To see the other types of publications on this topic, follow the link: Macroline.
Dissertations / Theses on the topic 'Macroline'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Macroline.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Pett, Richard. "Total synthesis of the macroline-related alkaloid (±)-alstonerine." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/17842.
Full textAbstract:
This thesis examines the total synthesis of the macroline-related indole alkaloid alstonerine and related compounds. It is divided into three sections: The first section provides a review of the total synthesis efforts reported by Cook, Martin, Kuethe, and Kwon, as well previous work within the Craig group. The second section discusses the results of our investigations. The optimisation of the synthesis of key intermediate α,β-unsaturated lactam alcohol via directed-aziridine ring-opening is presented in detail. Our progress towards the synthesis of macroline-related alkaloids macroline, alstolactone, anhydromacrosalhine-methine and alstonerinal, as well as their N4-tosyl derivatives, from the key intermediate is discussed. The findings from these studies are presented en route to the total synthesis of alstonerine. The third section contains experimental procedures and characterisation data for compounds synthesised.
2
Garet, Florence. "Mode d'action des antibiotiques du groupe des macrolides." Paris 5, 1988. http://www.theses.fr/1988PA05P265.
Full text
3
Talbi, Patrice. "Macrolides et éradication de Hélicobacter pylori." Bordeaux 2, 1994. http://www.theses.fr/1994BOR23066.
Full text
4
Zarate, Ruiz Griselda Araceli. "Vers la synthèse totale de la Thuggacine A." Thesis, Montpellier, Ecole nationale supérieure de chimie, 2011. http://www.theses.fr/2011ENCM0002.
Full textAbstract:
Le travail présenté dans ce manuscrit concerne la synthèse du fragment C12-C25 de la Thuggacine A, macrolide antibiotique, par deux voies de synthèse. La première voie de synthèse nous a permis de créer 4 des 5 centres stéréogéniques à partir du (R)-glycéraldéhyde acétonide. L'étape-clé d'induction asymétrique a montré que les 3 centres C18 à C20 présentent une configuration relative syn présente dans la Thuggacine A mais que les centres C17-C18 sont anti-configurés, configuration confirmée par cristallographie du composé 84. Les faibles rendements ainsi qu'un contrôle insuffisant de la diastéréosélectivité de ces 4 centres asymétriques nous ont conduit à étudier une stratégie de synthèse alternative. La deuxième voie de synthèse nous a permis d'obtenir le fragment C13-C25 en 10 étapes linéaires et avec un très bon contrôle de la stéréochimie des 5 centres stéréogéniques créés. Les 4 centres asymétriques C-17 à C-20 ont été construits grâce à deux réactions d'aldolisations type Evans, tandis que l'addition d'un allényl-stannane a permis l'introduction stéréosélective du centre C-16The herein presented study is concerned by the synthesis of the C12-C25 fragment of Thuggacine A, a potent antibiotic macrolide, through two distinct synthetic pathways. The first synthetic pathway enabled us to form 4 among 5 stereogenic centers from (R)-glyceraldehyde acetonide. The key induction asymmetric step showed that the 3 chiral centers C18-C20 were formed with a syn-configuration as in Thuggacine A and the C17-C18 stereocenters were anti-configurated, a result confirmed by X-ray cristallography of compound 84. Low yields and low diastereocontrol of these four chiral centers led us to envisage an alternative synthetic strategy. The second synthetic pathway enabled us ti obtain the C13-C25 fragment within ten linear steps and a high diastereocontrol of the five required stereogenic centers. The 4 chiral centers C-17 to C-20 were formed through two Evans's aldolization steps while the stereochemistry of the C16 center was secured by an allenyl-stannane homologation
5
Vicarini, Hubert. "Résistance inductible et constitutive des streptocoques et des entérocoques à l'érythromycine." Paris 5, 1997. http://www.theses.fr/1997PA05P007.
Full text
6
Peyramaure, Elisabeth. "Distribution de trois classes d'antibiotiques dans l'organisme : les macrolides, les quinolones et les céphalosporines." Paris 5, 1991. http://www.theses.fr/1991PA05P193.
Full text
7
Jensen-Cain, Donna Marie. "Macrolide Resistance in Mycobacterium avium." Diss., Virginia Tech, 1997. http://hdl.handle.net/10919/30560.
Full textAbstract:
Mycobacterium avium isolates resistant to clarithromycin and azithromycin have been recovered from patients undergoing antibiotic therapy. Comparison of DNA fingerprints of sensitive and resistant isolates showed that resistance resulted from mutation of the original, sensitive isolate in five of seven patients. In the other two patients, the clarithromycin-resistant isolates were unrelated to the sensitive isolate, suggesting that the resistant isolate resulted from either superinfection or selection of a resistant strain from a polyclonal population.
Investigation of the mechanisms of clarithromycin and azithromycin resistance in M. avium showed that high-level resistance resulted from a point mutation at position A-2058 in the 23S rRNA. Based on this finding, a rapid screen for clarithromycin-resistance in M. avium was developed based on PCR. Twenty-three clinical isolates were analyzed, seven of which were clarithromycin-resistant. The target product was amplified only in clarithromycin-resistant strains, all of which had mutations at position 2058.
A polyuridylic acid (poly U)-dependent in vitro translation system from M. avium was developed to investigate the effect of antibiotics on protein synthesis. Clarithromycin was an effective inhibitor of protein synthesis in cell-free extracts of a susceptible M. avium strain, whereas a high-level resistant strain was less susceptible to clarithromycin in vitro. Mixtures of extracts from sensitive and resistant strains showed a pattern of clarithromycin inhibition similar to the resistant strain, suggesting that resistance may be dominant in partial diploids. Three M. avium strains exhibiting step-wise, intermediate resistance to azithromycin were characterized in comparison to the sensitive parent. All strains were similar in hydrophobicity, growth medium requirements, and growth response to temperature. The azithromycin-resistant strains were resistant to several unrelated agents, including ciprofloxacin, rifabutin, and ethidium bromide. Addition of carbonyl cyanide m-chlorophenylhydrazone (CCCP) did not lower minimal inhibitory concentrations (MICs) for ciprofloxacin or ethidium bromide. Cell-free extracts of the strains were as sensitive to azithromycin in vitro as the parent strain. The results rule out inactivation, efflux, and mutations in the target as resistance mechanisms, and suggest intermediate resistance may be due to altered permeability of the cell wall or membrane.Ph. D.
8
Cousin, Sydney Louis. "Macrolide resistance in Neisseria gonorrhoeae /." Thesis, Connect to this title online; UW restricted, 2003. http://hdl.handle.net/1773/5078.
Full text
9
Bassuel, Virginie. "Macrolides, streptogramines et staphylocoques : étude d'une nouvelle résistance à l'érythromycine par efflux et d'une nouvelle streptogramine, injectable, le RP 59500." Paris 5, 1993. http://www.theses.fr/1993PA05P210.
Full text
10
Lovmar, Martin. "Macrolide Antibiotics in Bacterial Protein Synthesis." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6009.
Full text
11
Lee, Hoyoung. "Evolution of macrolide antibiotics in E.coli /." May be available electronically:, 2008. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
Full text
12
Shang, Shiying. "A unified synthetic approach to polyketides having both skeletal and stereochemical diversity /." Access full-text from WCMC, 2008. http://proquest.umi.com/pqdweb?did=1528359411&sid=7&Fmt=2&clientId=8424&RQT=309&VName=PQD.
Full text
13
Hu, Thomas Qiuxiong. "Synthesis and conformational studies of 10, 10-dimethyltridecanolide." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/27960.
Full textAbstract:
The synthesis of 10,10-dimethyltridecanolide (42) was achieved via a fifteen-step sequence in 9% overall yield.
The hydrolysis of macrolides 42, 35, and ester 109 was used to probe the conformational behavior of macrolide 42. The results of this study were rationalized through molecular mechanics (MM2) calculations of conformations for macrolide 42.
MM2 studies confirmed initial conformational analyses that macrolide 42 should exist predominantly in the [3434] conformation 42a. More importantly, they also revealed the existence of a [3344] conformation 42f.
Hydrolysis studies showed that macrolides 42 and 35 hydrolyzed more slowly than ester 109 due to the steric effect of the intermediates. They also suggested that the minor conformation 42f very likely controlled the hydrolysis process of macrolide 42. [Formula Omitted]Science, Faculty of
Chemistry, Department of
Graduate
14
Rey, Allan W. "Synthetic studies directed towards the antineoplastic macrolide bryostatins." Thesis, University of Ottawa (Canada), 1990. http://hdl.handle.net/10393/5938.
Full textAbstract:
This thesis describes stereocontrolled and practical routes to the C(1)-C(9), C(17)-C(20), and C(21)-C(27) synthons of bryostatins, which are a closely related family of 20-membered ring lactones embedding 1,3-polyol units. Bryostatins are isolated in minute quantities from the marine Bryozoan Bugula neritina and possess exceptional antineoplastic activity. Membrane-enclosed enantioselective enzymatic hydrolysis was successfully employed for the generation of gram quantities of the versatile building block (3R)-methoxymethoxypentadioic acid, monomethyl ester (51) (Chapter 2). This compound was used in the synthesis of the C(1)-C(5) segment of bryostatins. Preliminary synthetic studies towards the C(1)-C(9) subunit are described in Chapter 3. Wittig and dithiane approaches were unfortunately unsuccessful for the connection of an enzymatically derived 5 carbon unit with a D-pantolactone derived 4 carbon unit. Chapter 4 describes the practical synthesis of the C(1)-C(9) fragment of bryostatin in forms suitable for both structure/activity studies and synthetic elaboration. The pivotal step utilized a diastereoselective Mukaiyama aldol condensation of a diketene derived silylenol ether with an enzymatically derived chiral $\beta$-alkoxyaldehyde. Chapter 5 details the conversion of D-pantolactone and of D-galactono-1,4-lactone into the C(17)-C(20) and C(21)-C(27) synthons of bryostatins via a chiron approach. A study of nucleophilic additions onto chiral substituted $\gamma$-lactol templates is discussed in Chapter 6. This provided valuable information regarding the coupling of the C(17)-C(20) and C(21)-C(27) segments of bryostatins. As well, the results demonstrate the potential utility of $\gamma$-lactols as templates--a relatively unexplored area in asymmetric synthetic chemistry.
15
Jones, Tracey Ann. "Macrolide antibiotic resistance and production in Streptomyces narbonensis." Thesis, University of Leicester, 1997. http://hdl.handle.net/2381/29668.
Full textAbstract:
Narbomycin, a macrolide antibiotic produced by Streptomyces narbonensis, consists of a 14-atom polyketide to which the deoxyhexose sugar, desosamine, is attached. The aim of this study was to identify the desosamine biosynthetic gene cluster.;In Streptomyces there is a tendency for genes concerned with the same biochemical pathway to be grouped together in clusters. These biosynthetic gene clusters are often associated with genes conferring resistance to the antibiotic in the producing organism. The relationship between the resistance genes and the biosynthetic genes has been of great importance in studying antibiotic biosynthesis, since a number of biosynthetic clusters have been isolated using the corresponding resistance gene as a probe against cosmid libraries.;Two resistance determinants have been cloned from S. narbonensis, nmr A and nmrB. The nucleotide sequence was determined and both genes appear to encode 23S rRNA methyltransferases conferring MLS resistance.;A cosmid library of S. narbonensis DNA was constructed and probed with the narbomycin resistance genes. This led to the isolation of the narbomycin biosynthetic gene cluster. Mycaminose genes from the tylosin biosynthetic gene cluster of S. fradiae were also available as probes and were used in hybridisation analysis against the S. narbonensis cosmid library; leading to the identification of putative desosamine genes and a preliminary map of the narbomycin biosynthetic gene cluster.
16
Chin, Alex C. "Anti-inflammatory effects of the macrolide antibiotic tilmicosin." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/MQ31336.pdf.
Full text
17
O'Hagan, D. "Biosynthesis studies on the polyether and macrolide antibiotics." Thesis, University of Manchester, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374582.
Full text
18
Jenkins, Gail. "Inducible macrolide and lincosamide resistance in Streptomyces lividans." Thesis, University of Leicester, 1990. http://hdl.handle.net/2381/35260.
Full textAbstract:
Resistance to macrolide, lincosamide, and streptomgramin B type antibiotics, is widespread amongst Gram positive bacteria and is particuarly prevalent in the genus Streptomyces. The classical MLS resistance phenotype has, in a number of cases, been associated with N6,N6 dimethylation of 23S rRNA, and more specifically to methylation of the adenine residue at a position equivalent to 2058 in E. coli 23S rRNA. However, phenotypes differing from that associated with classical MLS resistance have also been reported, and this study describes the analysis of one such inducible resistance phenotype found in the non-producing organism Streptomyces lividans TK21. Two resistance genes have been isolated from S. lividans, with the aid of shotgun cloning techniques, and both have been analysed at the nucleotide level. The first, lrm, encodes a ribosomal RNA methylase of 36 KDa, that monomethylates the N6 amino group of an adenosine residue at a position equivalent to 2058 in 23S rRNA. The second resistance gene codes for a protein of 46 KDa, and though the precise function of this protein is as yet undetermined, a distant similarity does exist between this gene product and various eukaryotic UDP-glucuronosyl transferases. Transcription of lrm initiates from two promoters that lie some 253 and 377 nucleotides upstream from the translational initiation codon. The leader sequence is capable of forming a series of stable hairpin loops, and an area exists within this region that could encode a short leader peptide of 38 amino acids. It is therefore suggested that induction of lrm may be regulated by translational attenuation.
19
Gomes, Cláudia, Puchol Sandra Martínez, Noemí Palma, Gertrudis Horna, Lidia Ruiz-Roldán, Maria J. Pons, and Joaquim Ruiz. "Macrolide resistance mechanisms in Enterobacteriaceae: Focus on azithromycin." Taylor & Francis, 2016. http://hdl.handle.net/10757/620710.
Full textAbstract:
From its introduction in 1952 onwards, the clinical use of macrolides has been steadily increasing,
both in human and veterinary medicine. Although initially designed to the treatment of Grampositive
microorganisms, this antimicrobial family has also been used to treat specific Gram-negative
bacteria. Some of them, as azithromycin, are considered in the armamentarium against
Enterobacteriaceae infections. However, the facility that this bacterial genus has to gain or
develop mechanisms of antibiotic resistance may compromise the future usefulness of these antibiotics
to fight against Enterobacteriaceae infections. The present review is focused on the mechanisms
of macrolide resistance, currently described in Enterobacteriaceae.
20
Skinner, Michael Fredrick. "Biopharmaceutics and pharmacokinetics of the macrolide antibiotic Josamycin." Thesis, Rhodes University, 1992. http://hdl.handle.net/10962/d1003269.
Full textAbstract:
The investigations detailed herein have been conducted to address various aspects of the biopharmaceutics and pharmacokinetics of josamycin which to-date, have received little or no attention in the literature. Areas of investigation have included the selective determination of josamycin in serum and urine samples, the stability of josamycin in stored biological samples, intrinsic dissolution rates, solubility, acid and alkali stability and bioavailability and pharmacokinetics after dosing with a solution, powder and tablets. High performance liquid chromatography (HPLC) was used as the main analytical tool throughout these studies and proved to be highly versatile for the determination of josamycin in a number of different media. HPLC analysis afforded simple yet accurate determination of josamycin in samples from dissolution, solubility, tablet content and stability studies. Furthermore, the specificity afforded by HPLC was particularly useful for the separation of josamycin from degradation products formed in acid and alkali media. Since metabolites of josamycin are microbiologically active, microbiological assays do not determine the concentration solely of josamycin. An analytical method capable of the selective determination of josamycin in serum and urine samples is therefore required for the procurement of reliable bioavailability and pharmacokinetic data. HPLC affords this selectivity and a method for the selective determination of josamycin in serum and urine was successfully developed. The assay was simple yet precise, accurate and sensitive. Furthermore, it was well suited to the determination of josamycin in a large number of biological samples. Its success was largely due to the use of a solid phase extraction step using C₁₈ extraction columns, with a highly specific wash sequence followed by a phase separation step after elution from the extraction column. Chromatography was performed on a C₁₈ reversed-phase analytical column with UV detection of josamycin and internal standard at 231 nm and at 204 nm respectively using a programmable multi-wavelength detector. Only slight modification of the assay described should enable the selective determination of the metabolites of josamycin. This assay, therefore, lays the groundwork for future investigations into the pharmacokinetics of these metabolites. The re-usability of extraction columns was assessed in an attempt to reduce the cost of sample analysis. It was found that extraction columns could be used twice for the extraction of serum samples and up to four times for the extraction of urine samples. The difference between the re-usability of extraction columns for serum and urine samples was ascribed to various differences in the composition of the sample matrix. The stability of josamycin in stored serum and urine samples was also assessed.
21
Chung, Whasun Oh. "Macrolide resistance and its linkage to tetracycline resistance /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/9279.
Full text
22
Tavares, Júnior Eraldo Ramos. "Acesso à justiça e macrolides." Faculdade de Direito, 2015. http://repositorio.ufba.br/ri/handle/ri/17473.
Full textAbstract:
Submitted by Ana Valéria de Jesus Moura (anavaleria_131@hotmail.com) on 2015-04-28T16:14:14Z
No. of bitstreams: 1
Dissertação ACESSO À JUSTIÇA E MACROLIDES - UFBA - 2015_versão completa.pdf: 919039 bytes, checksum: 013bcbed42c7609239dc48c93b244820 (MD5)Approved for entry into archive by Ana Valéria de Jesus Moura (anavaleria_131@hotmail.com) on 2015-04-28T16:19:40Z (GMT) No. of bitstreams: 1 Dissertação ACESSO À JUSTIÇA E MACROLIDES - UFBA - 2015_versão completa.pdf: 919039 bytes, checksum: 013bcbed42c7609239dc48c93b244820 (MD5)
Made available in DSpace on 2015-04-28T16:19:40Z (GMT). No. of bitstreams: 1 Dissertação ACESSO À JUSTIÇA E MACROLIDES - UFBA - 2015_versão completa.pdf: 919039 bytes, checksum: 013bcbed42c7609239dc48c93b244820 (MD5)
A presente dissertação se propõe à análise do acesso à justiça diante de uma nova conflituosidade social. Parece não existir dúvidas de que a tutela jurisdicional individual não é suficiente para a pacificação das relações conflituosas em massa, que assolam os tribunais de todo o país, através de milhares de ações repetitivas, com o mesmo objeto, e quase sempre, com o mesmo pedido. Aqueles que diariamente militam nos fóruns brasileiros têm a absoluta certeza de que questões relativas litígios seriados desafiam uma tutela jurisdicional diferenciada. Torna-se, então, imprescindível o estudo e desenvolvimento do tema, fazendo uma análise da Jurisdição e do Processo à luz do paradigma democrático, da compreensão do acesso à justiça na atualidade, bem como da tutela coletiva de direito, em especial dos direitos individuais homogêneos. Assim, o presente trabalho começa analisando os conceitos clássicos do processo e a sua repercussão da realidade jurídica brasileira atual. Após, procurou-se apontar os principais problemas que impedem o incremento do acesso à justiça, em especial diante de uma sociedade extremamente massificada, apresentando sugestões para superação dos problemas. Por fim, procurou tecer algumas considerações acerca do incidente de coletivização das demandas repetitivas, inserido no Novo Código de Processo Civil, aprovado pelo Senado Federal e pendente de envio para sanção presidencial. Essas são algumas questões discutidas no presente trabalho, que não tem o fito de esgotar a matéria, mas de fomentar e contribuir para a discussão do tema.
23
Blakey, S. "Synthesis of an advanced macrolide intermediate for the aplyronines." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596715.
Full textAbstract:
Aplyronine A (5) is a polyketide metabolite isolated in microscopic quantities from the Japanese sea hare Aplysia kurodai by the Yamada group. Aplyronine A displays potent cytotoxic activity both in vitro and in vivo, and has been shown to act as a novel actin depolymerising agent. It possesses a number of complex structural features including a 24-membered macrolide ring, a terminal N-methyl-N-vinylformamide moiety, 17 stereocentres and two amino acid residues. The aim of this project was to complete a highly stereocontrolled total synthesis of aplyronine A, using asymmetric aldol chemistry to assemble the carbon and oxygen skeleton. The first part of this dissertation describes the development of a suitable C28-C34 coupling partner, culminating in the synthesis of C28-C34 ketone 136. Key steps in this synthesis include an asymmetric aldol coupling of ketone 60 and aldehyde 61, and the introduction of the N-methyl-N-vinylformamide moiety via a Wittig olefination. The second part of this dissertation describes the optimisation and scale up of the Paterson group route to 24-membered macrocycle 59, involving the synthesis of the C1-C11 iodide 57 and C15-C27 aldehyde 58. These fragments were coupled together using a highly (E)-selective Horner-Wadsworth-Emmons reaction, and subsequently advanced to provide significant quantities of 24-membered macrocycle 59. The third and final part of this dissertation describes the synthesis of an advanced macrolide intermediate, containing the full C1-C34 carbon backbone of the aplyronines, with the 15 stereocentres correctly configured. This relies on a complex aldol coupling at C27-C28 to introduce the side chain, followed by suitable elaboration into 222. Preliminary efforts to advance this intermediate to aplyronine C (7) are also described.
24
Dalby, S. M. "Total synthesis of the macrolide core of (+)-spirastrellolide A." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598247.
Full textAbstract:
Spirastrellolide A is a polyketide metabolite isolated from the Caribbean marine sponge Spirastrella coccinea, which represents a potential lead for the development of novel therapeutic agents for the treatment of cancer as well as various neurological and metabolic disorders. The results and discussion section provides a chronological account of work towards the total synthesis of spirastrellolide A. As part of preliminary studies towards the original structural assignment, the synthesis of the C1-C21 spiroacetal-containing fragment 141 is described first. Subsequent work towards the revised structure for spirastrellolide is then detailed, which led to the synthesis of the diastereomeric C1-C25 ABC fragments 146 and 147. Chapters 5-8 then describe the development and implementation of a revised strategy which culminated in the highly convergent synthesis of spirastrellolide A macrolactone 467, achieved in 1.0% yield over the longest linear sequence of 33 steps. This synthesis exploits a number of effective boron-mediated processes, including highly stereoselective aldol and alkylation methodology and most notably, B-alkyl Suzuki coupling of the advanced intermediates 449 and 349 and the stereoselective installation of the C23 and C24 stereocentres, as part of a double hydroboration process under substrate control. The key fragments 459 and 450 were advanced to BC-spiroacetal 462 employing a mild and highly efficient process for BC-spiroacetalisation, following which a further four steps provided macrolactone 467. Global deprotection of 467 provided the fully elaborated macrolide core of spirastrellolide A, which was in excellent agreement with the natural product data. Completion of the total synthesis finally requires installation of the C41-C47 side-chain.
25
Zhang, Ziyang. "A Platform for the Discovery of New Macrolide Antibiotics." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493421.
Full textAbstract:
The macrolide class of antibiotics has been widely used to treat bacterial infections for over 65 years. To date, all practical routes to clinically used macrolide antibiotics have relied on the chemical modification of the fermentation product erythromycin, a process referred to as semisynthesis. As bacterial resistance to semisynthetic macrolides emerges, a new approach to the discovery of structurally novel antibiotic candidates is urgently required.
This dissertation presents a general and practical strategy for the synthesis of macrolide antibiotics based on the convergent assembly of simple building blocks. Implementation of this strategy has led to the synthesis of novel macrolide antibiotic candidates in as few as 10 longest linear steps (from building blocks). The synthesis features a thermal macrocyclization reaction that proves generally successful for the construction of several macrolide scaffolds. In the past four years, my coworkers and I have prepared more than 350 fully synthetic macrolides with substantial structural diversity by adaptation of the synthetic route, variation of the building blocks, or a synergic combination of both. Preliminary antimicrobial testing against a panel of Gram-positive and Gram-negative strains reveals that many of the fully synthetic macrolides exhibit promising activities, and several of them are efficacious against pathogens resistant to currently used macrolide antibiotics.
Also described in this dissertation are chemical methods developed specifically for the practical synthesis of two key building blocks. The 3-amino sugar desosamine, a common constituent of many macrolide antibiotics, is synthesized in four steps from methyl vinyl ketone. The key step of the synthesis involves a new method developed for the single-step construction of 3-nitro sugars by the coupling of γ-nitro alcohols and glyoxal. This method has been applied to the preparation of an array of 3-amino sugars analogous to desosamine, which have been incorporated to provide novel macrolides with modified glycosidic residues. The synthesis of silyl enol ether 72 is enabled by an efficient directed Claisen reaction. The reaction of the lithium enolate of a tert-butyl ester and a phenyl ester in the presence of lithium hexamethyldisilazide affords a tert-butyl β-keto ester in high yield. Two subsequent steps transform this product to silyl enol ether 72.Chemistry and Chemical Biology
26
Neeland, Edward George. "Selective reactions of 14-membered macrolides-a conformational approach using MM2 calculation." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/29040.
Full textAbstract:
A number of 14-membered lactones, derived from 42 or 43 were used to investigate a series of alkylation, hydride reduction and hydrogenation reactions. These reactions yielded diastereoselective product distributions which were rationalized as proceeding through a [3434] conformation. A simple model for determining these low energy conformations was developed using MM2 calculations, energy trends of acyclic molecules, X-ray crystallography and NMR spectroscopy.
In order to unambiguously identify ring conformations, a method to generate polar maps of the large ring lactones was developed. These polar maps quickly differentiated complex ring conformations as well as identifying the symmetry elements of a conformation.
With the aid of polar maps, a new solid state conformation for 14-membered rings was discovered for two macrolides synthesized in this project. Furthermore, three additional unidentified examples of this conformation were recognized from the literature. Energy calculations showed this twisted conformation to be of very low energy. The discovery of the twist conformation led to an improved nomenclature for large rings which considers the number of bonds separating both corner and pseudo corner atoms. Under this proposed nomenclature, the twist conformation was designated the [34'3'4'] conformation.
During this investigation, a useful technique for assigning the stereochemistry of E and Z-trimethylsilyl (TMS) enol ethers was developed using ¹H NMR nuclear Overhauser effect difference spectroscopy (NOEDS) experiments. One advantage of this technique over the widely used ¹³C NMR method is that only one isomer is required to accurately assign the Eor Z. stereochemistry. [Formula Omitted]Science, Faculty of
Chemistry, Department of
Graduate
27
Rawson, D. J. "A total synthesis of (+)-(9S)-dihydroerythronolide A." Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317889.
Full text
28
Gledhill, Adrian Paul. "Synthesis of polysubstituted fatty acids via thiophene intermediates." Thesis, Nottingham Trent University, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304892.
Full text
29
Wood, Nicholas D. "Studies towards the synthesis of mycinolide III, mycinoic acids I & II and 1β,2α-dimethyl gibberellins." Thesis, University of Bristol, 1996. http://hdl.handle.net/1983/1322f2e7-4563-4a44-991b-a4bf89a5c81b.
Full text
30
Bower, S. "New methods in acyclic stereocontrol directed towards the synthesis of bafilomycin A1." Thesis, University of Cambridge, 1994. https://www.repository.cam.ac.uk/handle/1810/272787.
Full text
31
Karray, Fatma. "Etude de la biosynthèse de l'antibiotique spiramycine par Streptomyces ambofaciens." Paris 11, 2005. http://www.theses.fr/2005PA112085.
Full textAbstract:
Streptomyces ambofaciens synthétise l'antibiotique macrolide la spiramycine. La région contenant les gènes de biosynthèse de la spiramycine a été séquencé chez S. Ambofaciens. L'analyse de cette séquence d'environ 100 kb révèle la présence de 50 gènes, dont 41 sont probablement impliqués dans la biosynthèse de spiramycine, dans sa régulation ou dans la résistance à la spiramycine. Afin d'étudier le rôle de ces gènes dans la biosynthèse de spiramycine, nous avons construit des souches dans lesquelles certains gènes ont été inactivés par délétion en phase. Pour cela, nous avons développé des cassettes excisables facilement par recombinaison spécifique de site. Deux gènes régulateurs, srmR et srmS, ont été identifiés parmi les gènes de biosynthèse de la spiramycine. L'inactivation de chacun de ces deux gènes abolit la production de la spiramycine tandis que la surexpression de chacun d'eux augmente d'un facteur trois le niveau de production de la spiramycine. L'analyse d'expression par RT-PCR de tous les gènes de biosynthèse de la spiramycine, chez la souche sauvage, dans les mutants srmR et srmS et dans le double mutant srmR, srmS, a été effectuée. Ces résultats indiquent que SrmR est nécessaire à l'expression de srmS ; SrmS contrôlant quant à lui l'expression de la plupart des gènes de biosynthése de la spiramycine. La spiramycine est produite sous forme d'un mélange de spiramycine I, II et III. La spiramycine I est la forme la plus active. Nous avons identifié et inactivé le gène, orf6*, codant l'acétyltransférase responsable de la production de la spiramycine II et III. Le niveau de production de spiramycine I a été augmenté en surexprimant srmR dans ce mutant. -Streptomyces ambofaciens synthesizes the 16-membered macrolide antibiotic spiramycin. The biosynthetic gene cluster for spiramycin has been characterized in S. Ambofaciens. Sequence analysis of a region of more than 100 kb spanning the entire cluster revealed the presence of 50 genes, 41 of them being most probably involved in spiramycin biosynthesis, its regulation or resistance to the antibiotic. In order to study the role of the gene products in spiramycin biosynthesis, we constructed strains in which some genes were inactivated by in-frame deletion. For this purpose, we developed cassettes that can be easily excised by site-specific recombination. Two regulatory genes, srmR and srmS, were identified in the biosynthetic gene cluster. The disruption of each of these two regulatory genes eliminated spiramycin production while the over-expression of each of them increased three fold the level of spiramycin production. Expression analysis by RT-PCR for all the genes of the cluster in the wild type strain, in srmR and srmS deletion mutants and in the srmR, srmS double deletion mutant was performed. These results, together with complementation experiments, indicated that SrmR is required for srmS expression, SrmS being a pathway-specific activator that controls most of the spiramycin biosynthetic genes. Spiramycin is normally produced as a mixture of spiramycin I, II and III. Spiramycin I is the most active form of the antibiotic. We identified and inactivated the gene encoding the acetyltransferase responsible for the production of spiramycin II and III. The level of production of this mutant strain was further increased by over-expression of the regulatory gene srmR
32
MAYAN, BUSCARONS VALERIE. "Place des macrolides dans le traitement de premiere intention des bronchopneumopathies infectieuses communautaires de l'adulte." Aix-Marseille 2, 1990. http://www.theses.fr/1990AIX20076.
Full text
33
Wallwork, Benjamin, and n/a. "The Anti-Inflammatory Effect of Macrolide Antibiotics in Chronic Rhinosinusitis." Griffith University. School of Biomolecular and Biomedical Science, 2006. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20070201.160023.
Full textAbstract:
Chronic rhinosinusitis is a common disorder of chronic inflammation of the upper respiratory tract. It is associated with significant symptoms and impairment of the quality of life of sufferers. Despite recent advances in the medical and surgical management of chronic rhinosinusitis, there remains a population of patients who fail to obtain relief from their symptoms. Chronic inflammation of the mucosa of the nasal cavity and paranasal sinuses is one of the hallmarks of chronic rhinosinusitis. This inflammation is demonstrated by an increased number of chronic inflammatory cells, elevated levels of pro-inflammatory cytokines, increased expression of adhesion molecules and metaplastic changes in the epithelium. The current medical treatments for chronic sinusitis aim to reduce this inflammation and consequently improve symptoms. In recent years, evidence has emerged that macrolide antibiotics have an anti-inflammatory effect that is separate from their anti-bacterial effect. This effect was first described in the treatment of diffuse panbronchiolitis, a disorder of chronic inflammation of the lower respiratory tract. Following the success of macrolides in treating this condition it was trialed in chronic rhinosinusitis. Several open-label trials have subsequently demonstrated a beneficial effect. Laboratory studies have investigated the mechanism of the anti-inflammatory effect of macrolides. These have shown that macrolides effect cytokine production, inflammatory cell apoptosis, expression of adhesion molecules, neutrophil oxidative burst, bacterial virulence and mucociliary function. In this thesis we report a series of experiments designed to further investigate the mechanism of action and clinical effect of macrolides. In vitro studies using whole sections of chronic rhinosinusitis mucosa cultured for 24 hours in macrolide, prednisolone or control showed that macrolide and prednisolone produced significant reductions in the production of interleukin-5, interleukin-8 and granulocyte-macrophage colony stimulating factor. The same cultured specimens also showed a reduction in expression of transforming growth factor-?. No reduction was seen in the expression of the key pro-inflammatory nuclear transcription factor Nuclear factor-?B. In our in vivo experiments, biopsies were taken from chronic rhinosinusitis patients who had received a 3-month course of macrolide. These biopsies showed a reduction in the number of neutrophils present following treatment. There was no reduction in the number of other inflammatory cells or in the expression of TGF-? and NK-?B. We have performed the first ever double-blinded, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis. Patients receiving macrolide showed significant improvements in saccharine transit time, nasal endoscopic scoring and symptom scores following a 12 week course. Patients with low levels of serum immunoglobulin E showed significantly improved outcomes compared to those with high levels. Interleukin-8 levels in nasal lavage fluid were significantly reduced in the patients with low levels of IgE following macrolide treatment. No improvements in any of the objective or subjective outcome measures were seen in the placebo-treated patients. We have performed a series of experiments investigating the anti-inflammatory effect of macrolide antibiotics from 'the bench to the bedside'. These experiments have provided insight into the mechanism of action of macrolides in the laboratory setting and evidence of a beneficial effect in the treatment of chronic rhinosinusitis patients.
34
König, Ariane. "Genes for macrolide formation in rapamycin biosynthesis from Streptomyces hygroscopicus." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264158.
Full text
35
Morel, Jean-David. "Mechanism underpinning the immunosuppressive effects of the mycobacterial macrolide mycolactone." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCC316.
Full textAbstract:
La mycolactone est un lipide diffusible produit par Mycobacterium ulcerans, la bactérie responsable d'une maladie tropicale de la peau appelée ulcère de Buruli. La production de mycolactone dans la peau infectée par M. ulcerans provoque une nécrose tissulaire locale, tout en induisant des anomalies immunosuppressives au niveau systémique. Lorsque j'ai commencé mon doctorat, les mécanismes moléculaires à l'origine de ces effets étaient inconnus. Au cours de ma thèse, j'ai contribué à démontrer que la mycolactone est un nouvel inhibiteur du translocon Sec61,le canal régulant la biogenèse de la plupart des protéines sécrétées et membranaires dans les cellules eucaryotes. J’ai démontré qu’une mutation ponctuelle dans la sous-unité alpha de Sec61 protège les cellules des effets cytotoxiques et immunosuppresseurs de la mycolactone. J'ai montré que le blocage du translocon Sec61 par la mycolactone empêche efficacement la synthèse des principaux récepteurs immunitaires et des molécules de signalisation du système immunitaire,blockant la communication entre les cellules immunitaires et inhibant l'immunité antimycobactérienne. Par une série d'études protéomiques à grande échelle, j'ai démontré que la mycolactone est un inhibiteur à large action de Sec61 et j’ai identifié les substrats de Sec61 les plus impactés dans différents types cellulaires. Ces analyses m'ont également permis de décrire la réponse au stress induite par le blocage de la translocation des protéines, qui inclut des éléments de la réponse au stress protéostatique (UPR) et de la réponse intégrée au stress (ISR), provoquant finalement l'apoptose cellulaire. Plusieurs études ont impliqué le translocon Sec61 dans des processus qui requièrent le transport rétrograde de protéines à travers les membranes : la Dégradation Associée au Réticulum Endoplasmique (ERAD), processus essentiel du contrôle de la qualité des protéines et la cross-présentation, une voie essentielle à l'activation de l'immunité adaptative aux pathogènes intracellulaires et au cancer. J'ai montré que le blocage de Sec61 par la mycolactone n'affecte pas l'export de protéines vers le cytosol dans ces deux voies, suggérant que Sec61 ne peut pas fonctionner comme un rétrotranslocon. Mes travaux ont permis d’élucider le moléculaire responsable des divers effets de la mycolactone observés chez les patients atteints d’ulcère de Buruli et de révéler l’importance majeure de la translocation des protéines dans la régulation des réponses immunitaires et de l’homéostasie des protéinesMycolactone is a diffusible lipid produced by the human pathogen Mycobacteriumulcerans, the causative agent of a tropical skin disease called Buruli ulcer. Bacterial production of mycolactone in infected skin causes local tissue necrosis, while inducing immunosuppressive defects at the systemic level. When I started my PhD, the molecular mechanism(s) underpinning these effects were unknown. Over the course of my thesis, I contributed to demonstrate that mycolactoneis a novel inhibitor of the Sec61 translocon, a channel regulating the biogenesis of most secretedand membrane proteins in eukaryotic cells. Indeed, a single point mutation in the alpha subunit ofSec61 protected cells from the cytotoxic and immunosuppressive effects of mycolactone. I showed that mycolactone-mediated blockade of the Sec61 translocon efficiently prevents the synthesis ofkey immune receptors and signaling molecules, impeding the communication between immunecells that is required for the development of anti-mycobacterial immunity. Through a series of larges caleproteomic studies, I demonstrated that mycolactone is a broad-acting inhibitor of Sec61 and identified the Sec61 clients that are primarily down regulated by mycolactone in physiologicallyrelevant cell types. These analyses also allowed me to describe a unique stress response,encompassing elements of the unfolded protein response and integrated stress response, that isinduced upon protein translocation blockade and ultimately causes cell apoptosis. The Sec61 translocon has been proposed to play a role in other cell functions that require the retrograde transport of proteins across membranes, namely Endoplasmic Reticulum-Associated Degradation(ERAD), an essential process in protein quality control, and antigen export to the cytosol during cross-presentation, a pathway essential to the activation of adaptive immunity to intracellular pathogens and cancer. Using mycolactone, I showed that Sec61 blockade does not affect protein export to the cytosol in either of these pathways, arguing against Sec61 operating as are trotranslocon. Altogether, my work provided a molecular mechanism for the diverse effects of mycolactone in Buruli Ulcer patients, and thus for M. ulcerans virulence. Mycolactone representing the most potent Sec61 blocker identified to date, my studies also revealed the key importance of Sec61-mediated protein translocation in the regulation of immune responses and protein homeostasis
36
Arsic, Biljana. "Macrolide antibiotics as anti-bacterial and potential anti-malarial medicines." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/macrolide-antibiotics-as-antibacterial-and-potential-antimalarial-medicines(06d0269d-323f-4f46-9cf2-3eb7363b2796).html.
Full textAbstract:
Macrolide antibiotics are known as anti-bacterial agents. Erythromycin A, 14-membered macrolide antibiotic is known to exist in two forms-ketone (active) and hemiacetal form (inactive). It shows mild flexibility in silico. Its derivative, clarithromycin, 6-O-methyl erythromycin A, shows rigidity and activity against Gram-positive bacteria. The semisynthetic derivative of erythromycin A, azithromycin, 15-membered macrolide antibiotic, shows flexibility in silico and activity against Gram-negative bacteria. The combination of molecular modelling (molecular mechanics and/or molecular dynamics) with TRNOESY NMR data give us the active conformation of flexible molecules. Constraining the strong intramolecular hydrogen bonds can be helpful in the determination of the active conformation of the drug. We have developed modelling strategy for the construction of new 14- and 15-membered macrolideantibiotics with desired activity.Tylosin A and tylosin B, 16-membered macrolide antibiotics, show rigidity in silico. However, tylosin A is very unstable in aqueous solutions, so precise determination of hydrogen and carbon chemical shifts is extremely difficult. Nobody else before us tried to publish the full assignments of this compound in D2O. Accurate determination of hydrogen and carbon chemical shifts is necessary in order to further explore the properties of this compound.Anti-bacterial activity investigation of tylosin A and its derivative, tylosin B, shows lower activity both against Gram-positives and Gram-negatives compared to clarithromycin and azithromycin. Superposition of two molecules of azithromycin with one molecule of tylosin A reveals that two molecules of azithromycin actually occupy the space of one tylosin A molecule, which can explain found anti-malarial activity of tylosin A (both azithromycin and tylosin A show similar contacts to bacterial ribosomes).Clinical trials show that azithromycin has an anti-malarial activity. In order to investigate the potential anti-malarial activity of macrolide antibiotics, we had to construct the exit tunnel of the apicoplast ribosome from Plasmodium falciparum. Because of the unavailability of the crystal structure of P. falciparum ribosome (it is impossible to separate mitochondria and apicoplast, and both of them contain ribosomes), we used different computational methods and softwares in order to construct it. We used both homology modelling and ab initio modelling server for the construction of L4 (apicoplast-encoded P. falciparum ribosomal protein) and L22 (nuclear genome-encoded P. falciparum ribosomal protein) and RNA_2D3D software to construct the 23S rRNA from apicoplast ribosome of Plasmodium falciparum. Using Pymol software and MOE we have constructed the exit tunnel of apicoplast ribosome from P. falciparum. The model shows that it can bind one azithromycin molecule. It is the first model of the exit tunnel of the apicoplast ribosome from Plasmodium falciparum. Further work can be extended to the docking of other molecules than azithromycin into the modelled exit tunnel of Plasmodium falciparum.
37
Wallwork, Benjamin. "The Anti-Inflammatory Effect of Macrolide Antibiotics in Chronic Rhinosinusitis." Thesis, Griffith University, 2006. http://hdl.handle.net/10072/367299.
Full textAbstract:
Chronic rhinosinusitis is a common disorder of chronic inflammation of the upper respiratory tract. It is associated with significant symptoms and impairment of the quality of life of sufferers. Despite recent advances in the medical and surgical management of chronic rhinosinusitis, there remains a population of patients who fail to obtain relief from their symptoms. Chronic inflammation of the mucosa of the nasal cavity and paranasal sinuses is one of the hallmarks of chronic rhinosinusitis. This inflammation is demonstrated by an increased number of chronic inflammatory cells, elevated levels of pro-inflammatory cytokines, increased expression of adhesion molecules and metaplastic changes in the epithelium. The current medical treatments for chronic sinusitis aim to reduce this inflammation and consequently improve symptoms. In recent years, evidence has emerged that macrolide antibiotics have an anti-inflammatory effect that is separate from their anti-bacterial effect. This effect was first described in the treatment of diffuse panbronchiolitis, a disorder of chronic inflammation of the lower respiratory tract. Following the success of macrolides in treating this condition it was trialed in chronic rhinosinusitis. Several open-label trials have subsequently demonstrated a beneficial effect. Laboratory studies have investigated the mechanism of the anti-inflammatory effect of macrolides. These have shown that macrolides effect cytokine production, inflammatory cell apoptosis, expression of adhesion molecules, neutrophil oxidative burst, bacterial virulence and mucociliary function. In this thesis we report a series of experiments designed to further investigate the mechanism of action and clinical effect of macrolides. In vitro studies using whole sections of chronic rhinosinusitis mucosa cultured for 24 hours in macrolide, prednisolone or control showed that macrolide and prednisolone produced significant reductions in the production of interleukin-5, interleukin-8 and granulocyte-macrophage colony stimulating factor. The same cultured specimens also showed a reduction in expression of transforming growth factor-?. No reduction was seen in the expression of the key pro-inflammatory nuclear transcription factor Nuclear factor-?B. In our in vivo experiments, biopsies were taken from chronic rhinosinusitis patients who had received a 3-month course of macrolide. These biopsies showed a reduction in the number of neutrophils present following treatment. There was no reduction in the number of other inflammatory cells or in the expression of TGF-? and NK-?B. We have performed the first ever double-blinded, randomized, placebo-controlled trial of macrolide in the treatment of chronic rhinosinusitis. Patients receiving macrolide showed significant improvements in saccharine transit time, nasal endoscopic scoring and symptom scores following a 12 week course. Patients with low levels of serum immunoglobulin E showed significantly improved outcomes compared to those with high levels. Interleukin-8 levels in nasal lavage fluid were significantly reduced in the patients with low levels of IgE following macrolide treatment. No improvements in any of the objective or subjective outcome measures were seen in the placebo-treated patients. We have performed a series of experiments investigating the anti-inflammatory effect of macrolide antibiotics from 'the bench to the bedside'. These experiments have provided insight into the mechanism of action of macrolides in the laboratory setting and evidence of a beneficial effect in the treatment of chronic rhinosinusitis patients.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Biomedical Sciences
Full Text
38
Lee, Miseon. "THE DISCOVERY OF NOVEL MACROLIDE ANTIBIOTICS THAT ADDRESS BACTERIAL RESISTANCE." Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/436439.
Full textAbstract:
ChemistryPh.D.
Bacterial resistance is a formidable 21st-century global public health threat. If left unaddressed, we risk moving toward a “post-antibiotic era.” While resistance is a natural consequence of antibiotic use, the rate at which pathogenic bacteria have evaded multiple classes of drugs has markedly outpaced the introduction of new ones. New antibiotics are desperately needed to fill this void. Macrolides are one of the safest and most effective drug classes in medicine; however, resistance has compromised efficacy. To date, three generations have been developed with only the lattermost targeting bacterial resistance. Single next-generation macrolides will not keep pace with the inevitable onset of resistance; thus, there is a critical need to greatly accelerate the procurement of multiple future-generation antibiotics to tackle both current and future resistance mechanisms. My research is to meet this need by designing, synthesizing, and evaluating a novel, future-generation macrolide antibiotics that will serve as an armamentarium to be individually deployed on demand. In the previous research in Andrade group, we synthesized and evaluated various desmethyl ketolide analogs. The fact that 4-desmethyl telithromycin was fourfold less potent than telithromycin against A2058G mutants indicated replacing the 4-Me with hydrogen (i.e., desmethylation) to avoid a steric clash with the 2-amino group of G2058 was insufficient in rescuing bioactivity. Guided by MD simulation, we concluded a logical, superior alternative strategy was the replacement of the 4-Me group with one possessing a smaller vdW radius and capable of establishing favorable interactions with both wild-type and A2058G mutant ribosomes. Specifically, we reasoned that 4-fluoro solithromycin would be ideal candidate. The hypothesis was that the 4-fluoro moiety would engage in dipole-dipole interactions (C-F---H) with the exocyclic 2-amino group of guanine, which is based on accumulated evidence that strategic placement of organofluorine can strongly impact potency, selectivity, and physicochemical properties. In addition, the axially disposed of 4-fluorine would provide conformational stabilization from a gauche effect with the vicinal O5 group. The novel synthetic routes to unexplored desosamine analogs at the C3’-amino substituent to the macrolide antibiotic would play a role in bioactivity and resistance. Hofmann reaction was employed to execute the same 2,3-epoxide ring opening method without removing desosamine and re-glycosylating. This markedly reduces the steps, time, and cost involved in preparing novel desosamine-modified analogs. Significantly, this route enables the first synthesis of N,N’-disubstituted desosamine analogs from an epoxide, which was utilized to prepare novel analogs of clarithromycin. The application of in situ click chemistry toward the discovery of novel macrolide antibiotics first required the synthesis of suitable azide and aryl alkyne reactants. Alkyne partners were procured by commercial vendors or chemical synthesis. We targeted two logical, validated positions to tether the side chains, specifically N11 on the macrolactone and N3’ of desosamine. The first (N11) has been the most utilized. Moreover, extensive structure-activity relationships have revealed a four-carbon tether is ideal. Based on the solithromycin−E.coli X-ray structure, I designed, synthesized, and evaluated dehydro solithromycin, which possesses an (E)-alkene in the side-chain. The use of an unsaturated side chain would conformationally preorganize the bi-aryl side chain in order to pay the entropic penalty and thus favorably contribute to the overall binding. An insightful observation made from MD simulationed ribosomes bound with to solithromycin revealed that the interaction of the side-chain includes H-binding as well as π-stacking. The hypothesis was that employing tethered side-chains bearing motifs that maximize H-bonding and π-stacking would be superior antibiotics for treating resistant bacterial strains bearing erm¬-mediated N6 methyl and dimethylated ribosomes. To test this hypothesis, we developed various analogs with different alkynes by introducing different functional groups at the 3 and 5 positions on the aromatic ring. Another desosamine sugar modification is bis-azide. To date, the use of a two side chain strategy has not been reported. To access the requisite bis-azides, we employed a tactic the oxidative demethylation and alkylation of desosamine to afford bis-click solithromycin analogs.
Temple University--Theses
39
Chaume, Grégory. "Vers la synthèse totale de la griséoviridine, antibiotique de type streptogramine." Cergy-Pontoise, 2003. http://biblioweb.u-cergy.fr/theses/03CERG0256.pdf.
Full textAbstract:
Les streptogramines sont des macrolides antibiotiques de type apparentés pour lesquels pratiquement aucun germe ne présente actuellement de résistance acquise. Ils sont en fait constitués d'un mélange de deux groupes de composés A et B d'action synergique. L'objectif de ce travail de thèse a consisté en la synthèse totale de la griséoviridine, streptogramine du groupe A. La stratégie reposait sur la préparation initiale des fragments Nord-Est (C11-N23) et Sud-Ouest (C12-C22) en vue de leur couplage. La synthèse du fragment Nord-Est (C11-N23) a été réalisée selon deux approches différentes, soit par réaction de macrolactonisation, soit par couplage acétylénique-soufre dans des conditions réductrices. La synthèse du fragment Sud-Ouest est axée sur une réaction d'aldolisation énantiosélective. A ce jour, le couplage des deux unités est en cours.
40
Chaume, Grégory Ardisson Janick. "Vers la synthèse totale de la griséoviridine, antibiotique de type streptogramine." [S.l.] : [s.n.], 2008. http://biblioweb.u-cergy.fr/theses/03CERG0256.pdf.
Full text
41
Lowden, A. S. "Studies on the biosynthesis of rapamycin." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340997.
Full text
42
周永昌 and Wing-cheong Louis Chow. "Modulation of acute inflammatory response caused by surgical trauma ina mastectomy model." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1999. http://hub.hku.hk/bib/B31979622.
Full text
43
Butler, Aoife Patricia. "Studies directed towards the synthesis of bafilomycin Aâ†1." Thesis, University of Southampton, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242251.
Full text
44
HORMATALLAH, NOURJALIL. "Etat actuel et perspectives du traitement de maladies infectieuses a mycoplasma pneumoniae." Nancy 1, 1993. http://www.theses.fr/1993NAN1P072.
Full text
45
Berque-Bestel, Isabelle. "Contribution a la synthese stereocontrolee de macrolides de type erythromycine." Paris 11, 1998. http://www.theses.fr/1998PA114803.
Full text
46
Harper, Emily E., and Tara A. Jackson. "An Evaluation of Macrolide Drug-Drug Interactions for Quality in the Literature." The University of Arizona, 2011. http://hdl.handle.net/10150/623558.
Full textAbstract:
Class of 2011 AbstractOBJECTIVES: To evaluate the quality of evidence in the literature substantiating major drug-drug interactions of the macrolide antibiotics azithromycin, clarithromycin, and erythromycin with digoxin, ergot alkaloids, and pimozide. METHODS: In this descriptive retrospective analysis, a list of articles reporting on each drug-drug interaction was compiled from the online databases Medline and International Pharmaceutical Abstracts, and the drug compendia Micromedex and Facts & Comparisons. The studies included in this analysis were primary literature reports, written in English, and consisted of human subjects. All studies included were evaluated using a 5-point quality of evidence scale developed in the Netherlands to assess drug-drug interactions (van Roon scale). This scale rates the study type from lowest to highest quality, from zero to four. Case reports were additionally analyzed using the Drug Interaction Probability Scale (DIPS). The DIPS tool uses 10 questions to evaluate the probability that an adverse event is caused by a drug-drug interaction. RESULTS: Thirty-seven studies met the selection criteria. There were 28 studies involving digoxin, two studies involving pimozide and seven studies involving ergot alkaloids. The mean quality of evidence score on the van Roon scale was 2.3 + 0.75, where digoxin studies had a score of 2.3 + 0.74, ergot alkaloids had a score of 1.9 + 0.38 and pimozide only had two studies with evidence scores of 2 and 4. Sixty-two percent of the studies reviewed were case reports. CONCLUSION: The reports substantiating some drug-drug interactions may be of low quality and few in number.
47
Chow, Wing-cheong Louis. "Modulation of acute inflammatory response caused by surgical trauma in a mastectomy model." Hong Kong : University of Hong Kong, 1999. http://sunzi.lib.hku.hk/hkuto/record.jsp?B23636464.
Full text
48
Keller, Thomas Hugo. "Conformationally controlled reactions in 14-membered macrolides." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/28844.
Full textAbstract:
The conformationally controlled reactions of macrolides 42, 43, 72 and 74 were investigated. Treatment of these 14-membered lactones with hydride reducing agents and organocopper reagents led to diastereoselective product formation. The product distributions could be rationalized using low energy starting material or product conformations. A detailed conformational analysis involving MM2/MMP2 calculations and X-ray crystallographic studies led to a simple model for determining these low energy conformations.
In order to simplify the identification of ring conformations, an improved procedure for the generation of polar maps was developed. With the aid of polar maps, a previously unknown low energy conformation for 14-membered rings was discovered. The discovery of this new conformation led to an improved nomenclature system for large rings, which considers the number of bonds separating both corner and pseudo corner atoms. Under this proposed nomenclature, the newly discovered conformation is designated the [34'3'4'] conformation.
The work described in this thesis also led to a useful method for assigning the stereochemistry of trimethylsilyl enol ethers. Nuclear Overhauser effect difference spectroscopy (NOEDS) was used to unambiguously distinguish between E and Z trimethylsilyl enol ethers. One advantage of this technique over the widely used ¹³C NMR method is that only one isomer is required to accurately assign the E or Z geometry. [Formula Omitted]Science, Faculty of
Chemistry, Department of
Graduate
49
Reader, Michael. "Studies towards the synthesis of the macrolide portion of ulapualide A." Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294255.
Full text
50
Thirsk, Carl Edward. "Stereoselective routes to the total synthesis of the polyene macrolide viridenomycin." Thesis, Durham University, 2003. http://etheses.dur.ac.uk/3153/.
Full textAbstract:
Viridenomycin 11 is a polyene macrolide possessing a wealth of biological activity. As part of an ongoing program examining the stereoselective synthesis of polyene natural products, a strategy was explored to effect the total synthesis of viridenomycin 11.As a consequence of the adopted retrosynthetic strategy, the project was naturally divided into three main areas: efforts directed towards the southern (E, E, E, Z)-tetraene 210, towards the northern (E, Z, Z)-triene 209, and towards the core cyclopentenone 211.Both polyenic sections 209 and 210 were tackled with a view to utilizing palladium-coupling methodology developed in the group, whereby vinylboronates of type 122 undergo Heck coupling with alkenyl halides, affording polyenyl boronates that may then be converted into polyenyl iodides via stereoselective iodo-deboronation. The geometry of the new double bond is determined by the order of reagent addition during the iodo-deboronation. Vinylboronates such as 122 may thus be regarded as a vinyl dianion equivalent, permitting ready access to either alkene geometry, and allowing a polyene chain to be built up via an iterative process. Efforts towards 209 gave rise to a surprising reaction, in which it was discovered that iodoacrylates 214 are problematic Heck coupling partners due to a propensity to undergo novel Michael addition-elimination reactions with most amine bases, instead affording amino acrylates in excellent yields. Efforts towards 210 called for the development of new and robust methods for the elaboration of the amino acid phenylglycine, providing gready improved procedures for its conversion to the corresponding N-protected β-amino alcohol, N-protected β-amino-O-sulfonylates, N -protected β -amino iodides and N-protected β-amino nitriles, all valuable synthetic intermediates in their own right. An advanced synthon en route to 210 was prepared by Heck coupling of (Z)-iodide 214 with vinylboronate 272, representing a considerable in-road into the synthesis of this fragment. Markedly different chemistry was required to synthesize 211. Its retrosynthetic strategy called for a stereoselective aldol reaction, and as a consequence of this work it was found that novel oxazaborolidinone mediated Mukaiyama aldol additions between diene 4-(ferr-butoxy)-2,4-bis[(trimethylsilyl)oxy]-l,3-butadienyl methyl ether 335 and a wide range of electrophiles gave aldol products in isolated yields of up to 90%.