prepared. In this diploma thesis only one extract was processed (extract type A-ether, pH 9.7). Alkaloids from this extract were separated into bases whose chlorides were either soluble or insoluble in chloroform. From each of the above mentioned fractions phenolic and non-phenolic alkaloids were obtained. Alkaloids were separated from a fraction of alkaloids, whose chlorides are soluble in CHCl3, non-phenolic (A- non-phenolic Cl- S/CHCl3). From this mixture tetrahydropalmatine was isolated by the use of column chromatography on alumina and preparative TLC on silica gel. This compound was preliminary identified according to data of MS spectra, NMR spectra and optical rotation and by comparison with literature data . The biological activity of tetrahydropalmatine on human AChE and BuChE was found to be: IC50 876 ± 15.3 μM for HuAChE and IC50 > 1000 μM...
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Cinel, Bruno. "Biologically active secondary metabolites isolated from marine and terrestrial sources." Thesis, 2001. http://hdl.handle.net/2429/13670.
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A series of new and known secondary metabolites were isolated from marine and
terrestrial sources guided by two newly developed, cell-based assays. Investigations into the
antimitotic properties of a crude extract from the Caribbean octocoral Erythropodium
caribaeorum resulted in the isolation and identification of the known antimitotic agent
eleutherobin (61) and six novel structural analogues, 69-74. E. caribaeorum proved to be a new
and abundant source of eleutherobin (61), whose pre-clinical development had been impeded by
its scarcity, and the structural variations of the new diterpenoids offered key insights into
proposed pharmacophore models for microtubule-stabilizing compounds. In addition, single
crystal X-ray diffraction analysis and NOE difference experiments provided the first solid-state
and solution conformations for eleutherobin (61) and may aid in the development of new
models for microtubule stabilization.
[diagram]
The crude extract from a marine sponge, Stylissa flabelliformis, exhibited potent activity
in a new bioassay for G2 cell cycle checkpoint inhibitors. Bioassay-guided fractionation of this
active extract resulted in the isolation and identification of the natural product
[diagram]
debromohymenialdisine (91) and three related alkaloids (85, 94, 103). These compounds were
the first G2 checkpoint inhibitors to be found by a rational screen and were structurally distinct
from previously reported G2 checkpoint inhibitors. In addition, debromohymenialdisine (91)
was found to specifically act on the protein kinases Chkl and Chk2, thus providing a new
biochemical tool to probe the molecular basis of G2 checkpoint inhibition.
[diagram]
As a result of a large-scale screen of natural extracts for G2 checkpoint inhibitors, a
series of a-pyrones from the Taiwanese tree Cryptocarya concinna were found to exhibit potent
inhibitory activity. Bioassay-guided purification resulted in the isolation and identification of
the natural product cryptofolione (130) and three related polyketide lactones (148, 131, 138).
Synthetic modifications on these metabolites yielded four additional analogues and led to mode
of action and structure-activity relationship studies. The G2 checkpoint inhibitors isolated from
C. concinna were structurally different from previously known inhibitors and appear to act by a
novel mechanism of action.
[diagram]
30
Pischos, Sotiria. "Structural determination of biologically active peptaibol metabolites of Tolypocladium geodes LP237." Thesis, 1996. http://spectrum.library.concordia.ca/4329/1/MM10886.pdf.
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Nelson, Jim. "Investigation into the biologically active metabolites of Coccoloba acuminata and Minquartia guianensis." Thesis, 2002. http://hdl.handle.net/2429/13623.
Full textAbstract:
The comprehension of cellular processes remains central to the development of novel techniques for the treatment of disease. The use of small molecule protein inhibitors can aid in better understanding these processes and potentially be used therapeutically. The G2 checkpoint allows for cells to pause and repair DNA damage. In conjunction with radiation therapy, the use of G2 checkpoint inhibitors has demonstrated (in vitro) a greater mortality for cancer cells over healthy cells. The bioassay guided fractionation of Coccoloba acuminata afforded the G2 checkpoint inhibitor enf-kaur-16-en-15-oxo-18-oic acid (7). [diagram not included] At an optimal concentration of 12 μg/ml, diterpene 7 exhibited a maximum release of cells from G2 → M of 48%. A biotinylated linker was attached to 7 to form an affinity probe 14. [diagram not included] At an optimal concentration of 7 μg/ml, compound 14 released 39-41% of cells from G2 to M phase. The binding of Pin1 to phosphorylated tau plays a role in the formation of paired helical filaments, a hallmark of Alzheimer's disease. Therefore, inhibitors of the binding of Pin1 to phosphorylated tau could be used as a potential therapeutic for Alzheimer's disease. The bioassay guided fractionation of M. guianensis yielded the cytotoxic polyacetylene minquartynoic acid 8 [diagram not included] and two inhibitors of Pin1 binding 4-O-(α-rhamnopyranosyl)ellagic acid 9 [diagram not included] and 4-O-(β-xylopyranosyl)ellagic acid 10 [diagram not included]. The IC₅₀ is 0.7 μ/mL for 4-O-(β-xylopyranosyl)ellagic acid 10 [diagram not included] and 0.6 μ/mL for 4-O-(α-rhamnopyranosyl)ellagic acid 9 for inhibition of Pin1 binding to phosphorylated tau.
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James, Jacinda Terry. "Determination and manipulation of biologically active triterpenoid secondary metabolites in Centella asiatica." Thesis, 2013. http://hdl.handle.net/10210/8537.
Full textAbstract:
D.Phil. (Biochemistry)Plants are able to recognise and respond to signals from the environment through a complex array of biochemical pathways, which enables them to deter pathogenic micro-organisms and herbivores. Thousands of different structures of low-molecular weight organic compounds / natural products can be produced through an inducible chemical defence system; that can be manipulated for biotechnological purposes. The importance of natural products in medicine, agriculture and industry has led to numerous studies such as this, to understand the biosynthesis and biological activity of these substances...
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Ali, Hiba Abdel-Rahman. "Isolation and evaluation of biologically active secondary metabolites from selected medicinal plants of Sudan /." 2002. http://www.gbv.de/dms/bs/toc/361122403.pdf.
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Umbreen, Sumaira. "Synthesis and Biological Evaluation of β-Secretase Inhibitors, Proteasome Inhibitors and Losartan Active Metabolites." Phd thesis, 2007. https://tuprints.ulb.tu-darmstadt.de/821/1/Sumaira_Thesis_Part_1.pdf.
Full textAbstract:
Alzheimer's disease (AD) is the leading cause of dementia in the elderly, presenting itself clinically by progressive loss of memory and learning and its prevention is a major public health challenge. The key event in the progression of AD are the sequential cleavages of β-amyloid precursor protein (β-APP) by two proteolytic enzymes, beta-site APP-cleaving enzyme 1 (BACE-1 or memapsin 2) and γ-secretase to produce Aβ40 and Aβ42 in the human brain. From the therapeutic point of view, BACE-1 appears to be a promising drug target, which stimulated the design and synthesis of BACE-1 inhibitors. The present work describes the design, synthesis and biological evaluation of non-peptidic, semi-peptidic and peptidic BACE-1 inhibitors. The norstatine based BACE-1 inhibitors were synthesized to study the structure-activity relationship (SAR) at the P2´ position. The synthetic approach utilized L-phenylalaninol and isophthalamide derivatives, provided both hydroxyl diastereomers in a 1:1 ratio, which were isolated and investigated separately. To enable lead optimization and facile variation at the P1 position, a new synthetic route was developed by employing an organocatalytic approach. As a consequence, a variety of norstatine derivatives was synthesized by a proline catalyzed α-amination reaction followed by a Passerini reaction. For an easy removal of catalyst, clean and straightforward separation of the product, an immobilized proline derived catalyst was synthesized and successfully employed. A series of compounds was designed and synthesized as potential BACE-1 inhibitors, as analogues of MG132, which is known to have a broad specificity to inhibit cysteine, serine and aspartyl proteases. Biological evaluation of these compounds for BACE-1 and 20S proteasome displayed moderate BACE-1 inhibition. However, they turned out to be potent 20S proteasome inhibitors and promising drug candidates. The most potent 20S proteasome inhibitor BSc2118 that has low toxicity and effective inhibition encouraged further evaluation and optimization of the lead compound. The combined treatment of BSc2118 and calpain-specific inhibitor was evaluated on human melanoma cisplatin-resistant (MeWocis1) cells and found to affect two different proteolytic pathways, which can enhance the proteasome inhibitor–mediated death of the tumor cells, especially of the cisplatin-resistant cells. An agonist of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) acts to improve behavioural performance in an animal model of AD. Atherosclerosis, coronary heart disease and hypertension are identified as other risk factors for AD. A subgroup of angiotensin receptor type 1 (AT1) receptor blockers has been identified as ligands for the PPAR-γ. Therefore, two active losartan metabolites i.e. EXP3174 and EXP3179 were synthesized and characterized for the PPAR-γ–activating properties in the present work. Moreover, it was investigated that EXP3179 inhibits collagen-dependent platelet activation via glycoprotein receptor-VI independent of AT1-receptor antagonism, which has a potential impact on atherothrombosis. Beside this, it was explored that AT1 blockade in astrocytes decreases hypoxia-induced cell damage and inflammation. AT1-R blockade could be of therapeutic benefit during neurodegenerative disorders accompanied by inflammation, such as Alzheimer’s disease, Parkinson’s disease, stroke and multiple sclerosis due to its anti-inflammatory and vulnerability-reducing effect on astrocytes.
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Umbreen, Sumaira [Verfasser]. "Synthesis and biological evaluation of β-secretase [beta-secretase] inhibitors, proteasome inhibitors and Losartan active metabolites / vorgelegt von Sumaira Umbreen." 2007. http://d-nb.info/984602291/34.
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