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Dissertations / Theses on the topic 'Macrocyclic lactones'
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Reather, James Andrew. "Late steps in the biosynthesis of macrocyclic lactones." Thesis, University of Cambridge, 2000. https://www.repository.cam.ac.uk/handle/1810/251730.
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Savill, Karen. "Investigations of 1,2,4-trioxanes as precursors of macrocyclic lactones." Thesis, Heriot-Watt University, 1993. http://hdl.handle.net/10399/1392.
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Munt, Simon Peter. "Radical cyclizations : an approach to the bryostatins." Thesis, University of Oxford, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.258009.
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Mowbray, Charles Eric. "Arcimycins : selective degradation and semi-synthesis." Thesis, University of Exeter, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235913.
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Yilmaz, Esra [Verfasser]. "Metabolism of macrocyclic lactones and benzimidazoles in parasitic nematodes / Esra Yilmaz." Berlin : Freie Universität Berlin, 2019. http://d-nb.info/1201346665/34.
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Galazzo, Daniel. "A comparison of laboratory and field resistance to macrocyclic lactones in Haemonchus contortus /." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82236.
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Sustainable parasite control in livestock depends on anthelmintic drugs. The nematode Haemonchus contortus, the most important intestinal parasite of sheep and goats has developed resistance to all classes of anthelmintics including moxidectin, the most potent of the macrocyclic lactones. Pyrosequencing was used to screen H. contortus laboratory and field strains for single nucleotide polymorphisms (SNPs) associated with resistance in three genes, and determine their involvement in field resistance to macrocyclic lactones. Specific SNPs increased in frequency in ivermectin/moxidectin laboratory selected strains for all three genes. These did not protect a resistant field strain from a field dose of ivermectin and were not the major mechanism of resistance in the field strain. A gamma-aminobutyric acid chloride receptor SNP may be a potential marker for moxidectin resistance in the field. This study indicates results obtained from laboratory strains selected with sub-therapeutic doses of drug may not reflect the situation in the field.
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Godoy, Rosas Pablo. "Functional analysis of «Haemonchus contortus» P-glycoprotein-A and interaction with macrocyclic lactones." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=97122.
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Macrocyclic lactone (ML) resistance has been described in the parasitic nematode, Haemonchus contortus. One of the mechanisms involved could be the over expression of P-glycoproteins (Pgps) which are ABC transporters. These proteins may influence the concentration of MLs that reach their target. In H. contortus one ABC transporter that is overexpressed in ML resistant parasites is Pgp-A (HcPgp-A). The goal of this project was the expression of HcPgp-A, in transfected LLC-PK1 cells, and to see the effect of ivermectin and moxidectin on inhibition of rhodamine 123 transport by the transfected cells. Rhodamine123 was actively transported by HcPgp-A. Ivermectin was four fold more potent at inhibiting rhodamine 123 transport by HcPgp-A than was moxidectin. The work provides the first information showing that MLs can inhibit the transport of Pgp substrates by a parasitic nematode ABC transporter and may indicate an active role for H. contortus Ppgs in ML resistance.<br>La résistance aux lactones macrocycliques (LM) est bien connue chez le parasite nématode Haemonchus contortus. La surexpression de P-glycoprotéines (Pgp), qui sont des ABC transporteurs, pourrait être impliquée dans un des mécanismes de la résistance aux LM. Ces protéines peuvent influencer la concentration de LM qui atteint leur cible. Pgp-A (HcPgp-A) est un ABC transporteur d' H. contortus qui est surexprimé chez les parasites résistants aux LM. Le but de cette étude était d'exprimer la P-glycoprotéine-A d'H. contortus dans des cellules transfectées LLC-PK1 afin d'évaluer les effets de l'ivermectine et de la moxidectine sur l'inhibition du transport de la rhodamine 123. La rhodamine 123 s'est avérée être transportée activement par HcPgp-A. Les effets de l'ivermectine sur l'inhibition du transport de la rhodamine 123 par HcPgp-A étaient quatre fois plus importants que ceux de la moxidectine. L'étude a montré pour la première fois que les LM pouvaient inhiber le transport des substrats de la P-glycoprotéine grâce à un ABC transporteur d'un nématode parasite. Cette information pourrait indiquer un rôle actif des Pgps d'H. contortus dans la résistance aux LM.
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Ramcharitar, Steve Harrinarine. "The synthesis of macrocyclic ketones and lactones : approaches to naturally occurring macrolyde antibiotics." Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302875.
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Maiti, Tushar B. (Tushar Baran). "An Approach Towards the Total Synthesis of Clonostachydiol." Thesis, University of North Texas, 1995. https://digital.library.unt.edu/ark:/67531/metadc278800/.
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The syntheses of the unsymmetrical 14-membered bismacrolides have been reviewed. A total synthesis of clonostachydiol, the latest to join this family, has been attempted using trimethylsilyl acetylene as the builiding block and palladium catalyzed reactions for the formation of key bonds. The alkyne groups were introduced by Stille coupling of trimethylstannylethynyltrimethylsilane with an acid chloride for one fragment and by addition of lithiotrimethylsilyl acetylene to an aldehyde for the other. Lactic acid derivatives were chosen as starting materials for both fragments, thus introducing two of the chiral centers. The remaining stereocenters were introduced using stereoselective reductions of ketones.
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Firas, Bassissi Mohamad. "Le rôle des lipides et des lipoprotéines plasmatiques dans le transport et la pharmacocinétique des lactones macrocycliques (aspects pharmacologiques et toxicologiques)." Toulouse 3, 2006. http://www.theses.fr/2006TOU30025.
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Les Lactones Macrocycliques (LMs) sont des antiparasitaires largement utilisé en médecine vétérinaire contre les endo et les ectoparasites. Nos travaux révèlent pour la première fois l'implication des lipoprotéines dans le transport plasmatique des 5 différentes lactones (Ivermectine, Doramectine, Moxidectine, Abamectine, prinomectine) chez les différentes espèces animales cibles y compris l'homme. De plus nous avons pu mettre en évidence l'impact des perturbations du profil plasmatique en lipides et lipoprotéines sur la pharmacocinétique et la distribution plasmatique des LMs. Au même titre nous avons démontré le rôle crucial de la circulation lymphatique dans l'absorption intestinale de la moxidectine ce que nous a permis d'optimiser leur biodisponibilité suite à une coadministration des lipides par voie orale. De même la mise en oeuvre d'une formulation liposomale de l'ivermectine a produit une biodisponibilité convenable toutefois une évaluation de la distribution tissulaire et de l'efficacité de ces formulations prometteuses s'avérera nécessaire. En conclusion nos travaux suggèrent que les lipides et les lipoprotéines plasmatiques jouent un rôle prépondérant dans le transport et le devenir des LMs dans l'organisme hôte<br>Macrocyclic Lactones (MLs) are potent anthelmintic drugs widely used for control of both internal and external parasites in domestic animals and livestock. In a first step our work shows that the five MLs tested (Ivermectin, Doramectin, Moxidectin, Abamectin, Eprinomectin) were extensively distributed into plasma lipoproteins with a preferential association to HDL in both animal species including humans. In the second step we have reported the effect of dyslipidemias on the plasma distribution and pharmacokinetic of moxidectin in human and rabbit model. On the other hand our investigation clearly indicated the major contribution of lymphatic circulation in the process of intestinal absorption of moxidectin and subsequently to its systemic bioavailability. Our findings could allow the enhancement of oral MLs bioavailability by using lipid-based ormulation. Finally our data demonstrated that the use of liposomal formulation represents promising tool by improving the bioavailability and the efficacy of ivermectin and related drugs. Furthermore, in vivo and in vitro investigations are needed to demonstrate the ability of liposome to improve the ivermectin efficacy. In conclusion our works suggest that the lipids and lipoproteins play a primordial role in the transport and disposition of MLs in the host's organism
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Lopes, Alberto Moura Mendes 1981. "Caracterização do gene codificante da subunidade alpha do canal de cloreto (GluCl alpha) possivelmente associado à resistência às lactonas macrocíclicas em Cochliomyia hominivorax(Diptera: Calliphoridae) = Characterization of the gene encoding the alpha subunit of the chloride channel (GluCl alpha) possibly associated with resistance to macrocyclic lactones in Cochliomyia hominivorax(Diptera: Calliphoridae)." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/316431.
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Previous issue date: 2013<br>Resumo: O Brasil possui o maior rebanho bovino comercial do mundo, sendo este um dos setores de geração de renda mais importantes para o país. As infestações por ecto e endoparasitas estão entre os principais problemas que levam à diminuição da produtividade. Dentre eles, a Cochliomyia hominivorax (Coquerel), conhecida como mosca-da-bicheira, destaca-se como uma das principais causadoras de miíases, gerando prejuízos de aproximadamente US$ 1,7 bilhões/ano ao país. Produtos sistêmicos como as lactonas macrocíclicas/macrolactonas, ativadoras, dentre outros, do canal de cloreto (GLUCL?), vêm sendo utilizados intensivamente como medida preventiva e de tratamento nas infestações por C. hominivorax e diversos parasitas, e a intensa/prolongada utilização das lactonas macrocíclicas tem levado ao surgimento da resistência a tais produtos. A identificação dos mecanismos moleculares da resistência às lactonas macrocíclicas em outras espécies indica a ocorrência de possíveis alterações no canal de cloreto associados à resistência em C. hominivorax. Utilizando-se de sequências do canal de cloreto de outras espécies, previamente depositadas no banco de dados, além de sequências obtidas na caracterização do transcriptoma de C. hominivorax, o objetivo deste projeto é amplificar e sequenciar a região codificante do gene da subunidade desse canal de cloreto dependente de L-glutamato (GluCl?) em C. hominivorax. Além disso, serão comparadas as sequências de indivíduos resistentes e suscetíveis às macrolactonas visando à identificação da(s) mutação (ões) que confere(m) resistência a tais produtos e, consequentemente, o diagnóstico molecular da resistência<br>Abstract: Brazil has the largest commercial cattle herd in the world, being one of the most important sectors of income generation for the country. Infestations by ecto- and endo parasites are among the major problems that lead to low productivity. Among them, the Cochliomyia hominivorax (Coquerel), known as the New World Screwworm fly, stands out as a major cause of myiasis, resulting in losses of approximately US$ 1.7 billion each year to the country. Systemic products such as macrocyclic lactones/macrolactones (MLs), mainly the MLs member ivermectin, have been extensively used as a preventive measure and treatment in infestations by C. hominivorax and various parasites, and the intense/prolonged use of macrocyclic lactones have led to the emergence of resistance to such products. The macrolactones target-sites are the cys-loop ligand-gated ion channels receptors, specially the glutamate-gated chloride channel subunit (GLUCL?). The identification of the molecular mechanisms of macrocyclic lactones resistance in other species indicates that possible alterations in chloride channels and GLYR? and nAchR?7 are associated with macrolactones resistance in C. hominivorax. Using the glutamate-gated chloride channel subunit sequences from other species, previously deposited in the database, and sequences obtained in the characterization of the transcriptome of C. hominivorax, the aim of this project was to amplify and sequence the coding region of the glutamate-gated chloride channel subunit gene (GluCl?) in C. hominivorax. In addition, sequences will be compared among putative ivermectin resistant and susceptible individuals in order to identify mutation(s) conferring resistance to such product and thereby the molecular diagnosis of resistance<br>Mestrado<br>Genetica Animal e Evolução<br>Mestre em Genética e Biologia Molecular
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David, Marion. "Identification and functional characterization of an ABC transporter of Haemonchus contortus, the P-glycoprotein 13." Thesis, Toulouse 3, 2016. http://www.theses.fr/2016TOU30206/document.
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Les lactones macrocycliques (LM) sont des anthelminthiques (AH) à effet paralysant très utilisés chez les animaux et les humains contre les nématodes parasites. Cependant, leur succès thérapeutique est compromis par la résistance croissante aux LM, qui pourrait être en partie dû aux ABC transporteurs P-glycoprotéines (Pgps) sélectionnés et surexprimés chez les nématodes résistants aux LM. Dans ce travail, nous avons étudié plus précisément la P-glycoprotéine 13 du parasite de petits ruminants, Haemonchus contortus. Son orthologue chez le modèle nématode C. elegans, Cel-Pgp-13, est exprimé dans les amphides, structures qui ont été associées à la sensibilité aux AH chez C. elegans et H. contortus. Pour prédire la capacité des Pgps de nematode à transporter des drogues, incluant des LM et autres AH, nous avons développé un modèle de docking in silico. Nous avons utilisé la structure cristallographique de C. elegans Pgp-1 (Cel-Pgp-1), et nous avons montré la liaison avec une forte affinité de plusieurs ligands décrits comme activateurs de sa fonction ATPasique. Nous avons aussi décrit une forte affinité des LM, et un site spécifique de liaison de ces composés à Cel-Pgp-1. Cette approche représente un outil important pour prédire les interactions entre AH, et pour concevoir rationnellement de nouveaux inhibiteurs compétitifs des Pgps de nématode, dans le but d'améliorer les stratégies thérapeutiques. Sur la base de cette approche, nous avons prédit la structure 3D de Hco-Pgp-13 à partir du cristal de Cel-Pgp-1 afin d'étudier son intéraction avec des substrats potentiels, en particulier les LM. Nous avons trouvé des affinités similaires pour différents composés précédemment testés sur Cel-Pgp-1. In vitro, la mesure de l'activité ATPasique montre que l'actinomycine D est un substrat de Hco-Pgp-13. Nos données démontrent la présence possible d'un domaine de reconnaissance multispécifique sur ce transporteur de parasite. La détermination par immunofluorescence de l'expression de Hco-Pgp-13 a montré une distribution tissulaire large indiquant que Hco-Pgp-13 pourrait jouer un role important dans le transport de substrats endogènes et/ou exogènes. En conclusion, ce travail permet de mieux comprendre le rôle des Pgps de nématodes dans le transport de médicaments AH, tant au niveau de l'organisme modèle C. elegans que du nématode parasite H. contortus. Cette étude suggère la conservation de la fonction de tranporteur ABC multidrogue dans ces espèces. La localisation de Hco-Pgp-13 sur les structures amphidiales, et son éventuelle implication dans la résistance aux médicaments et à la survie de H. contortus à l'exposition à des composés AH, restent à préciser<br>Macrocyclic lactones (ML) are paralyzing anthelmintics used in animals and humans against parasite nematodes. However, their therapeutic success is compromised by the spread of ML resistance. This might be at least partly due to P-glycoproteins (Pgps) ABC transporters that are selected and overexpressed in ML-resistant nematodes. Deciphering the role of the 10 Pgps expressed in the parasite of small ruminants Haemonchus contortus is thus of major importance to guaranty anthelmintic (AH) efficacy of various drugs. Here we focused on Hco-Pgp-13 due to the expression in the amphids of its closest ortholog in the model nematode C. elegans. Indeed, the amphids represent a putative entry route of drugs to reach AH targets in the nervous system and have been linked to AH susceptibility in C. elegans and H. contortus. In order to predict the capacity of nematode Pgps to transport drugs, including ML and otherAH, we have developed an in silico drug docking model. We have used C. elegans Pgp-1 (Cel-Pgp-1) crystal structure and have showed a high affinity binding of several ligands that have been shown to be activators of its ATPase function. ML were also found to bind with high affinity to Cel-Pgp-1, on a specific binding site. This approach provides a valuable tool to predict drug-drug interactions and to rationally design new competitive inhibitors of nematode Pgps, in order to improve anthelmintic therapeutics. We then predicted a putative 3D structure of Hco-Pgp-13 based on the recently released crystal of Cel-Pgp-1, with which it presented a high homology. This allowed the study of the interaction of Hco-Pgp-13 with potential substrates, in particular ML. We found similar affinities for various drugs previously tested on Cel-Pgp-1, supporting the good homology of these two proteins. Together with in vitro ATPase assay experiments that confirmed the substrate status of actinomycin D, this indicates a possible multispecifc recognition capacity of this parasitic transporter. The determination of Hco-Pgp-13 localization using immunohistochemistry showed a wide tissue expression consistent with a critical role for Hco-Pgp-13 in endogenous and/or exogenous substrate transport. In conclusion, this work provides insights into the role of nematode Pgps in transporting AH drugs, both at the level of the model organism C. elegans and of the parasitic nematode H. contortus. This suggests a high homology of function conserved between ABC tranporters in these species. The localization of such protein on amphidial structures and its possible involvement in drug resistance and survival of H. contortus to exposure to AH compounds remain to be precised
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Albérich, Mélanie. "Impact de l'ivermectine sur les systèmes de détoxification des xénobiotiques : régulations chez l'hôte et chez le nématode." Thesis, Toulouse, INPT, 2014. http://www.theses.fr/2014INPT0102/document.
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Les infections par les nématodes gastro-intestinaux entrainent des baisses en productions animales et des pertes économiques majeures pour les éleveurs. Les lactones macrocycliques (LMs) sont parmi les antiparasitaires les plus utilisés dans la lutte contre les nématodes gastro-intestinaux en médecine vétérinaire. De part une utilisation intensive, des résistances aux LMs chez les parasites gastro-intestinaux se sont développées au sein des élevages du monde entier mettant en péril l'efficacité thérapeutique de ces molécules. Par ailleurs, le développement de nouveaux antiparasitaires est limité. Ainsi, un des enjeux pour assurer le contrôle de ces parasites est de ralentir les phénomènes de résistance aux LMs afin de prolonger leur efficacité. Le succès d'une telle stratégie repose sur les connaissances précises des mécanismes impliqués dans la résistance. Parmi eux, la modulation des systèmes de détoxification est décrite lors de phénomènes de résistance aux LMs. Au cours de ces travaux, nous avons étudiés la régulation des systèmes de détoxification, en réponse à l'ivermectine chez l'hôte. Nous avons montré, en comparaison à une administration unique, qu'une administration répétée d'ivermectine par voie orale chez la souris est responsable de l'induction de l'expression de certains gènes transporteurs ABC et cytochromes impliqués dans son métabolisme. Ceci entraîne, à la fois, une diminution de la concentration de la molécule parentale et une augmentation de la teneur de son métabolite principal dans le plasma et l'intestin. Ensuite, nous avons étudié l'implication des mécanismes de régulation des systèmes de détoxification, et notamment les récepteurs nucléaires, dans la tolérance à l'ivermectine chez le nématode C.elegans. Nous avons montré que le récepteur nucléaire nhr-a est important pour la tolérance et le développement de la résistance à l'ivermectine. Enfin, nous avons étudié l'impact d'inhibiteurs des transporteurs ABC sur l'efficacité de l'ivermectine. Nous avons mis en évidence la capacité de certains flavonoïdes et de l'ivermectine aglycone à potentialiser l'efficacité de l'ivermectine chez le nématode. Une exposition d'ivermectine induit la surexpression des systèmes de détoxification chez l'hôte. Ceci pourrait être la base des mécanismes moléculaires de la résistance chez le nématode. Cibler les systèmes de détoxification ou les mécanismes de résistance, par des inhibiteurs adaptés, représente une stratégie pertinente pour potentialiser l'efficacité de l'ivermectine<br>Infections with gastrointestinal nematodes (GINs) in livestock leads to major losses in production and consequently impact economically farmers. Their intensive use has led to widespread anthelmintic resistance which is nowadays the main threat on the sustainable control of GINs in livestock. The development of new anthelmintic is limited due to the cost of such process. Then, the challenge remains in optimizing the use of existing molecules. Therefore, it is urgent to limit and control MLs resistance in order to extend their efficacy and to avoid therapeutic failure. Resistance mechanisms remain to be elucidated. In that context, we investigated regulatory mechanism of detoxification systems of ivermectin implicated in therapeutic efficacy in host and resistance development in nematode. Therapeutic combinations of ivermectin with flavonoïds have been evaluated to potentiate its efficacy in nematode. We showed that repeated oral administration of ivermectin induced gene expression encoding some ABC efflux transporters and cytochromes involved in its metabolism. Compared with single administration, repeated ivermectin administration lowered plasma, liver and intestine drug concentration, while increasing main metabolite content in plasma and intestine. We have also shown that nuclear receptor nhr-a was important for ivermectin tolerance and ivermectin development of resistance in C. elegans. Finally, we demonstrated the ability of the flavonoïd phloretin to potentiate ivermectin efficacy in the nematode C. elegans. Taken together, these data suggest that induction of detoxification systems impact on ivermectin distribution and targeting their regulation could be an appropriate strategy to potentiate ivermectin efficacy in host and to reverse resistance in nematode
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Forrester, Sean Geritt. "Characterization of a macrocyclic lactone receptor subunit from Haemonchus contortus." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82872.
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Glutamate-gated chloride channels (GluCls) are the proposed site of action for macrocyclic lactone anthelminthics, such as IVM, and the milbemycins, such as MOX. The objective of this thesis was to determine whether Haemonchus contortus GluCls are important targets for these anthelminthics. To begin to address this we cloned a full length GluCl alpha-subunit cDNA from H. contortus (HcGluCla). This subunit shares a high homology with GluCl subunits from Caenhorhabditis elegans that have been shown to be important targets for IVM, suggesting that HcGluCla is also an IVM target. However, if HcGluCla is an IVM receptor then it should contain an IVM binding site. To investigate this, the HcGluCla gene was expressed in COS-7 cells. The resulting subunit bound [3H]IVM and [ 3H]MOX with affinities sufficiently high enough to explain their high in vivo potency. Interestingly, glutamate was an allosteric modulator of [ 3H]MOX and [3H]IVM binding where it increased the affinity of these drugs to HcGluCla. To gain further insight into the potentiation of IVM, various glutamatergic and non-glutamatergic ligands were screened for their ability to enhance [3H]IVM binding to HcGluCla. Of the ligands tested, only the GluCl agonists glutamate and ibotenate potentiated [3H]IVM binding. It is possible therefore that if IVM interacts with GluCls in vivo then IVM efficacy may be enhanced by GluCl agonists. To examine this, we tested whether ibotenate could enhance IVM efficacy in gerbils infected with H. contortus. In in vivo efficacy studies, ibotenate (at 1 mg/kg) increased IVM efficacy by 15% (p = 0.048). The enhancement of IVM efficacy in vivo by a GluCl agonist suggests that one of the IVM targets in H. contortus is the GluCl. Finally, to determine the potential physiological response from an interaction between IVM and H. contortus GluCls, we expressed HcGluCla in Xenopus oocytes. HcGluCla expressed in oocytes formed a homomeric channel that responded to
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Brown, Jesse. "Resorcylic Acid Lactone Thioesterases as Potential Biocatalysts." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/38741.
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A key missing tool in the chemist’s toolbox is an effective biocatalyst for macrocyclization. Macrocycles limit the conformational flexibility of small molecules, often improving their ability to bind selectively and with high affinity to a target, making them a privileged structure in drug discovery. Resorcylic acid lactones (RALs) are a class of fungal macrocyclic polyketides that exhibit anti-cancer and anti-malarial activity among others. The thioesterases (TEs) found in the biosynthetic pathways for the zearalenone (Zea) and radicicol (Rdc) resorcylic acid lactones are responsible for macrocyclization and show promising traits as biocatalysts. These RAL TEs show the highest substrate tolerance of any polyketide thioesterase to date. These TEs can efficiently cyclize 12- 18-membered rings, 14-membered macrolactams, and amino acid containing substrates. Their robustness is evident in their ability to retain activity after lyophilization/re-suspension and in high DMSO concentrations. Furthermore, the ability of Zea and Rdc TEs to macrocyclize depsipeptide substrates illustrates the first time a polyketide synthase TE has efficiently processed a peptide-containing substrate. The unique substrate tolerance of this class of TEs shows great potential as a viable biocatalyst. Herein we describe the synthesis and enzymatic results of diverse group of substrates, with the TEs from the radicicol and zearalenone biosynthetic pathways, as well initial results on the chemoenzymatic synthesis of asperterrestide A.
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FERREIRA, Fabr?cia Ferreira e. "Remiss?o da demodiciose canina ap?s o tratamento com a doramectina em diferentes protocolos." Universidade Federal Rural do Rio de Janeiro, 2016. https://tede.ufrrj.br/jspui/handle/jspui/1833.
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Previous issue date: 2016-03-23<br>Canine demodicosis is an inflammatory skin disease, frequently diagnosed in veterinary clinics, caused by the proliferation of mites of the species Demodex sp. In recent years, important findings about the disease have been reported, mainly aspects related to treatment, with the insertion of new molecules or new treatment regimens. Doramectin is a macrocyclic lactone that has been used empirically by veterinarians, who use different routes, doses and intervals in its administration, with no homogeneus results. This study aimed to evaluate the use of doramectin in the treatment of dogs affected by the generalized form of demodicosis. Of the forty-six dogs diagnosed with the disease during the study, 20 were selected for the study and divided into three groups: Group I ? treated with doramectin at a dose of 600 mcg/kg once a week orally, group II ? treated at a dose of 300 mcg/kg orally every 3 days and group III ? treated at a dose of 600 mcg/kg every 7 days subcutaneously. The animals were treated until three consecutive negative skin scrapings were obtained, with intervals of at least fifteen days between them (parasitological cure). The days required to obtain the parasitological cure were 105, 82 and 100 according to the indicated groups; and their treatment efficiencies were 75, 100 and 83%, respectively. Doramectin was effective in treating generalized demodectic mange in dogs, regardless of the dose, route and interval of administration. However, the best results were obtained in the group treated at a dose of 300 mcg/kg orally every 3 days. There were no reported adverse reactions with the use of macrocyclic lactone.<br>Demodiciose canina ? uma doen?a inflamat?ria da pele, frequentemente diagnosticada nos consult?rios veterin?rios, causada pela prolifera??o de ?caros da esp?cie Demodex sp. Nos ?ltimos anos, importantes descobertas sobre a doen?a foram reportadas, principalmente os aspectos relacionados ao tratamento, com a inser??o de novas mol?culas ou novos esquemas de tratamento. A doramectina ? uma lactona macroc?clica que vem sendo usada de forma emp?rica por m?dicos veterin?rios, que a utilizam por diferentes vias, doses e intervalos na sua administra??o, com resultados heterog?neos. O objetivo do estudo foi avaliar a utiliza??o da doramectina no tratamento da demodiciose generalizada em c?es. Dos 46 animais diagnosticados com a doen?a, 20 foram selecionados e divididos em tr?s grupos experimentais: grupo I ? tratado com doramectina dose de 600 mcg/kg semanalmente por via oral, grupo II ? tratado na dose de 300 mcg/ kg por via oral a cada 3 dias e o grupo III ? tratado na dose de 600 mcg/kg a cada 7 dias por via subcut?nea. Os animais foram tratados at? a obten??o de tr?s raspados negativos consecutivos com pelo menos 15 dias de intervalo entre eles (cura parasitol?gica). Os dias necess?rios para obten??o da cura parasitol?gica foram 105, 82 e 100 de acordo com os grupos assinalados e as respectivas efic?cias ao tratamento foram 75, 100 e 83%. A doramectina demonstrou ser eficaz no tratamento da demodiciose generalizada em c?es independente da dose, via e intervalo de sua administra??o. Entretanto, os melhores resultados obtidos foram observados no grupo tratado com a dose de 300 mcg/ kg por via oral a cada 3 dias. N?o foram reportadas quaisquer rea??es adversas com a utiliza??o da lactona macroc?clica.
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Gerhard, Alexander Paul [Verfasser]. "The role of nematode P-glycoproteins in the mechanism of macrocyclic lactone resistance / Alexander Paul Gerhard." Berlin : Freie Universität Berlin, 2021. http://d-nb.info/1240674724/34.
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Sargison, Neil Donald. "Development of genetic crossing methods to identify genes associated with macrocyclic lactone resistance in the sheep nematode parasite, Haemonchus contortus." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/4395.
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There is a pressing need to develop strategies to reduce the emergence of macrocyclic lactone anthelmintic resistance in sheep flocks. Management practices aimed at maintaining anthelmintic susceptible nematodes in refugia while achieving a satisfactory level of production may prove to be useful. However, sensitive molecular tests are required to monitor the subtle effects of these practices on the frequency of resistance alleles within nematode populations. To-date, conventional studies of candidate genes coding for the known methods of action of macrocyclic lactone anthelmintics have produced a complex picture, highlighting the relevance of different approaches to the identification of resistance markers. This thesis describes the development of a single nematode parent genetic crossing method and discusses its application to identify molecular markers for anthelmintic resistance. Parasitological and molecular verification of successful inbreeding of the MHco3 strain of H. contortus derived from the progeny of a genetic cross between single nematode parents is described. The single parent genetic crossing method has enabled the production of diverse inbred lines of the MHco3 H. contortus and may prove useful for genome assembly, or for the development of a genetic map. The study has afforded insights to the biology of H. contortus and effects of host immunity on nematode parasites. New information is presented concerning the period during which adult female nematodes continue to shed fertilised eggs after removal of males, the development of unfertilised H. contortus eggs, and the population genetics of mixed infections of two different strains of H. contortus. Novel backcrossing experiments initially between a macrocyclic lactone resistant (MHco4 or MHco10) and a susceptible (MHco3) strain of H. contortus and then between ivermectin treated backcross generations and the parental susceptible strain are described. The resources provided by these experiments should enable comparative genomic analysis and conventional molecular biology to identify resistance genes derived from the parental resistant strains in fourth backcross generations that are the same as a parent ivermectin susceptible population, apart from the presence of alleles linked to anthelmintic resistance, derived from parent resistant strains.
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LEYGUE, ESTREME NADINE. "Macrocylisation en series lactame, lactone et thiolactone : mise en evidence d'un tetralactame comme complexant selectif du calcium." Toulouse 3, 1987. http://www.theses.fr/1987TOU30124.
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Bliard, Christophe. "Synthèse d'hydrates de carbone, de sucres fluorés et d'analogues d'avermectine." Paris 11, 1987. http://www.theses.fr/1987PA112380.
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Les avermectines sont des composés antiparasitaires possédant une activité exceptionnelle ; ils sont obtenus par culture de microrganismes. Ce travail présente la synthèse de plusieurs analogues de l'avermectine-B₁a dans le but d'améliorer ses propriétés biologiques. Le premier chapitre présence une revue des propriétés biologiques, chimiques et structurales des avermectines ainsi que les études de métabolisme qui nous ont guidés dans le choix de nos analogues. Ceux-ci sont obtenus par dégradation partielle du composé naturel, protection sélective suivie ce qlycosylation avec différents analogues de l'oléandrose obtenus par synthèse. Le second chapitre présente la synthèse des analogues fluoré de l'aoléandrose et l'obtention des analogues fluorés de l'avermectine. A cette occasion, une nouvelle réaction de migration d'un groupement anomérique dans les sucres de type ∝-manno est développée. Le troisième chapitre présente la synthèse d'analogues non fluorés de l'oléandrose et la réalisation de plusieurs des analogues de l'avermectine-B₁ a correspondants. Les preuves de structure (méthodes spectroscopiques) ainsi que l'activité biologique de plusieurs de ces analogues sont présentées au chapitre IV<br>The work presented in this thesis deals with the synthesis of various analogues of avermectin-b₁a, a recently discovered Patent anthelmintic agent. In the first chapter we describe the discovery, structure determination, chemical properties, and biological activity of the members of the avermectin family. The important role of the di-oleandrose disaccharide branched on the polycyclic macrolide, in the biological activity, is pointed out. The aim of this work was to synthesize a more resistant analogue in order to delay the metabolic hydrolysis of the terminal sugar unit, essential for a good activity. We attempted to increase the strength of the glycosidic linkage between the two oledandrose units by introducing electron withdrawing atoms at the C-2" position or by modifyingThe stereochemistry of the second oleandrose unit. In the second chapter we disclose the synthesis of several fluorinated oleandrose derivatives and their glycosidation with the protected avermectin monosaccharide. A new migration process of the anomeric group is included in the synthesis as a key step. Unexpectedly, glycosyl fluorides appear to be stable under a variety of reaction conditions and we use them as synthetic intermediates. Oleandrose derivatives bearing C-2 geminal difluoro substituants are obtained by treating a C-2 fluoroglycal with either xenon difluoride or trifluoromethyl hypofluorite. The third chapter deals with the synthesis of hydroxylated, aminated, and stereisomeric analogues of oleandrose and their incorporation into the corresponding avermectin framework by glycosidation. And finally the fourth chapter deals with the structure determination of different avermectin analogues on the basis of spectroscopie data. The biological activity of these new avermectin derivatives has been tested, however, due to a patent problems only part of the results is revealed. Sorne of these compounds appear to have a higher activity against ectoparasites than the natural product
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Hutt, Jean. "Synthese d'analogues de la vitamine d::(3) : synthese chirale de composes polyhydroxyles." Université Louis Pasteur (Strasbourg) (1971-2008), 1986. http://www.theses.fr/1986STR13326.
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La transformation de la cfarvone en quatre diastereoisomeres precurseurs du cycle a des dihydrovitamines et dihydrotachysterols est decrite dans la premiere partie. Par couplage d'un acetylure derive des cycles c/d de la vitamine d::(3) avec la cetone precurseur du cycle a, puis sa formation du systeme dienique a l'aide de titane a basse valence nous avons obtenu des dihydrotachysterols majoritairement. D'un autre cote, l'utilisation de sulfoxydes optiquement actifs dans l'intention de creer des centres hydroxyles chiraux et son application a la synthese du fragment polyhydroxyle de l'amphotericine b et du l-arabinitol est decrite dans la deuxieme partie. Les trois etapes-cles de cette methodologie sont: reduction stereospecifique d'un beta-cetosulfoxyde; condensation stereospecifique; cis-hydroxylation d'un beta-hydroxysulfoxyde
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BREUILLES, PASCAL. "Syntheses de dicetones un, quatre." Paris 6, 1988. http://www.theses.fr/1988PA066645.
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Trois nouvelles methodes de synthese de dicetones 1-4 sont proposees: la premiere par addition oxydante, a l'aide de sels de manganese et de cuivre, de cetones a des isopentenyl sulfones; la seconde par substitution allylique de sulfures ou de sulfones par des cetones enolisables; la troisieme par cycloaddition a une enone d'un nouveau reactif: la chloromethyl-2 allylphenylsulfone. Les produits de ces trois reactions sont des cetones comportant un groupe methylene en position 4 alors facilement transformees en dicetones par ozonolyse. L'utilite synthetique de ces trois methodes est illustree par la synthese de plusieurs composes naturels: pyrenophorine, acide chrysanthemique et jasmone
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Fenster, Erik. "Conformationally controlled reactions of unsaturated macrocyclic lactones and keto lactones." Thesis, 2000. http://hdl.handle.net/2429/10608.
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As part of a study of the chemistry of macrocyclic compounds in our
laboratory, the 14-membered unsaturated lactones 29 and 30 were synthesized
with high stereoselectivity (>16:1 EIZ) via the ring closing olefin metathesis
(RCM) reaction of the open chain diene esters. The configuration of the double
bond in these unsaturated lactones was determined by 1H homonuclear
decoupling NMR experiments. Equilibrium studies demonstrated that the RCM
reaction proceeds under thermodynamic control in the cases of 29 and 30. The
keto lactones 67 and 68 were synthesized via the hydroboration of 30 followed by
TPAP oxidation of the hydroxy lactone products.
The conformationally controlled reactions of the macrocyclic lactones 29,
30, 67 and 68 were investigated. Treatment of the unsaturated lactone 29 with
borane tetrahydrofuran complex, disiamylborane and 9BBN led to the formation
of the hydroxy lactones 47 and 48 in a 1:1 regioisomeric ratio. Treatment of the
unsaturated lactone 30 with the same hydroborating reagents led to the formation
of the hydroxy lactones 51, 52, 53 and 54 in a 1:1 regioisomeric ratio but with
good 7r-face selectivity (>7:1 using 9BBN). The epoxidation of 30 using MCPBA
and methyl(trifluoromethyl)dioxirane, leading to epoxides 63 and 64 also showed
moderate 7t-face selectivity (>3:1 using MCPBA at -78 °C). Treatment of keto
lactones 67 and 68 with NaBH4 and K-Selectride under a variety of reaction
conditions led to the formation of hydroxy lactones 52, 53 and 51, 54,
respectively. The hydroxy lactones were obtained in good stereoselectivity
(>10:1 using K-Selectride at -78 °C) in the case of 67, and in low stereoselectivity
(1:1.5 using K-Selectride at -78 °C) in the case of 68.
In general, the stereoselectivity exhibited in the reactions of these
macrocyclic lactones could be rationalized from the conformational analysis of
the starting materials or the products. The relative stereochemistry of the
stereogenic centers within the compounds synthesized during the course of the
project were successfully assigned with the use of chemical correlations and Xray
analysis.
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Sharadendu, Anurag. "Synthesis and reactivity of macrocyclic β-keto lactones". Thesis, 1996. http://hdl.handle.net/2429/4760.
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As a part of a continuing study of the chemistry and conformational behaviour of
macrocyclic β-keto lactones, 3-oxo-13-tetradecanolide (74) and 3-oxo-15-hexadecanolide (84) were synthesized via intra- and intermolecular
alcoholysis of hydroxy Meldrum's acid derivatives. A number of 14- and
16-membered lactones, derived from 74 and 84 were used to investigate a
series of alkylation and reduction reactions.
[more abstract available in pdf]
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Wang, Chun-Chih, and 王俊智. "Cobalt-Catalyzed Highly Regio- and Stereoselective Reductive Ene-Ene and Ene-Yne Coupling Reactions: Application in the Synthesis of Lactones, Lactams and Macrocyclic Lactones." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/32656386242429095336.
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博士<br>國立清華大學<br>化學系<br>92<br>In this work, we report two cobalt-catalyzed olefins dimerization modes: (a) reductive dimerization of conjugated alkenes to yield directly the saturated linear diesters, dinitrile, and disulfone 2a-2g, offering a more convenient method to the synthesis of adipic acid and, (b) cobalt-catalyzed head-to-tail dimerization of vinylarenes 4a-4l in good yields.
On the other hand, we have recently developed a reaction mode of cobalt-catalyzed tail-to-tail reductive dimerization of conjugated alkenes. This provides an efficient and mild route for the corresponding saturated linear products. Herein, we describe that application for the cobalt-catalyzed reaction mode to synthesis of macrocyclic di- and tetralactones 6a-6i in good yields under normal dilution conditions.
The cobalt-catalyzed highly regio- and stereoselective reductive coupling reaction of alkynes and conjugated alkenes to form a new chain molecule 8a-8j, was conducted in the presence of CoI2(L) and zinc metal powder. Several 4-(4-alkyl phenyl)-3-butynyl acrylates also undergo reductive coupling macrocyclicization reaction to afford macrocyclic dilactone 12a-12c in 45-80% yields. This procedure allows for the synthesis of a variety of functionalized lactones, lactames and macrocyclic dilactones in moderate to good yields. Treatment of various propargyl alcohol with methyl acrylate proceeded successfully in the presence of CoI2(dppe), water and zinc metal powder in a mixture of acetonitrile and 1,4-dioxane (v/v = 1/1) at 80℃ affording the corresponding γ-methylideneδ-lactones 9a-9h in good yields. Several propargyl amines also react with methyl acrylate to afford γ-methylideneδ-lactames 9i-9k in 72-84% yields. Seven-membered lactones 10a-10i could also be prepared by slow addition of methyl 2-(3-hydroxy-1-alkynyl)benzoate to the reaction mixture of conjugated alkene in presence of CoI2(dppe), water and zinc metal powder and acetonitrile at 80℃. The above catalytic reactions are completely regioselective and highly stereoselective. Possible mechanisms for the reductive coupling cyclization reactions as well as unique features of these processes are discussed.
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Bissonnette, Stéphane. "Recherche de la mutation ABCB1-1 chez des chiens exprimant des signes de toxicité subchronique suite à l'administration quotidienne de lactones macrocycliques." Thèse, 2008. http://hdl.handle.net/1866/7203.
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Demeler, Janina [Verfasser]. "The physiological site of action and the site of resistance to the macrocyclic lactone anthelmintics in sheep parasitic trichostrongyloid nematodes / vorgelegt von Janina Demeler." 2005. http://d-nb.info/978192788/34.
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Cusson, Jean-Philippe. "Étude de la cyclisation de lactones à 9 membres par réaction de métathèse et formation catalytique de liens benzyliques asymétriques." Thèse, 2017. http://hdl.handle.net/1866/19342.
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Préalablement, une synthèse de l’aliskiren, un inhibiteur de la rénine développé pour le traitement de l’hypertension, a été réalisée auprès du groupe Hanessian. Durant cette synthèse, une réaction clé de cyclisation par métathèse, menant à la formation de lactone à neuf membres, a été réalisée. Durant cette réaction, nous avons observé une différence de réactivité entre les diastéréomères, menant à la formation de monolactones et de dilactones, générant ainsi de l’intérêt pour l’étude des facteurs en cause. Le présent mémoire rapporte et détaille les résultats de cette analyse quant à la formation de monomères versus celle de dimères par cyclisation à l’aide de catalyseurs de Grubbs et l’impact de différentes conditions réactionnelles et la diastéréochimie relative sur la réaction.
Un intérêt pour la formation de liens benzyliques nous a incité à approfondir notre compréhension d’une méthodologie de substitution nucléophile diastéréosélective catalysée par des acides. Le rationnel mit de l’avant par les groupes Bach et Olah a procuré une compréhension du mécanisme réactionnel sur lequel nous avons basé nos observations subséquentes. Nous avons porté notre attention sur l’alkylation d’arènes, de phénols et de sulfonamides. Diverses régiosélectivités et diastéréosélectivités ont pu être observées en présence de substrats dérivés de la synthèse de l’aliskiren, de nitroalcools ainsi que de azidoalcools en utilisant plusieurs acides de Lewis et de Brønsted.<br>Previously, a synthesis of aliskiren, a renin inhibitor developed for the treatment of hypertension, was developed in the Hanessian group. As part of that synthesis, they used a ring-closing metathesis which led to the formation of a nine-membered lactone, a key intermediate of the synthesis. During the reaction, we observed a difference in reactivity between the various diastereoisomers leading to the formation of mono- and dilactones, inciting us to study the various factors involved. The present master’s thesis reports and details the results of the study of monomers versus dimers formation by cyclization using Grubbs’s catalysts and the effect of various reaction conditions and relative configuration on the reaction.
An interest for the formation of benzylic bonds drove us to deepen our comprehension of a methodology of diastereselective nucleophilic substitution catalysed by acids. The rational brought forth by the Bach and Olah groups served as a basis for our understanding of the mechanism involved upon which we based our following observations. We focused our attention on the alkylation of arenes, phenols and sulfonamides. Various regioselectivities and diastereoselectivities were observed on substrates derived from the aliskiren’s synthesis, nitroaocohols and azidoalcohols while using various Lewis and Brønsted acids.