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1
Zheng, Zehua. "Synthesis of bioactive natural products." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/59815.
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Crude extracts of the rare macrofungus Serpula sp. collected from a wooded area in Sri Lanka showed antimicrobial activity. The novel fungal metabolite serpulanine (2.1) was isolated from the crude extract in very small amounts along with a number of additional secondary metabolites. In order to obtain sufficient quantities of serpulanine (2.1) for biological evaluation, a synthetic route was developed to the natural product and a small library of analogs that have been evaluated in a panel of bioassays. Serpulanine (2.1) inhibits the histone deacetylase I/II with a clear dose response curve. Halitoxins (3.1) that are frequently isolated from marine sponges have a complex macrocyclic chemical structure made of different numbers of monomeric alkylpyridinium units. An unknown halitoxin-related natural product named alotau potently inhibited the dephosphorylation activity of calcineurin. With the goal to elucidate the structure of alotau, compounds of one, two and three pyridinium rings (3.10, 3.7 and 3.8) were synthesized. Though these compounds have NMR spectra similar to the natural alotau, according to bioassay results, none of them recapitulates the activity of the unknown natural product alotau. (+)-Makassaric acid 4.1 was isolated in the Andersen Lab from the marine sponge Acanthodendrilla sp. It showed promising activity in a zebrafish screen for new drugs to treat stroke patients. The convergent synthetic scheme shown below was undertaken to conduct structure activity relationship (SAR) studies. The key intermediate 4.17 has been obtained, and further synthetic efforts will be needed to produce 4.1.Science, Faculty of
Chemistry, Department of
Graduate
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Nelson, A. "Synthesis of bioactive indolizidine alkaloids." Thesis, Queen's University Belfast, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421009.
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Shan, Yulong. "Bioactive carbohydrates : isolation, synthesis and conjugation." Thesis, Bangor University, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.556079.
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In this thesis four projects related to bioactive carbohydrates are described. The first project is about the extraction of iminosugars from Hyacinthoides non-scripta. This is the first time that extraction from English bluebell seeds has been described. Efficient extraction and isolation methods are reported. Another project discusses the development of a total synthetic carbohydrate conjugate vaccine candidate against Streptococcus pneumoniae type 14 using Gold nanoparticles as carrier. The synthetic pathway of the introduction of a linker for conjugation, and the deprotection of the tetrasaccharide corresponding to the repeating unit of the Streptococcus pneumoniae type 14 capsular polysaccharide is described. The biological results of the developed vaccine candidate are briefly discussed. In the third project, attempts to synthesise regioselectively sulfated disaccharides to be used in binding studies with FedF adhesin of E. coli are described. In this section, an improved high-yielding method based on the Heyns rearrangement for the synthesis of N-acetyl lactosamine (LacNAc) is also reported. In the fourth part, conjugation of the Lewis b hexasaccharide to be used for studies of Lewis b blood group antigen binding adhesin is reported.
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Carbain, Benoît. "A convenient synthesis of bioactive cyclohexenephosphonates." Thesis, University of Sussex, 2010. http://sro.sussex.ac.uk/id/eprint/2367/.
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Influenza virus infection and the shikimic acid pathway are two of many examples of microbe-host interactions and microbial biosynthetic pathways that are interesting for investigation by means of small molecules. A particularly interesting structural motif common to both is the cyclohexenecarboxylic acid. In the former, this structural motif has been employed as a mimetic of the sialyl cation intermediate and forms the scaffold of the anti-influenza drug and neuraminidase inhibitor Oseltamivir (or TamifluTM). In the latter pathway, crucial modifications towards aromatic amino acids are carried out via shikimic acid, a cyclohexenecarboxylic acid, as a substrate. A straightforward method to replace the carboxylate moiety in such structures with a phosphonate would provide access to a wide variety of mimetics, for instance monoesters, that still retain a negative charge under physiological conditions usually required for bioactivity. The aim of this research project was to develop an efficient synthesis of the cyclohexenephosphonate scaffold from chiral pool precursors via two key steps, a Hunsdiecker-Barton iododecarboxylation followed by a palladiummediated coupling step to introduce the phosphonate moiety, thus giving a convenient access to interesting bioactive molecules. This approach has successfully been applied to the shikimic acid to afford ‘phospha'-shikimic acids and 3-dehydro-‘phospha'-shikimic acids, and further development of this strategy has led to the synthesis of ‘phospha'-Tamiflu and its derivatives from an Oseltamivir precursor.
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Usai, Igor. "Synthesis of novel bioactive doxycycline derivatives." kostenfrei, 2008. http://www.opus.ub.uni-erlangen.de/opus/volltexte/2008/1082/.
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Hu, Yaogang. "Design and Synthesis of Bioactive Peptidomimetics." Scholar Commons, 2015. https://scholarcommons.usf.edu/etd/5504.
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Protein-Protein Interactions (PPIs) play a very important role in biological functions and therefore the inhibition of specific Protein-Protein Interactions has a huge therapeutic value. The most successful small molecular PPIs inhibitors do not fit with the prevalent `Rule of Five' drug profile. To overcome the disadvantages of small molecular PPIs inhibitors, peptide based PPIs inhibitors were developed. Herein we describe the development of a new class of peptidomimetics AA-peptides. The AApeptides were designed based on chiral PNA backbone. Substitution of nucleobases yields AApeptides that are resistant to proteolysis and capable of mimicking peptides. Two types of AApeptides were discussed in this dissertation "α-AApeptides" and "γ-AApeptides". The AApeptides were shown to disrupt p53/MDM2 protein-protein interaction and tomimic fMLF tripeptide to target G protein-coupled formyl peptide receptors (FPRs). Moreover, the lipidated α-AApeptides can mimic the structure and function of natural antimicrobial lipopeptides and show broad-spectrum activity against both Gram-positive and Gram-negative bacteria. Lastly I have designed and synthesized a serials of phosphopeptides to disrupt cancer related STAT3-STAT3 dimerization.
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Tyrrell, Andrew J. "Approaches to the synthesis of bioactive pyrrolizidines." Thesis, University of Oxford, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497131.
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Miranda, Vanessa. "Synthesis of new bioactive autoinducer-2 analogues." Doctoral thesis, Universidade Nova de Lisboa, Instituto de Tecnologia Química e Biológica António Xavier, 2019. http://hdl.handle.net/10362/94059.
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" Bacteria behaviours are regulated on a communitywide scale by producing, secreting, detecting and responding to extracellular small signaling molecules (autoinducers) that accumulate in the environment in proportion to cell density. This process is called quorum sensing (QS). (...)"N/A
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Isoni, Valerio. "Asymmetric synthesis of bioactive alkaloids from Amaryllidaceae." Thesis, University of Southampton, 2013. https://eprints.soton.ac.uk/355712/.
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A new route towards the diasteroselective synthesis of (+)-maritidine, a bioactive alkaloid from Amaryllidaceae, has been proposed. In our approach, an intramolecular Heck reaction was used to form the quaternary stereocentre C10b driven by the stereochemical information at C4a of the precursor. Allylic oxidation of intermediate 3.25 followed by diasteroselective reduction, introduced the alcohol at C3 with the correct stereochemistry. An advanced intermediate (3.29) in the synthesis of (+)-maritidine was produced, and routes to complete the total synthesis were proposed. A series of polymer-supported sulfonate ester linkers were developed for use in the resin-linker-vector (RLV) approach for the synthesis of [18F]-radiopharmaceuticals used as imaging probes in positron-emission-tomography (PET). Upon exposure of the RLV construct to [18F]-fluoride, a small quantity of [18F]-radiotracer is released in solution which is separated from the unreacted material and cleaved resin, by simple filtration. The RLV strategy was successfully applied for the synthesis of the known radiopharmaceutical O-(2-[18F]-fluoroethyl)-L-tyrosine, [18F]-FET. A C-H activation-cyclisation sequence was used to achieve the synthesis of the Amaryllidaceae alkaloid oxoassoanine as well as a phenanthridinoid analogue, part of potential non-charged dual reactivators of acetylcholinesterase (AChE) poisoned by organophosphorous (OP) nerve agents.
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Soldati, Roberto <1986>. "Synthesis of new bioactive β-lactam compounds." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/6974/1/Soldati_Roberto_Tesi.pdf.
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New biologically active β-lactams were designed and synthesized, developing novel antibiotics and enzymatic inhibitors directed toward specific targets.
Within a work directed to the synthesis of mimetics for RGD (Arg-Gly-Asp) sequence able to interact with αvβ3 and α5β1-type integrins, new activators were developed and their Structure-Activity Relationships (SAR) analysis deepened, enhancing their activity range towards the α4β1 isoform. Moreover, to synthesize novel compounds active both against bacterial infections and pulmonary conditions of cystic fibrosis patients, new β-lactam candidates were studied. Among the abundant library of β-lactams prepared, mainly with antioxidant and antibacterial double activities, it was identified a single lead to be pharmacologically tested in vivo. Its synthesis was optimized up to the gram-scale, and pretreatment method and HPLC-MS/MS analytical protocol for sub-nanomolar quantifications were developed. Furthermore, replacement of acetoxy group in 4-acetoxy-azetidinone derivatives was studied with different nucleophiles and in aqueous media. A phosphate group was introduced and the reactivity exploited using different hydroxyapatites, obtaining biomaterials with multiple biological activities. Following the same kind of reactivity, a small series of molecules with a β-lactam and retinoic hybrid structure was synthesized as epigenetic regulators. Interacting with HDACs, two compounds were respectively identified as an inhibitor of cell proliferation and a differentiating agent on steam cells. Additionally, in collaboration with Professor L. De Cola at ISIS, University of Strasbourg, some new photochemically active β-lactam Pt (II) complexes were designed and synthesized to be used as bioprobes or theranostics.
Finally, it was set up and optimized the preparation of new chiral proline-derived α-aminonitriles through an enantioselective Strecker reaction, and it was developed a chemo-enzymatic oxidative method for converting alcohols to aldehydes or acid in a selective manner, and amines to relative aldehydes, amides or imines. Moreover, enzymes and other green chemistry methodologies were used to prepare Active Pharmaceutical Ingredients (APIs).
11
Soldati, Roberto <1986>. "Synthesis of new bioactive β-lactam compounds." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/6974/.
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New biologically active β-lactams were designed and synthesized, developing novel antibiotics and enzymatic inhibitors directed toward specific targets.
Within a work directed to the synthesis of mimetics for RGD (Arg-Gly-Asp) sequence able to interact with αvβ3 and α5β1-type integrins, new activators were developed and their Structure-Activity Relationships (SAR) analysis deepened, enhancing their activity range towards the α4β1 isoform. Moreover, to synthesize novel compounds active both against bacterial infections and pulmonary conditions of cystic fibrosis patients, new β-lactam candidates were studied. Among the abundant library of β-lactams prepared, mainly with antioxidant and antibacterial double activities, it was identified a single lead to be pharmacologically tested in vivo. Its synthesis was optimized up to the gram-scale, and pretreatment method and HPLC-MS/MS analytical protocol for sub-nanomolar quantifications were developed. Furthermore, replacement of acetoxy group in 4-acetoxy-azetidinone derivatives was studied with different nucleophiles and in aqueous media. A phosphate group was introduced and the reactivity exploited using different hydroxyapatites, obtaining biomaterials with multiple biological activities. Following the same kind of reactivity, a small series of molecules with a β-lactam and retinoic hybrid structure was synthesized as epigenetic regulators. Interacting with HDACs, two compounds were respectively identified as an inhibitor of cell proliferation and a differentiating agent on steam cells. Additionally, in collaboration with Professor L. De Cola at ISIS, University of Strasbourg, some new photochemically active β-lactam Pt (II) complexes were designed and synthesized to be used as bioprobes or theranostics.
Finally, it was set up and optimized the preparation of new chiral proline-derived α-aminonitriles through an enantioselective Strecker reaction, and it was developed a chemo-enzymatic oxidative method for converting alcohols to aldehydes or acid in a selective manner, and amines to relative aldehydes, amides or imines. Moreover, enzymes and other green chemistry methodologies were used to prepare Active Pharmaceutical Ingredients (APIs).
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Stevens, Kiri. "Methodology for the synthesis of NP25302 and other bioactive natural products." Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:ae18879e-d75e-4280-ba55-1ae08e64034f.
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Total synthesis of the pyrrolizidine alkaloid NP25302: (+)-NP25302 is an unusual vinylogous urea containing pyrrolizidine alkaloid shown to exhibit cell adhesion inhibition. It was envisaged that this natural product could be accessed by a novel 5-endo-dig cyclisation to construct the pyrrolizidine core, and a Curtius rearrangement to install the vinylogous urea motif. This methodology was first tested on a model system, furnishing nor-NP25302 from L-proline in 12 steps and 9% overall yield. The total synthesis of (±)-NP25302 was completed in 9 steps and 26% overall yield from ethyl 2-nitropropionate using similar methodology. Studies into the stereospecificity of the Au(I)-catalysed cyclisation of monoallylic diols: During the synthesis of (+)-isoaltholactone in the Robertson group, the key Au(I)-catalysed cyclisation was observed to occur with some stereospecificity. Further investigations were therefore conducted into the stereochemical outcome of this reaction using stereodefined allylic alcohols, and from the combined results a mnemonic was proposed to predict the stereochemistry of the products of this reaction. Studies into the total synthesis of ascospiroketals A and B: Investigations were conducted into the total synthesis of the recently isolated natural products ascospiroketals A and B. A second generation synthesis was used to construct advanced intermediates 1 and 2.
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Lear, Sam. "Total synthesis of bioactive peptides and whole proteins." Thesis, Durham University, 2016. http://etheses.dur.ac.uk/11946/.
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Total chemical synthesis is an essential tool for the validation of natural product structures and the discovery and elaboration of novel therapeutic scaffolds. Chapter 1 (Part I) surveys existing treatments for trypanosomatid neglected tropical diseases, and the synthesis of a novel class of antiparasitic cyclic depsipeptides is reported (Chapter 2) alongside a full NMR assignment and structure calculation using NMR-derived distance restraints. The synthetic peptides exhibit activity profiles in agreement with published results, and a series of ester-to-amide substitution analogues also synthesized show similar low micromolar potency. Chapter 3 describes the synthesis of lassomycin, a tuberculocidal lasso peptide reported to exhibit a unique unthreaded topology. The naturally occurring peptide was synthesized alongside C-terminally amidated and truncated analogues, but none were biologically active. Given clear differences observed in the two-dimensional NMR data for synthetic lassomycin, it is suggested that the reported natural product in fact exists in the threaded form. The chemical synthesis of whole proteins is addressed in Part II, and current progress in the field is reviewed (Chapter 4). Work towards the total chemical synthesis of acyl carrier protein using a two fragment approach is described in Chapter 5. The N-terminal fragment was synthesized using the sulfonamide linker, and while the C-terminal fragment presented difficulties due to extremely low solubility, solubilization using backbone protection was demonstrated. The development of a modified Dawson linker for the synthesis of peptide N-acylureas without overacylation is also described. Finally, Part III details the synthesis of tumor targeting peptides used for imaging and inhibition of cancer cell growth, and which cause tumor size reduction in vivo. A novel web utility used for the automated assignment of peptide mass spectra throughout this thesis is also presented.
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Chlubnová, Ilona. "Chemo-enzymatic synthesis of bioactive furanosyl-containing glycoconjugates." Rennes 1, 2010. http://www.theses.fr/2010REN1S196.
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Hexofuranoses are absent from mammals, but are present in numerous microorganisms, often highly pathogenic. This makes them very attractive targets for the development of new antimicrobial drugs. As an alternative to organic synthesis, the use of enzymes has been increasingly appreciated in the synthesis of glycoconjugates. Here we report the use of alpha-l-Arabinofuranosidase Araf51 for the synthesis of furanosyl-containing glycoconjugates. This enzyme was really efficient in catalysing oligomerisations of l-arabinofuranoside and d-galactofuranoside up to the formation of pentasaccharides, as well as in the synthesis of furanosides containing structurally modified d-galactofuranosides and pyrano-furano disaccharides. Many of synthesised compounds represented biologically relevant structures found in some clinically important pathogens. Biological tests proved that these neofuranosides have robust immunostimulatory properties and can become a potentially very useful new type of adjuvantsLes hexofuranoses sont absents chez les mammifères, mais sont présents dans de nombreux micro-organismes souvent hautement pathogènes, ce qui les rend très intéressants pour le développement de nouveaux médicaments antimicrobiens. Les enzymes sont de plus en plus souvent utilisées pour la synthèse de glycoconjugués comme une alternative à la synthèse organique. Dans ce travail, nous présentons l'utilisation d’alpha-l-Arabinofuranosidase Araf51 pour la synthèse de glycoconjugés contenant des unités furanosidiques. Cette enzyme s’est révélée très efficace pour catalyser les oligomérisations des dérivés du l-arabinofuranoside et ceux du d-galactofuranoside jusqu'à la formation de pentasaccharides, ainsi que dans la synthèse de furanosides contenant des motifs structuralement modifiés du d-galactofuranose et des disaccharides de type pyrano-furano. Un grand nombre de composés synthétisés présentent des structures d’intérêt biologique que l’on retrouve dans certains agents pathogènes. Les essais biologiques ont montré que ces néofuranosides ont de fortes propriétés immunostimulatrices et peuvent potentiellement constituer un nouveau type d’adjuvants
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Eaton, Alexander Lee. "Isolation and Synthesis of Bioactive Compounds from Plants." Diss., Virginia Tech, 2015. http://hdl.handle.net/10919/64367.
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As a part of a continuing search for bioactive compounds with the International Cooperative Biodiversity Group (ICBG), and in collaboration with the Natural Products Discovery Institute of the Institute for Hepatitis and Virus Research (IHVR), twelve plant extracts were investigated for their antiproliferative activity against the A2780 cell line, three plant extracts were investigated for their antimalarial activity against Plasmodium falciparum, and three plant extracts were investigated for their anti-inflammatory activity (PPAR-y inhibition). Bioassay-guided fractionation of extracts led to the identification of four new antiproliferative compounds (2.1-2.3, 3.1), five new anti-inflammatory compounds (6.4a, 6.5a-b, 6.6a, 6.6c), and twenty-eight known compounds from eight of the extracts. In addition, mallotojaponin C, an antimalarial natural product, and derivatives were synthesized and investigated for their antimalarial activity.Ph. D.
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Chyan, Ming-Kuan. "Synthesis and Study of Bioactive Compounds: I. Pyrethroids; II. Glutathione Derivatives." Thesis, University of North Texas, 1995. https://digital.library.unt.edu/ark:/67531/metadc278848/.
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Part I: In the first study of pyrethroids, twenty-one novel pyrethroid esters bearing strong electron-withdrawing groups (e.g., halomethylketo and nitro groups) in the double bond side chain of the cyclopropane acid moiety have been synthesized and evaluated for insect toxicity. Rather than the usually employed Wittig reaction for these syntheses, the novel pyrethroid acid moieties were prepared by amino acidcatalyzed Knoevenagel condensations under mild conditions. In the second study of pyrethroids, fourteen pyrethroid-like carbonates were synthesized by condensation of a variety of alcohols and the chloroformates of the corresponding known pyrethroid alcohols.
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Lahore, S. "¿SYNTHETIC STUDIES TOWARDS BIOACTIVE FUNGAL METABOLITES¿." Doctoral thesis, Università degli Studi di Milano, 2014. http://hdl.handle.net/2434/229905.
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The problem of the development of new pesticides is very urgent, mainly because of the appearance of pest forms resistant to permitted pesticides and for the strict requirements in terms of their safety for people and the environment. Small molecules produced in biological contexts have been, and still are, a large reservoir of new biologically active substances, which can become scaffolds for the discovery of new agrochemicals.
The aim of this PhD work was to synthesize naturally occurring potentially antifungal and herbicidal compounds and to test their biological activity.
Efforts mainly focused towards the total synthesis of Bulgarein, a fungal metabolite produced by the fungus Bulgaria inquinans. Bulgarein possesses a benzo[j]fluoranthene skeleton, that can be found in a number of polyketide-derived fungal metabolites endowed with significant biological activity, in particular inhibition of Topoisomerase I. As no attempt to synthesize any of these compounds has been reported in literature so far, a synthetic sequence to the benzo[j]fluoranthene nucleus has been developed. Crucial steps for our strategy include a Suzuki coupling followed by a McMurry ring closure. The approach is modular and rapid and can be utilized to synthesize natural products, biologically active analogues or building blocks for the preparation of materials. Following this strategy, the first total synthesis of the recently isolated natural product benzo[j]fluoranthene-4,9-diol was carried out. Efforts were made to adapt the sequence for the synthesis of Bulgarein and other variously substituted compounds with this skeleton.
As a second topic in this research, attention was dedicated to another natural compound, Farinomalein A, a structurally rather simple maleimide isolated in 2009 from the entomopathogenic fungus Paecilomyces farinosus. Farinomalein shows potent inhibition of Phytophthora sojae, a plant pathogen that every year causes enormous damage to soybean crops. Recently, three new farinomalein derivatives (Farinomalein C, D & E) were isolated from an endophyte from the mangrove plant Avicennia marina, growing in Oman.
Due to the interesting antifungal activity of this class of compounds, a practical synthesis of farinomalein A was developed, which may have value in the large-scale preparation of the natural compound. Starting from farinomalein A, all the three derivatives were successfully synthesized . The antifungal activity of the derivatives was evaluated against Cladosporium cladosporioides and other pathogenic fungi.
An approach to the synthesis of Ascaulitoxin, a phytotoxic metabolite produced by the fungus Ascochyta caulina, was also developed.
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Semak, Vladislav. "Synthesis of 1S-ethyl-4-substituted quinolizidines and other potentially bioactive compounds." Doctoral thesis, Universitat de Barcelona, 2012. http://hdl.handle.net/10803/97241.
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Esta Tesis Doctoral se presenta como Compendio de publicaciones. Los capítulos en los que se ha dividido la presente Tesis son los siguientes:
Capítulo 1 – parte A: Enantioselective, Protecting Group-Free Synthesis of 1S-Ethyl-4-Substituted Quinolizidines
Se ha descrito una síntesis enantioselectiva que no implica grupos protectores para acceder a la quinolizidina clave 6 a partir de la lactama bicíclica derivada de fenilglicinol 1. La adición de un reactivo organometálico a 6 ocurre de manera estereoselectiva para conducir a las quinolizidinas 1S-etil-4-sustituidas 4-epi-207I y 7-9. Siguiendo una secuencia sintética análoga, se preparó el compuesto 9a-epi-6. Sin embargo, la adición de reactivos de Grignard al compuesto 9a-epi-6 no ocurre de manera estereoselectiva.
Capítulo 1 – parte B: A practical procedure for the removal of the phenylethanol moiety from phenylglycinol-derived lactams
Las lactamas bicíclicas no racémicas derivadas de fenilglicinol se han relevado como intermedios clave en la preparación de compuestos nitrogenados enantiopuros. En este capítulo se describe la eliminación del inductor quiral de piperidonas sustituidas utilizando aire u oxígeno en medio básico.
Capítulo 2: Synthesis of triheptanoin and formulation as a solid diet for rodents
En el presente estudio se describe la síntesis eficaz de triheptanoina de elevada pureza a partir de glicerol y ácido heptanoico, en presencia de carbono sulfonado como catalizador. La triheptanoina se formula como un sólido estable para que constituya la base de una dieta cetogénica mediante la combinación de custro gentes de formulación comerciales; dos tipos de sílica, celulosa microcristalina y talco. La adecuación de la dieta se prueba en ratones C57BI/6 en un periodo de 15 días, comparando el estado general y el cambio de peso corporal.
Capítulo 3: Toluene dioxygenase (TDO) mediated oxidation of halogen-substituted benzoate esters
Una serie de esteres benzoicos metílicos sustituidos en o-, m- y p- se han sometido a hidroxilación enzimática via fermetación con E. coli JM109 8pDTG601A). Solo se metabolizaron los benzoatos sustituidos en orto. El 2-fluorobenzoato de metilo produjo regioselectivamente solo un diol mientras que el 2-cloro, 2-bromo y 2-iodobenzoato de metilo proporciona una mezcla de regioisómeros.
Capítulo 4: Dauben–Michno oxidative transposition of allylic cyanohydrins
Enantiomeric switch of (–)-carvone to (+)-carvone
Cuando cianohidrinas alílicas se someten a la reacción de oxidación de Dauben-Michno a bajas temperaturas se accede a β-cianoenonas en buenos a excelentes rendimientos. El potencial de esta trasposición oxidativa se pone de manifiesto en enonas que contienen un plano latente de simetría como por ejemplo la conversión de la (-)-carvona en su enantiomero.A dissertation submitted by Vladislav SEMAK to obtain a doctoral degree from University of Barcelona. This thesis was developed under the supervision of Dr. Carmen Escolano Mirón from Faculty of Pharmacy, University of Barcelona. This doctoral thesis is presented as a compendium of publications. The thesis is divided in four chapters: CHAPTER 1 – PART A: Enantioselective, Protecting Group-Free Synthesis of 1S-Ethyl-4-Substituted Quinolizidines (Amat, M.; Semak, V.; Escolano, C.; Molins, E.; Bosch, J. Org. Biomol. Chem. 2012, 10, 6866-6875.) A practical enantioselective protecting group-free four-step route to the key quinolizidinone 6 from phenylglycinol-derived bicyclic lactam 1 is reported. The organometallic addition reaction upon 6 takes place stereoselectively to give 1-ethyl-4-substituted quinolizidines 4-epi-207I and 7-9. Following a similar synthetic sequence, 9a-epi-6 is also accessed. However, the addition of Grignard reagents upon 9a-epi-6 proceeds in a non-stereoselective manner. In order to gain insight into the different stereochemical outcome in the two series, theoretical calculations on the iminium salts A and B have been performed. The study concludes that the addition of the hydride, which is the step that determines the configuration of the final products, occurs in a stereoelectronic controlled manner. CHAPTER 1 – PART B: A practical procedure for the removal of the phenylethanol moiety from phenylglycinol-derived lactams (V. Semak; C, Escolano; C. Arróniz; J. Bosch; M. Amat Tetrahedron: Asymmetry 2010, 21, 2542-2549.) Chiral non-racemic bicyclic lactams derived from phenylglycinol have been appointed as key building blocks for the preparation of enantiopure nitrogen compounds. The removal of the chiral inductor leading to substituted piperidones by using air or oxygen in basic media is presented in this chapter. CHAPTER 2: Synthesis of triheptanoin and formulation as a solid diet for rodents (Semak, V.; Semakova, J.; Halbaut, L.; Asó, E.; Ferrer, I.; Calpena, A.; Escolano, C.; Perales, J. C. Eur. J. Lipid Sci. Technol. 2012, 114, 889-895.) In the present study, we successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal as a catalyst. Triheptanoin oil was then formulated as a solid, stable and palatable preparation using a ketogenic base and a combination of four commercially available formulation agents: hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose, and talc. Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change. CHAPTER 3: Toluene dioxygenase mediated oxidation of halogen-substituted benzoate esters (Semak, V.; Metcalf, T. A.; Endoma-Arias, M. A. A.; Mach, P.; Hudlicky, T. Org. Biomol. Chem. 2012, 10, 4407-4416.) A series of ortho-, meta-, and para-halogen-substituted methyl benzoate esters was subjected to enzymatic dihydroxylation via the whole-cell fermentation with E. coli JM109 (pDTG601A). Only ortho-substituted benzoates were metabolized. Methyl 2-fluorobenzoate yielded one diol regioselectively whereas methyl 2-chloro-, methyl 2-bromo- and methyl 2-iodobenzoates each yielded a mixture of regioisomers. Absolute stereochemistry was determined for all new metabolites. Computational analysis of these results and a possible rationale for the regioselectivity of the enzymatic dihydroxylation is advanced. CHAPTER 4: Dauben–Michno oxidative transposition of allylic cyanohydrins. Enantiomeric switch of (–)-carvone to (+)-carvone. (Hudlicky, J. R.; Werner, L.; Semak, V.; Simionescu, R.; Hudlicky, T. Can. J. Chem. 2011, 89, 535-543.) Allylic cyanohydrins were subjected to Dauben–Michno oxidation at low temperatures to provide β-cyanoenones in good to excellent yields. The potential of this oxidative transposition as a means of an enantiomeric switch of enones containing a latent plane of symmetry was tested by conversion of (–)-carvone to its enantiomer.
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Saito, Yu. "Synthesis of bioactive compounds: Synthetic study of D-Lac-terminated peptidoglycan fragment structures." Thesis, KTH, Kemiteknik, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-300085.
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Peptidoglycan (PGN) är en bakteriecellväggskomponent och känd för att känna igen olika receptorer eller enzymer för att leda aktiveringsimmunsystemet. Den allmänna strukturen för PGN består av sockerkedjor inklusive N-acetylglutamin (GlcNAc), N-acetylmuraminsyra (MurNAc) och tvärbundna peptidkedjor. PGN-fragment med D-Lac-ändpeptider har hittats från vankomycinresistenta enterokocker men ett kemiskt syntetiserat PGN-fragment med en D-Lac-ändpeptid har inte undersökts i detalj. Således fokuserade vi på syntesen av PGN-fragmentstrukturer som inkluderar en D-Ala-D-Lac-rest vid den terminala delen av peptidkedjan. För att syntetisera dessa fragmentstrukturer planerade vi att kombinera fastfassyntes (för Lac-peptiddelen) och lösningsfassyntes (för glykanberedning och kondensation). Detta tillvägagångssätt är fördelaktigt för framställning av peptidoglykanfragment med en komplex grenad peptiddel. Först beredde vi sockerdelen MurNAc-derivatet i lösningsfassyntes från ett glukosderivat. Medan den Lac-innehållande peptiden framställdes med fastfas-peptidsyntes med användning av 2-klortritylkloridharts. Med denna förening gav kondensationen av dessa två föreningar det önskade D-Lac-avslutade peptidoglykanfragmentet.Peptidoglycan (PGN) is a bacterial cell wall component and known to be recognized by various receptors or enzymes to lead the activation immune system. The general structure of PGN consists of sugar chains including N-acetylglutamine (GlcNAc), N-acetylmuramic acid (MurNAc) and cross-linked peptide chains. PGN fragments having D-Lac terminus peptides have been found from vancomycin-resistant enterococcus, but a chemically synthesized PGN fragment having a D-Lac terminus peptide has not been examined in detail. Thus, we focused on the synthesis of PGN fragment structures that include a D-Ala-D-Lac residue at the terminal part of the peptide chain. In order to synthesize these fragment structures, we planned to combine solid-phase synthesis (for the peptide- Lac part) and solution-phase synthesis (for glycan preparation and the condensation). This approach is advantageous for the preparation of peptidoglycan fragments having complex branched peptide moiety. First, we prepared the sugar moiety MurNAc derivative in solution-phase synthesis from a glucose derivative. While, the Lac-containing peptide was prepared with solid-phase peptide synthesis using 2-chlorotrityl chloride resin. Having this compound, the condensation of these two compounds gave the desired D-Lac-terminated peptidoglycan fragment.
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Pereira, Alban R. "Marine natural products : synthesis and isolation of bioactive analogues." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/7526.
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Tauramamide (2-12), a linear acylpentapeptide recently isolated from cultures of
Brevibacillus laterosporus (PNG-276) collected in Papua New Guinea, was synthesized in 9
steps and 29% overall yield. Besides confirming the proposed structure, synthetic (2-12)
allowed the antimicrobial assessment of this novel antibiotic. Additionally, a new analogue of
the surfactin depsipeptides family named dealkylsurfactin (2-48), was prepared in 10 steps and
14% overall yield. The compound was employed as a biological tool in binding studies between
the mitotic regulator isomerase Pinl and the microtubule-associated protein tau, a crucial
interaction involved in Alzheimer's disease.
Chemical exploration of Garveia annulata, a seasonal hydroid collected in Barkley
Sound, British Columbia, led to the isolation of twelve secondary metabolites including four new
compounds (3-53 to 3-56). Nine of these metabolites showed inhibition of indoleamine 2,3-
dioxigenase (IDO), with the annulins among the most potent in vitro IDO inhibitors isolated to
date. IDO plays a central role in immune escape, which prevents the immunological rejection of
tumors or the allogeneic fetus.
The ceratamine inspired antimitotic agent (4-142) and inactive analogue (4-157) were
synthesized in no more than 8 steps, with overall yields of 20% and 15% respectively. Activity
evaluation of these analogues suggested that potency improves with planarity and that the
synthetically laborious imidazo[4,5,d]azepine core heterocycle of ceratamines is not required for
activity.
Haplosamate A (5-62), isolated from the marine sponge Dasychalina fragilis collected in
Papua New Guinea, was found to be the first member of a new family of cannabinoid-active
sterols. Saturation transfer double-difference (STDD) NMR experiments confirmed that (5-62)specifically binds the cannabinoid human receptors CB1 and CB2 via the classical cannabinoid
pharmacophore.
A growing appreciation of the therapeutic potential of PI3K inhibitors has encouraged the
development of new inhibitory compounds with enhanced potency, selectivity and
pharmacological properties. Such substances are destined to the treatment of inflammatory and
autoimmune disorders as well as cancer and cardiovascular diseases. An optimization program
intended to develop more stable and isoform-selective PI3K inhibitors based on the marinederived
natural product liphagal (6-1), led to the preparation of a small library of synthetic
analogues.
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Hunter, Darren F. A. "Synthesis of bioactive pyrrolidine and piperidinone derivatives from carbohydrates." Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418528.
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Weston, Matthew. "Towards the asymmetric total synthesis of bioactive Celastraceae sesquiterpenoids." Thesis, University of Sheffield, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274986.
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Gill, Iqbal Singh. "Enzymatic synthesis of short bioactive peptides in novel media." Thesis, University of Reading, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335913.
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Zerla, D. S. "Synthesis of chiral bioactive molecules by Catalytic Asymmetric Reduction." Doctoral thesis, Università degli Studi di Milano, 2009. http://hdl.handle.net/2434/147565.
Full textAbstract:
Synthesis of chiral bioactive molecules by Catalytic Asymmetric Reduction
1) Carnosine is an endogenous dipeptide (β-alanyl-L-histidine) presents in the human muscles and nerve tissue which has a protective and detoxifying effect on the toxic metabolites. D-Carnosine is cited as an equivalent to L-carnosine, but due to its durability to hydrolysis by the carnosinases, seems to produce better therapeutic results than the L-form. To study the bioavailability and pharmacokinetic profile of D-carnosine, a deuterium labelled derivative is needed.
The optically active D or L histidine for carnosine synthesis can be preparated by asymmetric hydrogenation of the corresponding dehydro-aminoacid using Rh(I)-diphosphine complexes in presence of strong non coordinating acid.
2) The great success of Diphosphine-Ru systems in the reduction of
funzionalized ketones was reappraised by low activity in the
hydrogenation of un-funzionalized ketones which need the presence of an ancillary ligand in the complex for its reduction. In this thesis the effect of a rigid chirality on the ancillary diamine ligand using an ampy analogue, 8-amino-5,6,7,8-hydro-quinoline (CAMPY), will be studied in asymmetric hydrogenation and asymmetric transfer hydrogenation reactions.
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Straniero, V. "DESIGN AND SYNTHESIS OF NOVEL BIOACTIVE PEPTIDES AND PEPTIDOMIMETICS." Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/217536.
Full textAbstract:
Nowadays there’s a growing interest in biologically active peptides for the development of new therapeutics; however in some cases, they could not directly use as drugs, due to their inherent limitations, such as rapid metabolism and low oral activity. As a result, peptides are modified into peptidomimetics with specific characteristics, in a rational design.
The present PhD project is focused on the synthesis of several peptides and peptidomimetics, structurally different and presenting individual features, properties, targets and pharmaceutical applications. In particular, two are the research studies we’ve developed during the three years, these are the design of novel Carnosine-like derivatives and of new Farnesyl Transferase Inhibitors (FTIs).
Concerning the first topic, we investigated how Carnosine (β-alanyl-L-histidine) structural changes influence its role as scavenger of HNE (4-hydroxy-trans-2,3-nonenal) and other toxic aldehydes.
For this reason we modified the carnosine structure firstly replacing the Hystidinil- portion with different aromatic system, secondly substituting the β-alanyl portion with ten different amino acids, chosen in order to cover exhaustively the available chemical space. Finally we rigidified the whole structure, inserting a 2-oxazolidinone; the entire compound underwent biological evaluation, testing their ability to quench HNE.
As a result, some of the twenty dipeptides showed impressing scavenging activities and great selectivity towards toxic aldehydes, suggesting us that they can represent truly promising candidates for the design of improved carnosine derivatives.
Regarding the second subject, we designed, synthesized and tested several peptidomimetics of the CAAX box, where CAAX is the sequence Cysteine-Valine-Isoleucine-Methionine, able to block the farnesylation of RAS proteins and therefore cell proliferation.
The design started from a nanomolar range FTI, previously synthesized by our group, where the central dipeptide (AA) is replaced with a 4-amino-2-o-tolylbenzoyl spacer and the Cysteine (C) with the residue 2-amino-4-thiazolylacetyl. The synthesis of the novel FTIs followed two separate approaches; at first we kept the aromatic spacer and modified the N-terminal residue with other heterocycles; the unimproved antiproliferative activity suggested us to apply other kind of modification. Therefore we replaced the o-tolyl with six heteroaromatic residues, in addition the synthesized compounds presented, as N- terminal residue, the 2-amino-4-thiazolylacetyl itself or the 1,4-benzodioxan-2-ylmethyl or the 1,4-benzodioxan-2-ylformyl. In all the three series of compounds, the 2-thienyl, 1-naphtyl and the 3-furanyl derivatives showed the highest FTase inhibition, at low micromolar level.
Taken together, our biological activities provide interesting results, confirming that peptides and peptidomimetics should be employed as therapeutics.
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Stucchi, M. "MULTICOMPONENT APPROACHES TO THE SYNTHESIS OF SMALL BIOACTIVE MOLECULES." Doctoral thesis, Università degli Studi di Milano, 2015. http://hdl.handle.net/2434/330951.
Full textAbstract:
In this PhD thesis, we exploited the potentialities of four different multicomponent reactions (MCRs), namely Ugi four-component reaction (U-4CR), N-split Ugi reaction (N-split U-4CR), van Leusen three-component reaction (vl-3CR) and Biginelli reaction (Bg-3CR), developing five different approaches to the synthesis of small bioactive molecules.
In particular, we successfully applied the build/couple/pair strategy obtaining a small library of ketopiperazine-based minimalist peptidomimetics, by means of diastereoselective U-4CR/post-cyclization sequences, employing optically pure amino acid-derived α-amino aldehydes and α-isocyanoacetates as starting materials. Computer-assisted NMR NOE analysis allowed us to determine the configuration of the newly formed stereocenters, while molecular dynamics simulation and biological evaluation clearly underlined the potentiality of selected compounds to interfere with protein-protein interactions (PPIs).
We also focused our attention on another class of peptide-like compounds, namely diamine-based peptidomimetics, by carefully optimizing the N-split U-4CR conditions for the introduction of N-protected amino acids and α-isocyanoacetates components, in a stereoconservative way. This methodology largely simplifies the synthesis of such compounds, opening the way to the use of more complex secondary diamines, able to induce well-defined secondary structures in the related peptidomimetic and hopefully targeting novel PPIs.
Furthermore, by combining the same N-split U-4CR with common transformations, a library of dopamine receptor agonists was rapidly obtained, with biological activities in the nanomolar range. Although the desired D2/D3 selectivity was not achieved, structure-activity relationship (SAR) and docking studies allowed us to understand the key pharmacophoric elements in these novel structures, leading the way to the design of improved molecular scaffolds.
By employing the vL-3CR in an iterative way, we designed a novel C2-C5’ linked polyimidazole-based minimalist framework, able to mimic the i, i+1, i+2 and i+3 amino acid residues of a β-strand motif. Its conformational behaviour was investigated through solution-phase NMR and molecular dynamics studies, allowing to demonstrate its ability to mimic a poly-alanine β-strand.
Finally, we explored the possibility to combine MCRs with organocatalysis, developing the first BINOL-derived phosphoric acid catalysed Biginelli-like reaction on a ketone. In particular, employing N-substituted isatins as carbonyl substrates, we achieved the synthesis of a small library of biologically relevant enantioenriched spiro[indoline-pyrimidine]-diones derivatives. The assignment of the configuration at the new oxindole C-3 stereocenter was assessed through quantum-mechanical methods and NMR spectroscopy, while computational studies on the reaction transition state allowed us to explain the enantioselectivity and the stereochemical outcome.
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Secci, Francesco. "Strained carbocyclic systems in the synthesis of bioactive products : methodologies and total synthesis." Paris 11, 2006. http://www.theses.fr/2006PA112296.
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Tang, Shoubin. "Structural and Synthetic Studies of Bioactive Natural Products." Diss., Virginia Tech, 2005. http://hdl.handle.net/10919/26104.
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As part of an ongoing investigation for anticancer agents from natural resources, four plant extracts were determined to contain interesting bioactivity. These extracts were separated by chromatography to afford a number of bioactive compounds that were characterized by spectral analysis.
Fractionation of the fruit extract of Cryptocarya crassifolia led to the isolation of two known flavonoids and two known cryptocaryalactones. Fractionation of the bark extract of the same plant also gave the same two cryptocaryalactones. All these compounds were weakly active in a cytotoxicity assay.
Two new isoflavones were isolated from the roots of an Egyptian lotus plant, Lotus polyphyllos. Both compounds were characterized by UV, NMR, and mass spectroscopic analysis
The methanol extract from the leaves and bark of a Brexiella sp. were found to display significant cytotoxic activity versus the A2780 mammalian cell line. Two highly active cardenolides, glucodigimetholide and xysmalogenin glucoside, were isolated and found to be responsible for the bioactivities. Both compounds were characterized by spectroscopic analysis and comparison to the known literature data.
Two marine extracts were also investigated. The pyridoacridine alkaloids, amphimedine and neoampimedine, were isolated from the marine sponge Petrosia sp., and three bromo-tyrosine alkaloids were isolated from the marine sponge Porphyria flintae. The structures of these known compounds were all elucidated by comparison to literature data.
Two 6-amino-glycoglycerolipids had been previously isolated from a marine algae species and shown to inhibit the activity of the enzyme Myt-1 kinase. These compounds and some related compounds were synthesized and their bioactivities against Myt1 kinase were determined.
Two isotopically labeled paclitaxel analogs (2D, 19F) were prepared in preparation for studies of the tubulin-binding conformation of paclitaxel by REDOR NMR. A new macrocyclic A-nor-paclitaxel was also synthesized, and was found to have good cytotoxicity and improved tubulin-binding activity as compared with paclitaxel.Ph. D.
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Tran, Wendy. "Synthesis of Bioactive Natural Products & Derivatives as Novel Anti-infectives." Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/23995.
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Throughout history natural products have served as a valuable resource for the treatment of various diseases. To this day, many of these ancient remedies and their derivatives are still in use. However, in recent years, antibiotic discovery has stagnated at a time where there has also been the alarming emergence of antibiotic resistance which threatens to undermine the effectiveness of existing therapies. As such, novel antimicrobial agents are urgently needed that possess unique mechanisms of action to those currently in use. A promising class of natural products that exhibit antimicrobial activity are the non-ribosomal peptides (NRPs). This thesis describes the synthesis and biological evaluation of a number of NRP-derived molecules with a view to discovering new antibiotic leads. Chapters 2 & 3 describe the design and synthesis of potent anti mycobacterial derivatives based on the sansanmycin natural product scaffold. This involved the development of a late stage diversification route, thereby providing a platform for expedient access to a diverse library of analogues. These analogues were subjected to biological evaluation, from which key structure activity relationships were elucidated for inhibition of the growth of Mycobacterium tuberculosis – the etiological agent of tuberculosis (TB). These studies ultimately led to the identification of a new lead compound which was further evaluated in two animal models of TB infection. Chapter 4 describes efforts towards the synthesis of the janthinocins, a class of NRPs with potent activity against Gram positive bacteria. The synthetic strategy relied on late stage, chemoselective transformations to install key functionalities namely, selective oxidation of tryptophan to afford β ketotryptophan and elimination of β methylcysteine to form dehydrobutyrine. A deoxy-variant of janthinocin B was successfully synthesised which was subjected to late stage oxidation to the parent natural product, albeit on a small scale.
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Trippier, Paul Charles. "Synthesis of highly substituted heterocycles : the oxazolomycins." Thesis, University of Oxford, 2006. http://ora.ox.ac.uk/objects/uuid:b758987c-7a0c-4c1b-982c-61b4d383680a.
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This thesis is concerned with studies towards the total synthesis of a class of natural products - the oxazolomycins. Attention was focused on the left-hand side triene fragment and right-hand side lactam heterocyclic system. This thesis describes the synthesis of a racemic terminal phenyl analogue of oxazolomycin A and C, possessing the left-hand side triene geometry as required. A novel truncated pyridine analogue is also described. The molecules represent a racemic total synthesis of analogues of phthoxazolin A and inthomycins B and C. The synthesis is based upon a crucial Stille cross-coupling reaction between stannane and diene iodide fragments. The stannane fragment was synthesised using literature precedented methods and the vinyl halide prepared using a highly stereoselective Wittig, Takai homologation or Stork reaction leading to a variety of ratios of mixtures of Z, E and E, E diene halides. These investigations led to the availability of 1:1, 3:1 and 1:3 mixtures of Z, Z, E : Z, E, E left hand side triene fragments possessing the required stereochemistries for oxazolomycin A and C. Utilising existing methodology developed in the Moloney group, investigations were carried out towards construction of β-keto esters possessing terminal hydroxyl functions, suitable for diastereoselective aldol ring closure. Following extensive protecting group manipulation and N-acylation coupling optimisation, a TIPS protected β-keto acid, existing as predominantly the keto tautomer, was successfully coupled to an oxazolidine heterocycle. This N-acylated oxazolidine upon Dieckmann cyclisation would present an advanced intermediate of opposite configuration (Lserine is used here as a cheaper starting material for the construction of the oxazolidine instead of D-serine) to the oxazolomycin right-hand side.
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Khanizeman, Rabi'ah Nisha. "Studies towards the synthesis of bioactive natural products and development of new synthetic methods." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066644.
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Plus de la moitié des médicaments mis sur le marché entre 1981 et 2014 sont des produits naturels ou des dérivés. Ainsi, les structures des produits naturels sont une excellente source d'inspiration pour la découverte de nouveaux médicaments. L'introduction de cette thèse met en lumière le rôle important joué par les produits naturels en chimie médicinale. De plus, la préparation de produits naturels peut déboucher sur le développement de nouvelles méthodes de synthèse. Ainsi, au cours de cette thèse une approche synthétique de plusieurs produits naturels a été réalisée. Ces composés présentent des motifs clés tels que des amino-alcools 1,3, des diamines 1,3 ou un tétrahydropyrane. Les études synthétiques réalisées comprennent le développement de nouvelles méthodes pour accéder à ces structures. D'autre part, une réaction de Heck permettant l'accès à des précurseurs de tri-aryl éthylènes a été mise au pointIt has been estimated that more than half of all approved drugs, from the period 1981 to 2014, are either natural products or their derivatives. This, thus, indicates that natural products (NP), together with natural product derived and natural product inspired structures are significant as sources for potential leads towards the discovery of new drugs. The introduction of this thesis thereby highlights the importance of natural products in the field of drug discovery. In addition, the introduction emphasizes on the importance of natural products as a field of research. This is as the synthesis of natural products can result in the development of new synthetic methods which can then be applied to a broader range of applications across the field of chemistry. This new information, thus, bridges a gap in the scientific knowledge and allows for progress in science. Therefore the content of this thesis describes the syntheses and development of new synthetic methods towards bioactive natural products containing 1,3-amino alcohol, 1.3-diamine, THP-ring as well as tri-aryl ethylene unit which represent the key themes of (+)-negamycin (Chapter 1), (-)-cernuine and (+)-cermizine D (Chapter 2), enigmazole A (Chapter 3) and tamoxifen (Chapter 4), respectively
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Kilburn, John Paul. "Novel solid-phase synthesis strategies for the preparation of heterocycles and guanidines." Thesis, Open University, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247056.
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Li, Sifeng. "Hydrofunctionalization of alkenes and their applications in the synthesis of bioactive compounds." HKBU Institutional Repository, 2020. https://repository.hkbu.edu.hk/etd_oa/812.
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Heterocycles are privileged structural motifs found in many natural products and biologically active compounds. Given the prevalence of this structural unit, there has been considerable interest and challenge in developing methods for construction optically pure heterocycles in organic synthesis and pharmaceutical chemistry. The skeleton of hydronaphthalene and indole are pervasive structural motifs in the pharmaceutical drugs that exhibit various bioactivities. This dissertation is mainly focused on the development of transition-metal-catalyzed asymmetric functionalization of alkenes, including the hydroselenation and hydroamination of various oxa/azabicyclic olefins for the synthesis of bioactive compounds and structural modification of oleanolic acid. An efficient rhodium catalytic system consisting of Rh(COD)2OTf/(S)-xyl-Binap, and n-Bu4NI was developed for the asymmetric hydroselenation of various oxa/azabicyclic olefins with diaryl diselenides instead of the unstable, malodorous selenol compounds. Under these reaction conditions, a wide range of heterobicyclic alkenes produced selenol containing hydronaphthalene derivatives in high yields (up to 96%) along with excellent enantioselectivities (up to 97%), overcoming the self- promoted racemic hydroselenation. The exo-configuration of the exclusive addition product was confirmed by X-ray crystal structure analysis. The strategy has also been applied to the kinetic resolution of unsymmetric oxabenzonorbornadiene. Further, these selenium compounds can catalyze the oxidative coupling reaction of 2-naphthols. Then, for the synthesis of trans 1-indolyl dihydronaphthalenols, a highly enantioselective Rh/Pd dual-metal sequentially catalytic system was revealed through intermolecular and intramolecular cascade hydroamination in the reaction of oxabenzonorbornadienes with 2-alkynylanilines. The exclusive trans-configuration of 1-(2-phenyl)indolyl dihydronaphthalenol was identified by X-ray crystal analysis. Various substituents, such as aryl, heteroaryl, alkyl, and silyl groups on alkynyl starting material can be used as compatible nucleophiles in the reaction to give excellent iii enantiomeric excesses (up to 99%) with good yields (up to 88%) under mild conditions. The reaction can be performed on a gram scale, while the indole derivatives could be transformed at the hydroxyl and indolyl funtionalities. The in silico and in vitro screening showed that the novel 1-indolyl dihydronaphthalenol products can serve as potential lead compounds for treating inflammation disease. At last, a series of functional groups, including carboxyl, phosphate, sulfone, triazole, tertiary amine, and glycosyl have been incorporated into oleanolic acid to improve its water solubility. A wide range of their derivatives have been obtained, and it was found that carboxyl salt, phosphate salt, and sulfonate salt contribute to the increase of the solubilities in water; up to 8 g/L was gained for carboxylate salt, which also provides the possibility to improve the bioavailability of these compounds
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Xynos, Ioannis D. "Bioactive glasses for the in vitro synthesis of bone tissue." Thesis, Imperial College London, 2001. http://hdl.handle.net/10044/1/11494.
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Yan, Luping. "Bioactive marine natural products : analogue synthesis, SAR, and target identification." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/50069.
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3,6,7-trihydroxycoumarin C11 (2.14) was first isolated from the green alga Dasycladus vermicularis in 1983. C11 and 3,7,8-trihydroxycoumarin C21 (2.15), alongside their precursors C12 (2.18) and C22 (2.20), were synthesized for a target-based screen for anti-HCV drugs, where ideal hits eliminate fluorescence signals by inhibiting the proteolytic activity of HCV NS3pro/Pep4A against a synthetic peptide “BS-IQFS”. With C12 and C22 serving as negative controls, C11 and C21 inhibited the NS3pro/Pep4A activity in vitro. The IC₅₀’s of C11 and C21 were 3.07 μM and 2.10 μM, respectively.
A bioassay-guided fractionation identified sintokamides A – E (3.11 – 3.15) from extracts of the sponge Dysidea sp. in 2008. In a phenotypic screen, the chlorinated dipeptides showed strong to modest inhibition of luciferase activity caused by AR NTD transactivation in LNCaP cells. Larger quantities of sintokamides A and B were isolated from the sponge for further biological study. After developing a practical synthetic route, a comprehensive SAR of the sintokamides was available from the in vitro activities of 29 synthetic analogues/precursors based on a 1,17-dinorsintokamide skeleton. LPY26 [(4R,10R)-3.233] showed the best biological activity in the synthetic analogues prepared to date and it was selected as a drug lead. Mechanism of action study using synthetic probes LPY30 (4.7) and LPY31 (4.8) revealed that the hexachlorinated 1,17-dinorsintokamides covalently bound to the AR, but not to the same AF1 region in the AR NTD as EPI-001 (3.8).
The structure of latonduine A (5.1) isolated from the sponge Stylissa carteri and its total synthesis were published in 2003. Later, latonduine A was shown to be active in a phenotypic screen to find drug leads for the treatment of cystic fibrosis caused by the F508del mutation. Latonduine A could efficiently correct immunofluorescent F508del-CFTR trafficking from the endoplasmic reticulum to the plasma membrane in the engineered cells. Synthetic latonduine A and N-biotinylated latonduine A (5.17) were prepared to support biological studies aimed at identifying its cellular protein target(s). These studies culminated in the finding that latonduine A is an inhibitor of PARP-3 with an EC₅₀ of 400 pM in CFBE41o- cells.Science, Faculty of
Chemistry, Department of
Graduate
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Blanc, Antoine. "Synthesis on the solid phase of a bioactive tryptathionine octreotate." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/61821.
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Forestieri, Roberto. "Isolation, structure elucidation, and total synthesis of bioactive natural products." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/45668.
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Shabbir, Ghulam. "The synthesis and mechanism of formation of some bioactive heterocycles." Thesis, University of Hertfordshire, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365934.
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Almaliti, Jehad S. "Natural Products-Inspired Synthesis and Biological Evaluation of Bioactive Agents." University of Toledo Health Science Campus / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1384555204.
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Antonopoulou, Io. "Use of feruloyl esterases for chemoenzymatic synthesis of bioactive compounds." Licentiate thesis, Luleå tekniska universitet, Kemiteknik, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:ltu:diva-62836.
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Feruloyl esterases (FAEs, EC 3.1.1.73) represent a subclass of carboxylic acid esterases that under normal conditions catalyze the hydrolysis of the ester bond between hydroxycinnamic acids (ferulic acid, sinapic acid, caffeic acid, p-coumaric acid) and arabinose residues in plant cell walls. Based on their specificity towards monoferulates and diferulates, substitutions on the phenolic ring and on their amino acid sequence identity, they have been classified into four types (A-D). The use of FAEs as accessory enzymes for the degradation of lignocellulosic biomass and their synergism with other hemicellulases has been studied for application in many industries, such as the food, the biofuel and the paper pulp industry. In the recent years, the use of FAEs as biosynthetic tools has been underlined. Under low water content, these enzymes are able to catalyze the esterification of hydroxycinnamic acids or the transesterification of their esters resulting in compounds with altered lipophilicity, revealing a great potential for tailor-made modification of natural antioxidants for use in cosmetic, cosmeceutical and pharmaceutical industries. The first part of the thesis is focused on the optimization of reaction conditions for the synthesis of two bioactive esters: prenyl ferulate and L-arabinose ferulate using 5 FAEs (FaeA1, FaeA2, FaeB1, FaeB2 and MtFae1a) from Myceliophthora thermophila in detergentless microemulsions. Reaction conditions were optimized investigating parameters such as the medium composition, the substrate concentration, the enzyme load, the pH, the temperature and the agitation. Regarding the synthesis of prenyl ferulate, FaeB2 offered the highest transesterification yield (71.5±0.2%) after 24 h of incubation at 30oC using 60 mM vinyl ferulate (VFA), 1 M prenol and 0.02 mg FAE/mL in a mixture comprising of 53.4: 43.4: 3.2 v/v/v n-hexane: t-butanol: 100 mM MOPS-NaOH pH 6.0. At these conditions, the competitive hydrolysis was 4-7 fold minimized. Regarding the synthesis of L-arabinose ferulate, FaeA1 offered highest transesterification yield (35.9±2.96%) after 8 h of incubation at 50oC using 80 mM VFA, 55 mM L-arabinose and 0.02 mg FAE/mL in a mixture of 19.8: 74.7: 5.5 v/v/v n-hexane: t-butanol: 100 mM MOPS-NaOH pH 8.0. It was revealed that the type B FAEs from M. thermophila show higher preference to more lipophilic acceptors like prenol, while the type A FaeA1 was more efficient in the synthesis of the more hydrophilic L-arabinose ferulate. The second part of the thesis is focused on the investigation of the basis of the type A classification of a well-studied FAE from Aspergillus niger (AnFaeA) by comparing its activity towards methyl and arabinose hydroxycinnamate esters. For this purpose, L-arabinose ferulate and caffeate were synthesized enzymatically. kcat/Km ratios revealed that AnFaeA hydrolyzed arabinose ferulate 1600 times and arabinose caffeate 6.5 times more efficiently than methyl esters. This study demonstrated that short alkyl chain hydroxycinnamate esters which are used nowadays for FAE classification can lead to activity misclassification, while L-arabinose esters could potentially substitute synthetic esters in classification.
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AMABILI, PAOLO. "α-Hydrazido acids for the synthesis of bioactive amphiphilic compounds." Doctoral thesis, Università Politecnica delle Marche, 2017. http://hdl.handle.net/11566/245568.
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Con lo scopo di ottenere nuovi foldameri (oligomeri con un folding prevedibile), sono stati sintetizzati nuovi mimici di β-peptidi caratterizzati dalla formale sostituzione Cβ→Nβ(acile) modificando β-amminoacidi a base pirrolidin-2-onica, utilizzati precedentemente nei nostri laboratori per la preparazione di esameri. Sono stati quindi sintetizzati nuovi oligomeri di α-idrazidoacidi conformazionalmente costretti in un anello imidazolidinonico (AOPIC) che sono stati poi analizzati usando tecniche spettroscopiche (NMR e CD) e computazionali (MD). Lo studio computazionale, oltre a fornire la prova teorica della presenza di un’elica-8 come unica struttura stabile, ha evidenziato anche la forte tendenza alla formazione di una sequenza “hydrazido-turn”, in cui cicli addizionali a 5-termini sono presenti contemporaneamente ai cicli ad 8-termini.
Ci siamo poi dedicati alla ricerca di nuovi analoghi dei precedenti oligomeri che non fossero però chirali e conformazionalmente costretti, quindi più facili ed economici da sintetizzare, con lo scopo di ottenere la stessa struttura secondaria ma con minore sforzo sintetico e una migliore versatilità nella sostituzione delle catene laterali. Infatti, un’appropriata disposizione delle catene laterali, può essere un ottimo punto di partenza per la realizzazione di foldameri anfifilici da testare come antibiotici. Sono infatti molte le problematiche associate all’utilizzo di farmaci a base peptidica e, a causa del rapido e preoccupante sviluppo di fenomeni di resistenza agli antibiotici, i mimici sintetici degli AMPs (SMAMPs) stanno ricevendo molta attenzione come nuovi potenziali farmaci. A questo proposito, abbiamo sviluppato la sintesi di derivati anfifilici a base di α-idrazidoacidi anfifilici che possono rappresentare una nuova classe di piccoli mimici sintetici di peptidi antimicrobici (SMMAMPs). Da primi esperimenti di valutazione dell’attività antimicrobica mediante la valutazione della concentrazione inibente minima (MIC), i nostri composti sono risultati essere promettenti agenti antimicrobici, utili per applicazioni biologiche eventualmente a seguito di un’ottimizzazione strutturale per migliorarne le proprietà farmacologiche.Novel mimics of β-peptides based on the formal substitution Cβ→Nβ(acyl) were synthesized with the aim to obtain new foldamers (oligomers with a predictable folding). Thus, we modified pirrolidin-2-one tethered β-amino acids, previously used in our laboratory to prepare hexamers, devised a new imidazolidinone-tethered α-hydrazido acid (AOPIC) suitable to give oligomers that were analysed using spectroscopic (NMR and CD) and computational (MD) techniques. The computational analysis, besides furnishing the theoretical proof of the 8-helix as the only stable structure, strongly evidenced a “hydrazido-turn” sequence, where additional 5-membered H-bonded cycles were enclosed within the 8-membered ones. In the search for simpler and cheaper analogues, we directed our attention towards analogues of the previously employed oligomers, where constrictions and chirality were missing, with the aim to obtain a secondary structure with minor synthetic effort and increased versatility in side chains substitution. In fact, an appropriate disposition of side chains could be a good starting point for the synthesis of amphiphilic foldamers to be tested as antibacterial agents. Since many difficulties are connected with the use of peptide drugs, synthetic mimics of AMPs (SMAMPs) are receiving ever more interest and importance as new drug candidates, owing to the rapid and widespread development of antibiotic resistances. Thus, within this topic, we carried out the synthesis of amphiphilic α-hydrazido acid derivatives, which could be novel lead compounds for developing a new class of SMMAMPs. The Minimum Inhibitory Concentration (MIC) was evaluated for a few properly derivatized α-hydrazido acid monomers, and the preliminary results showed a promising antimicrobial activity suitable for biological applications, eventually leading to a structure optimization for improvement of the pharmacological properties.
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Tinarelli, Alessandro <1975>. "Novel Methodologies for the Synthesis of Scaffolds for Bioactive Molecules." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2010. http://amsdottorato.unibo.it/2291/1/Tinarelli-Alessandro-tesi.pdf.
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Tinarelli, Alessandro <1975>. "Novel Methodologies for the Synthesis of Scaffolds for Bioactive Molecules." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2010. http://amsdottorato.unibo.it/2291/.
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Zang, Qin. "Towards the total synthesis of peloruside A analogues." Laramie, Wyo. : University of Wyoming, 2008. http://proquest.umi.com/pqdweb?did=1663059931&sid=1&Fmt=2&clientId=18949&RQT=309&VName=PQD.
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Stout, Elizabeth Paige. "Discovery and synthesis of bioactive natural product probes from marine systems." Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/37301.
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Flora and fauna from terrestrial and marine environments provide libraries of natural compounds for drug discovery. The last four decades have seen major advances in ocean exploration that have allowed chemists and biologists to explore previously inaccessible and rare marine organisms. The study of under-explored marine organisms can result in the discovery of structurally novel and unusual natural products with drug potential. Prior to 2005, no natural products had been reported from the Fijian red macroalgae Callophycus serratus or Neurymenia fraxinifolia. As a result of the work described in this thesis and others in the same research group, 33 unique brominated meroditerpenes have been isolated and elucidated alpha-pyrone natural products were discovered from N. fraxinifolia, enriching the natural product library for drug development. Several natural products isolated from C. serratus exhibited sub-micromolar inhibition against the human malaria parasite Plasmodium falciparum, including a drug-resistant strain. Derivatization of the natural product bromophycolide A into fluorescent probes allowed the determination of a non-enzymatic mechanism of action against the human malaria parasite P. falciparum. Through a combination of detailed SAR mapping, molecular fluorescent imaging of live cells, UV-vis spectroscopic analyses, and protein affinity techniques, the mechanism of action of bromophycolide A against P. falciparum was determined to involve inhibition of heme crystallization. These studies identify a new class of natural products that target heme detoxification in both drug-sensitive and drug-resistant P. falciparum and suggest an avenue to circumvent drug resistance.
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Chen, Xiaoyun [Verfasser]. "The synthesis of bioactive sulfoximines and N-alkynylated sulfoximines / Xiaoyun Chen." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2014. http://d-nb.info/1066984204/34.
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Derudas, Marco. "Design, synthesis and biological evaluation of novel bioactive nucleosides and nucleotides." Thesis, Cardiff University, 2009. http://orca.cf.ac.uk/55855/.
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At the present there are 36 approved antiviral drugs in the UK of which half are nucleoside analogues. However, the emergence of drug resistance and of new virus strains necessitates new drugs. In particular in this thesis, different nucleoside analogues were studied as potential antivirals. One of the major issues related to nucleoside analogues is the emergence of resistance due to a lack of bioactivation to the monophosphate form. To overcome this issue, the phosphoramidate ProTide technology can be applied. This strategy allows the delivery of the monophosphate form directly inside the cell. Bicyclic nucleoside analogues are a new class of anti-varicella zoster agents of which Cfl743 is the most potent anti-varicella zoster compounds reported to date. Its 5'-valyl derivative, FV100, is currently in phase II clinical trials. A series of derivatives to increase the activity and to investigate the mechanism of action of this new class of compound are reported. Moreover, attempts to improve the scale up synthesis of FV100 are described. Ribavirin is a broad spectrum antiviral drug. The application of the ProTide approach to this compound was not successful. Enzymatic and molecular modelling studies have been performed in order to understand the lack of activity. Acyclovir and its esters are currently the treatment of choice for herpes simplex and varicella-zoster infections. The application of the ProTide technology gave surprising results. In fact, these compounds have been found to be active against HIV, whilst ACV itself did not show any activity. Moreover, these compounds retained activity versus thymidine kinase deficient strains against which acyclovir lost activity. These striking results prompted us to investigate other different nucleoside analogues, through a virtual screening using reverse transcriptase, guanylate or adenylate kinase and human polymerase y. The selected nucleoside analogues from this study include: ganciclovir, penciclovir and their derivatives. ProTides of these are thus pursued.
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Montgomery, Laura Jane. "Investigations of the biosynthesis and biomimetic synthesis of bioactive natural products." Thesis, University of Warwick, 2008. http://wrap.warwick.ac.uk/4420/.
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This thesis describes work towards the biomimetic synthesis and understanding the biosynthesis of two families of natural products: prodiginines and quartromicins. Prodiginines are a large family of red pigmented tripyrrole antibiotics. Although they have not been used clinically, the promising anti-cancer, immunosuppressive and antimalarial activity they display at non-toxic doses has generated renewed interest in their utilisation. The synthesis of an analogue of the proposed pyrrole-2-carboxyl-RedO intermediate in prodiginine biosynthesis has been achieved. The resulting NAC thioester and analogues of it have been used to investigate the prodiginine biosynthetic pathway in Streptomyces coelicolor, and to examine the production of prodiginine analogues by mutasynthesis. Quartromicins, novel anti-viral antibiotics, are a structurally unique group of spirotetronate natural products produced by Amycolatopsis species. They are unusual symmetric macro cyclic compounds which possess a 32-membered carbocyclic structure with four spirotetronic acid units connected by enone or dienone linkers in a head-to-tail fashion. These macrocyclic compounds are intriguing because they have alternating endo- and exo- spirotetronic acid units, with the opposite "comers" being identical. Although the quartromicins have therapeutic potential, very little is known about their biosynthesis. In this research a biosynthetic pathway to the quartromicins has been proposed based on hypothetical pathways to related natural products. The synthesis of the two putative key intermediates in quartromicin biosynthesis has been achieved. An improved method for the synthesis of exomethylene tetronates has been developed, and novel rearrangements have been discovered. The two putative key intermediates have been used to investigate the biomimetic synthesis of the carbon skeleton of the quartromicin algycone, and mass spectrometric evidence for formation of homo- and heterodimers, and a heterotetramer of the key intermediates has been obtained.
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Filipa, P. da Cruz Ana. "C-branched carbohydrate lactones : Versatile intermediatesin the synthesis of branched bioactive." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509913.
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Fara, Mario Antonio. "Cell penetrating peptoid carriers : microwave assisted synthesis and bioactive molecules delivery." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/10889.
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Effective methods for the selective passage of therapeutic molecules or probes through biological barriers are essential for the study of cellular functions. Cell penetrating cationic peptoids, based on a lysine like unit, were efficiently synthesised a combination of solid phase synthesis strategies and microwave heating. A linear 7mer peptoid was thus prepared by direct solid phase synthesis and conjugated to both a peptide hormone (α- Melanocyte Stimulating Hormone, a 13mer peptide) and to peptide nucleic acids (9mer, 12mer and 15mer prepared using Dde/Mmt protected monomers) targeting tyrosinase mRNA. These conjugates were able to efficiently penetrate different cell lines (average uptake > 90%), and even more, to penetrate human skin, with the heptapeptoid carrier being able to deliver a 12mer PNA deep inside the dermis stratus. Antisense DNA oligomer (19mer, targeting tyrosinase mRNA) conjugated to the heptapeptoid carrier by a disulfide linkage was able to down-regulate tyrosinase expression, showing the potential of the carrier in delivering DNA into cells. Delivery of macromolecules such as protein and plasmid DNA were attempted. Heptapeptoids functionalised with a tetradentate Ni2+ ligand were tested for the delivery of hexahistidine (His6) tagged GFP protein into cells, while 3 generations of a novel peptoid dendrimer were prepared and tested for the cellular delivery of DNA.