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Allsebrook, Andrew M. "QPRTase : quinolinic acid analogue synthesis and non-enzymic decarboxylation of N-alkylquinolinic acids." Thesis, University of St Andrews, 1998. http://hdl.handle.net/10023/14376.
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Quinolinate phosphoribosyltransferase (QPRTase, E.C. 2.4.2.19) is considered to be a unique enzyme in that it is thought to catalyse two distinct chemical reactions. Both the transfer of a phosphoribosyl group from 5-phosphoribosyl-1- pyrophosphate onto the nitrogen of quinolinic acid and the subsequent decarboxylation of the intermediate to form nicotinic acid mononucleotide are thought to be catalysed by the QPRTase system. Analogues of quinolinic acid were designed as potential inhibitors of QPRTase. These contain acidic groups at the 2- and 3- positions but are unable to decarboxylate. However, such compounds may be able to undergo the phosphoribosyl transfer reaction, potentially increasing their inhibitory potency. These compounds may be useful as "biological tools" allowing the neurological effects of an increase in quinolinic acid levels to be investigated. The compounds may show anti-fungal activity blocking the kynurenine pathway for NAD production. 2-Sulfonicotinic acid was synthesised by the oxidation of 2-mercaptonicotinic acid by either basic potassium permanganate, or iodine, with the structure was confirmed by X-ray crystallography. In biological testing the acid was shown to be neither an agonist nor antagonist of the NMDA receptor, or to be neurotoxic. A number of synthetic routes towards 2-phosphononicotinic acid, an alternative quinolinic acid analogue, were attempted though none were successful. These included orthometallation strategies and palladium coupling reactions to incorporate the phosphonic acid group at the 2- position. Nucleophilic addition routes, methods of building up the pyridine ring and including non-selective phosphonic acid addition were also examined. However, a related derivative, 2-(phosphonomethyl)nicotinic acid, was successfully synthesised. The non-enzymic decarboxylation of N-alkyl quinolinic acids was investigated, for comparison with the decarboxylation reaction catalysed by QPRTase. Both N- methyl and N-ethylquinolinic acid were synthesised, and the pH versus rate profiles measured. The rate maximum for both compounds was at pH 1.5, with the rate decreasing both above and below the maximum. N-Methylquinolinic acid was 10 times faster than quinolinic acid itself, demonstrating the effect of the nitrogen substituent. The N-ethyl derivative decarboxylated a further 1.5 times faster, showing the effect of increasing the size of the substituent. An Arrhenius plot was also carried out, giving an activation energy for the reaction of 153 kJ mol-1. Attempts to prepare the N-propyl derivative were unsuccessful, as decarboxylation occurred very readily to give N- propylnicotinic acid.
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Miranda, Allan F. "Modulation of quinolinic acid-induced excitotoxicity by endogenous kynurenine pathway intermediates." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/nq22484.pdf.
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Urenjak, Jutta A., and Tihomir P. Obrenovitch. "Accumulation of quinolinic acid with euro-inflammation: does it mean excitotoxicity?" Thesis, Kluwer Academic, Plenum Publishers, New York, 2003. http://hdl.handle.net/10454/2833.
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Morgan, Elaine M. "The role of nitric oxide in N-methyl-D-aspartate receptor-mediated neurotoxicity." Thesis, University of Southampton, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243084.
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Catton, Gemma R. "Mechanistic studies on quinolinate phosphoribosyltransferase /." St Andrews, 2007. http://hdl.handle.net/10023/485.
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Kariyawasam, Sandhya Himani. "An investigation into the biochemical changes in Tourette syndrome and associated conditions with a potential for pharmacological manipulation." Thesis, Aston University, 1999. http://publications.aston.ac.uk/10977/.
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Kynurenine (KYN) is the first stable metabolite of the kynurenine pathway, which accounts for over 95% of tryptophan metabolism. Two previous studies by this research group reported elevated plasma KYN in Tourette syndrome (TS) patients when compared with age and sex matched controls and another study showed that KYN potentiated 5-HT2A-mediated head-shakes (HS) in rodents. These movements have been suggested to model tics in TS. This raised the questions how KYN acts in eliciting this response and whether it is an action of its own or of a further metabolite along the kynurenine pathway. In the liver, where most of the kynurenine pathway metabolism takes place under physiological conditions, the first and the rate limiting enzyme is tryptophan-dioxygenase (TDO) which can be induced by cortisol. In extrahepatic tissues the same step of the pathway is catalyzed by indoleamine-dioxygenase (IDO), which is induced by cytokines, predominantly interferon-y (INF-y). Plasma neopterin, which shows parallel increase with KYN following immune stimulation, was also found elevated in one of these studies positively correlating with KYN. In the present work animal studies suggested that KYN potentiates and quinolinic acid (QUINA) dose dependently inhibits the 5-HT2A-mediated HS response in mice. The potentiating effect seen with KYN was suggested to be an effect of KYN itself. Radioligand binding and phosphoinositide (PI) hydrolysis studies were done to explore the mechanisms by which kynurenine pathway metabolites could alter a 5-HT2A-receptor mediated response. None of the kynurenine pathway metabolites tested showed direct binding to 5-HT2A-receptors. PI hydrolysis studies with KYN and QUINA showed that KYN did not have any effect while QUINA inhibited 5-HT2A-mediated PI hydrolysis. Plasma cortisol determination in TS patients with elevated plasma KYN did not show elevated plasma cortisol levels, suggesting that the increase of plasma KYN in these TS patients is unlikely to be due to an increased TDO activity induced by increased cortisol. Attention deficit hyperactivity disorder (ADHD) is commonly associated with TS. Salivary cortisol detected in a group of children primarily affected with ADHD showed significantly lower salivary cortisol levels when compared with age and sex matched controls. Plasma tryptophan, KYN, neopterin, INF-y and KYN/tryptophan ratio and night-time urinary 6-sulphatoxymelatonin (aMT6s) excretion measured in a group of TS patients did not show any difference in their levels when compared with age and sex matched controls, but TS patients failed to show the expected positive correlation seen between plasma INF-y, neopterin and KYN and the negative correlation seen between plasma KYN and night-time urinary aMT6s excretion seen in healthy controls. The relevance of the kynurenine pathway, melatonin secretion and cortisol to Tourette Syndrome and associated conditions and the mechanism by which KYN and QUINA alter the 5-HT2A-receptor mediated HS response are discussed.
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Heron, Paula Michelle. "An investigation of the neuroprotective effects of estrogen in a model of quinolinic acid-induced neurodegeneration." Thesis, Rhodes University, 2002. http://hdl.handle.net/10962/d1003237.
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The hippocampus, located in the medial temporal lobe, is an important region of the brain responsible for the formation of memory. Thus, any agent that induces stress in this area has detrimental effects and could lead to various types of dementia. Such agents include the neurotoxin, Quinolinic acid. Quinolinic acid (QUIN) is a neurotoxic metabolite of the tryptophan-kynurenine pathway and is an endogenous glutamate agonist that selectively injures and kills vulnerable neurons via the activation of the NMDA class of excitatory amino acid receptors. Estrogen is a female hormone that is responsible for reproduction. However, in the last decade estrogen has been shown to exhibit a wide range of actions on the brain, including neuroprotection. Estrogen has been shown to exhibit intrinsic antioxidant activity and protects cultured neurons against oxidative cell death. This is achieved by estrogen’s ability to scavenge free radicals, which is dependent on the presence of the hydroxyl group at the C3 position on the A ring of the steroid molecule. Numerous studies have shown that estrogen protects neurons against various toxic substances and may play a role in delaying the onset of neurodegenerative diseases, such as Alzheimer’s disease. Neuronal damage due to oxidative stress has been implicated in several neurodegenerative disorders. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. The study aims to elucidate and further characterise the mechanism behind estrogen’s neuroprotection, using QUIN as a model of neurotoxicity. Initial studies confirm estrogen’s ability to scavenge potent free radicals. In addition, the results show that estrogen forms an interaction with iron (II) and also acts at the NMDA receptor as an agonist. Both mechanisms reduce the ability of QUIN to cause damage to neurons, since QUIN-induced toxicity is dependent on the activation of the NMDA receptor and the formation of a complex with iron (II) to induce lipid peroxidation. Heat shock proteins, especially Hsp 70 play a role in cytoprotection by capturing denatured proteins and facilitating the refolding of these proteins once the stress has been relieved. Estrogen has been shown to increase the level of expression of Hsp70, both inducible and cognate forms of the protein. This suggests that estrogen helps to protect against cellular protein damage induced by any form of stress the cell may encounter. The discovery of neuroprotective agents, such as estrogen, is becoming important as accumulating evidence indicates a protective role in vivo. Thus further research may favour the use of these agents in the treatment of several neurodegenerative disorders. Considering how devastating diseases, such as Alzheimer’s disease, are to a patient and the patient’s families, the discovery of new protective agents are a matter of urgency.
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Thian, Stefanie. "The quinolinic acid lesion of the neostriatum examined in the context of neuronal transplantation." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624769.
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Ting, Ka Ka Clinical School St Vincent's Hospital Faculty of Medicine UNSW. "Quinolinic acid and its effect on the astrocyte with relevance to the pathogenesis of Alzheimer??s disease." Publisher:University of New South Wales. Clinical School - St Vincent's Hospital, 2008. http://handle.unsw.edu.au/1959.4/41288.
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There is evidence that the excitotoxin quinolinic acid (QUIN) synthesized through the kynurenine pathway (KP) by activated microglia may play a role in the pathogenesis of several major neuroinflammatory diseases and more particularly in Alzheimer??s disease (AD). The hypothesis of this project is QUIN affects the function and morphology of astrocytes. In this study I used human foetal astrocytes stimulated with AD associated cytokines including IFN-gamma, TNF-alpha, TGF-alpha and different concentrations of QUIN ranging from low physiological to high excitotoxic concentrations. I found that QUIN induces IL-1beta expression in human astrocytes and subsequently, contribute to the inflammatory cascade that is present in AD pathology. Glial fibrillary acid protein (GFAP) and vimentin protein expression were complementary in expression to each other after 24 hr stimulation with different QUIN doses. However, there were marked increases in GFAP levels and reduction in vimentin levels compared to controls with QUIN treatment indicating that QUIN can trigger astrogliosis in human astrocytes. Glutamine synthetase (GS) activity was used as a functional metabolic test for astrocytes and I found a dose-dependent inhibition of GS activity by QUIN. This inhibition was inversely correlated with iNOS expression whereby reduced GS activity is accompanied with an increase expression of iNOS in human astrocytes. These results suggest that reduction in GS activity can lead to accumulation of extracellular glutamate then leading to exacerbated excitotoxicity via NMDA receptor over-activation and ultimately neuronal death. PCR array results showed that at least four different pathways were activated with pathological concentration of QUIN including p38 MAPK that is associated with pro-inflammatory cytokine production, ERK/MAPK growth and differentiation that can modulate structural proteins, mitochondrial-induced apoptotic cascade and cell cycle control pathway. QUIN-induced astrogliosis and excitotoxicity could lead to glial scar formation and prevention of axonal growth thus exacerbation of neurodegeneration via synaptosomal NMDA receptor over-activation. All together, this study showed that, in the context of AD, QUIN is an important factor for astroglial activation, dysregulation and death, which can be mediated by the previously mentioned pathways.
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Chen, Yiquan Medical Sciences Faculty of Medicine UNSW. "The involvement of the Kynurenine pathway in amyotrophic lateral sclerosis." Publisher:University of New South Wales. Medical Sciences, 2009. http://handle.unsw.edu.au/1959.4/43774.
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Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease of unclear aetiology, although the general consensus is of a multifactorial disease. The kynurenine pathway (KP), activated during neuroinflammation, is emerging as a possible contributory factor in ALS. The KP is the major route for tryptophan (TRP) catabolism. The intermediates generated can be either neurotoxic, such as quinolinic acid (QUIN), or neuroprotective, such as picolinic acid (PIC), an important endogenous metal chelator. The first and inducible enzyme is indoleamine 2,3-dioxygenase (IDO). As the extent of the involvement of the KP in ALS is unknown, the main aim of this thesis was to attempt to answer that question. The techniques used in this work include HPLC, GC/MS, RT-PCR, immunohistochemistry and immunocyctochemsitry. The main findings of this project are: (1) the complete KP is present in the mouse motor neuron cell line, NSC-34; (2) QUIN toxicity on NSC-34 cells may be ameliorated through the administration of NMDA antagonists, neuroprotective kynurenines, kynurenine inhibitor and QUIN monoclonal antibody; (3) in ALS patients, QUIN CSF and serum levels are significantly elevated, while PIC serum levels are significantly reduced; (4) ALS brain and spinal cord tissue show extensive microglia activation and positive immunoreactivity IDO and QUIN in spinal motor neurons and Betz cells in the motor cortex; and (5) kynurenine pathway inhibitor and analogue, R061-8048 and tranilast, are able to prolong the survival in the G93A SOD1 ALS transgenic mouse model. In conclusion, this study provide the first strong evidence for the involvement of the KP in ALS, and these data point to an inflammation-driven excitotoxic-chelation defective mechanism in ALS, which is amenable to KP analogue and inhibitor in ALS transgenic mice.
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Lee, Christopher James. "Neuroprotective effects of overexpression of the inhibitor of apoptosis proteins in the quinolinic acid model of excitotoxic injury." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0020/MQ48164.pdf.
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Yan, Edwin B., Tony Frugier, Chai K. Lim, Benjamin Heng, Gayathri Sundaram, May Tan, Jeffrey V. Rosenfeld, David W. Walker, Gilles J. Guillemin, and Maria C. Morganti-Kossmann. "Activation of the kynurenine pathway and increased production of the excitotoxin quinolinic acid following traumatic brain injury in humans." BioMed Central, 2015. http://hdl.handle.net/10150/610324.
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ABSTRACT: During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims. Acute QUIN levels were further correlated with outcome scores to explore its prognostic value in TBI recovery. METHODS: Twenty-eight patients with severe TBI (GCS ≤ 8, three patients had initial GCS = 9-10, but rapidly deteriorated to ≤8) were recruited. CSF was collected from admission to day 5 post-injury. TRP, kynurenine (KYN), kynurenic acid (KYNA), QUIN, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA) were measured in CSF. The Glasgow Outcome Scale Extended (GOSE) score was assessed at 6 months post-TBI. Post-mortem brains were obtained from the Australian Neurotrauma Tissue and Fluid Bank and used in qPCR for quantitating expression of KP enzymes (indoleamine 2,3-dioxygenase-1 (IDO1), kynurenase (KYNase), kynurenine amino transferase-II (KAT-II), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyl transferase (QPRTase) and IDO1 immunohistochemistry. RESULTS: In CSF, KYN, KYNA and QUIN were elevated whereas TRP, AA and 3HAA remained unchanged. The ratios of QUIN:KYN, QUIN:KYNA, KYNA:KYN and 3HAA:AA revealed that QUIN levels were significantly higher than KYN and KYNA, supporting increased neurotoxicity. Amplified IDO1 and KYNase mRNA expression was demonstrated on post-mortem brains, and enhanced IDO1 protein coincided with overt tissue damage. QUIN levels in CSF were significantly higher in patients with unfavourable outcome and inversely correlated with GOSE scores. CONCLUSION: TBI induced a striking activation of the KP pathway with sustained increase of QUIN. The exceeding production of QUIN together with increased IDO1 activation and mRNA expression in brain-injured areas suggests that TBI selectively induces a robust stimulation of the neurotoxic branch of the KP pathway. QUIN's detrimental roles are supported by its association to adverse outcome potentially becoming an early prognostic factor post-TBI.
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Catton, Gemma Rachel. "Mechanistic studies on quinolinate phosphoribosyltransferase." Thesis, University of St Andrews, 2008. http://hdl.handle.net/10023/485.
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Quinolinate phosphoribosyltransferase (QPRTase, EC 2.4.2.19) is an intriguing enzyme which appears to catalyse two distinct chemical reactions; transfer of a phosphoribosyl moiety from 5-phosphoribosyl-1-pyrophosphate to the nitrogen of quinolinic acid and decarboxylation at the 2-position to give nicotinic acid mononucleotide. The chemical mechanism of QPRTase is not fully understood. In particular, enzymatic involvement in the decarboxylation step is yet to be conclusively proven. QPRTase is neurologically important as it degrades the potent neurotoxin, quinolinic acid, implicated in diseases such as Huntington’s disease and AIDS related dementia. Due to its neurological importance and unusual chemistry the mechanism of QPRTase is important. Described here is a mechanistic study on human brain QPRTase. Human brain QPRTase was successfully expressed in E. coli BL21 (DE3) from the pEHISTEV-QPRTase construct and the protein was efficiently purified by nickel affinity chromatography. The crystal structure was solved using multiwavelength methods to a resolution of 1.9 Å. Human brain QPRTase was found to adopt an energetically stable hexameric arrangement. The enzyme was also found to exist as a hexamer during gel filtration under physiological conditions. Kinetic studies allowed the measurement of the kinetic parameters for quinolinic acid. The data gave a Km of 13.4 ± 1.0 μM and a Vmax of 0.92 ± 0.01 μM min-1. There was no evidence for cooperative binding of quinolinic acid to the six subunits of the QPRTase hexamer. The enzyme showed maximum activity at approximately pH 6. The active site of human brain QPRTase is a deep pocket with a highly positive electrostatic surface composed of three arginine residues, two lysine residues and one histidine residue. Mutation of these residues resulted in either complete loss or significant reduction in enzymatic activity showing they are important for binding and/or catalysis. A possible mechanism involving QPRTase in the decarboxylation of quinolinic acid mononucleotide was proposed. A series of quinolinic acid analogues were synthesised and tested as inhibitors of QPRTase. The inhibition studies highlighted some key interactions in the active site.
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Tronel, Claire. "Evaluation des effets de molécules à visée neuroprotectrice dans un modèle in vivo de neuroinflammation chez le rat : étude mécanistique et caractérisation du modèle au cours du temps." Thesis, Tours, 2013. http://www.theses.fr/2013TOUR3806/document.
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La mise au point de médicaments ciblant la neuroinflammation, une composante importante de la physiopathologie des maladies neurodégénératives, fait l’objet de nombreuses recherches. Dans ce travail de thèse, nous avons étudié les effets de deux molécules potentiellement anti-inflammatoires et neuroprotectrices : l’hémine, un inducteur de l’hème oxygénase 1(HO-1) et ; le C16, un inhibiteur de la protéine kinase activée par l’ARN (PKR) dans un modèle de neuroinflammation in vivo par injection intrastriatale d’acide quinolinique (AQ) chez le rat. Nos résultats ont montré que l’induction de la HO-1 produit des effets délétères tandis que l’inhibition de la PKR induit des effets neuroprotecteurs et antiapoptotiques. Ce travail a par ailleurs permis de décrire l’évolution cinétique de la neuroinflammation sur 90 jours dans le modèle AQ, la capacité du tissu cérébral à se régénérer après la lésion et l’intérêt de ce modèle dans l’étude des effets d’agents neuroprotecteurs administrés au long coursNeuroinflammation is a key part of the physiopathology of neurodegenerative diseases and is an interesting target in their treatment. In this PhD work, we studied the effects of two potentially anti-inflammatory and neuroprotective molecules, hemin and C16, in an in vivo rat model of neuroinflammation by intrastriatal injection of quinolinic acid (QA). We showed that heme oxygenase 1 (HO-1) induction by hemin has deleterious effects whereas inhibition of the protein kinase RNA activated (PKR) by C16 treatment induced neuroprotective and anti-inflammatory effects. Concurrently, we evaluated longitudinal evolution of neuroinflammation in our model. Results showed the kinetic of the inflammatory phenomena; the ability of cerebral tissue to recover integrity and the capability of this model to evaluate potential neuroprotective and anti-inflammatory drugs in a long-time study
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Ignarro, Raffaela Silvestre 1987. "Efeito da inibição da enzima JAK2 sobre a morte neuronal, astrogliose e neurogênese no estriado de camundongos adultos após injeção unilateral de ácido quinolínico." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314752.
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Orientadores: Fabio Rogério, Carlos Amilcar ParadaDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: A injeção de ácido quinolínico (AQ), um agonista glutamatérgico do receptor N-metil-D-aspartato, no estriado de roedores induz morte seletiva de neurônios espinhosos médios, gliose reativa e neurogênese na zona subventricular, acompanhada da migração dos neurônios recém-gerados para o estriado lesado. Tais achados são também descritos na doença de Huntington (DH). Há indícios de que a via de sinalização JAK/STAT esteja envolvida no mecanismo de ação do AQ, bem como na patogênese da DH. A interação das citocinas da família da IL-6 com seus receptores desencadeia a ativação de enzimas da família das Janus-Quinases (JAKs), que por sua vez permitem o recrutamento e a ativação de fatores de transcrição da família das proteínas transdutoras de sinais e ativadoras da transcrição (STATs). Embora as principais características da DH sejam a presença da coréia e déficits na execução de movimentos voluntários, poucos testes são realizados abordando o comportamento locomotor dos animais no modelo de lesão por AQ. Neste trabalho, estudamos o efeito do AG490, um inibidor da JAK2, na gliose, perda neuronal e neurogênese no estriado de camundongos adultos C57BL/6J após a administração estereotáxica unilateral de AQ (30nmol). Imediatamente após a lesão, os animais receberam uma injeção subcutânea de AG490 (10mg/kg) ou veículo (PBS+DMSO), e injeções diárias por 6 dias adicionais. Além disso, investigamos o possível efeito da lesão por AQ na atividade física voluntária diária (AFVD) em rodas de atividade. A distância percorrida pelos camundongos foi monitorada por 28 dias após a injeção unilateral de QA (30nmol) ou PBS no estriado. Cortes coronais do cérebro (40?m) obtidos em criostato foram utilizados para quantificação de neurônios por estereologia e para a análise de expressão protéica, através de imunoistoquímica e Western Blotting para GFAP e doublecortina, marcadores de gliose e neuroblastos, respectivamente. A área total de células doublecortina-positivas (ACDP) e o número de neurônios (NN) no lado lesado (L) e contralateral à lesão (CL) foram avaliados. O Índice de Neurogênese (IN=ACDP(L)/ACDP(CL)) e o Índice de Sobrevivência Neuronal (ISN=NN(L)/NN(CL)) foram calculados. Após a administração de AQ, o estriado ipsilateral apresentou intensa gliose e células doublecortina positivas com características de células migratórias. O Western Blotting para GFAP mostrou uma redução ipsilateral de 19% nos animais tratados com AG490, em comparação aos animais do grupo tratado apenas com veículo (0.82±0.05; 1.010±0.06, n=9, p<0.05). O ISN foi 25% maior nos camundongos que receberam AG490 em comparação aos animais controles (0.75 ± 0.07; 0.60 ± 0.03; n=8, p<0.05). O IN mostrou uma diminuição de 21% no grupo AG490 em relação ao grupo de animais tratados apenas veículo de diluição (1.08±0.06; 1.37±0.09, n=5, p<0.05). A AFVD média, medida em quilômetros por dia, não se alterou nos animais que receberam injeção intra-estriatal de QA (30nmol) em comparação aos animais do grupo controle (3.97±0.34; 3.90±0.21, n=8, p>0.05). Portanto, nossos resultados suportam um papel para a JAK2 na morte neuronal, gliose, e neurogênese estriatais após lesão com AQ. O tratamento com o inibidor AG490 causou neuroproteção e diminuição da gliose, sugerindo que a reação astrocitária pode prejudicar a sobrevivência neuronal neste modelo experimental
Abstract: Injection of quinolinic acid (QA), a N-methyl-D-aspartate receptor agonist, in murine striatum induces death of medium spiny neurons, gliosis and neurogenesis in the subventricular zone with migration of newly synthesized neurons to damaged striatum. Such findings are also described in Huntington's disease (HD). The Janus-kinase (JAK) pathway would take part in QA mechanism of action and HD pathogenesis as well. The interaction of interleukin-6 family of cytokines with its receptor triggers the activation of enzymes of the family of JAKs, which in turn allow the recruitment and activation of transcription factors, known as signal transducers and activators of transcription (STATs). Although the main features of HD are the presence of chorea and deficits in performing voluntary movements, few tests are realized regarding locomotor behavioral on QA model. We studied the effect of AG490, an inhibitor of JAK isoform 2 (JAK2), on gliosis, neuronal loss and neurogenesis in the striatum of adult C57BL/6J mice after unilateral estereotaxic administration of QA (30 nmol). Immediately after injury, animals received a subcutaneous injection of AG490 (10 mg/kg) or vehicle (PBS + DMSO), and then once daily injections for 6 days. Furthermore, in a parallel experiment, we investigated the possible effect of the lesion by AQ on the voluntary daily physical activity (VDPA) in running wheels. The distance traveled by mice was monitored daily for 28 days after unilateral injection of QA (30 nmol) or PBS into the striatum. Frozen brain sections (40?m) were used for neuronal stereological quantification and immunohistochemical and Western Blotting analyses for GFAP and doublecortin, markers of gliosis and neuroblasts, respectively. The total area of doublecortin-positive cells (ADPC) and the number of neurons (NN) in the lesioned (L) and contralateral (CL) sides were evaluated. Neurogenesis index (NI = ADPC in L/ ADPC in CL) and neuronal survival ratio (NSR = NN in L/ NN in CL) were calculated. After QA administration, ipsilateral striatum showed intense gliosis and doublecortin-positive cells with few processes and ovoid bodies, morphological features corroborating a migratory activity. Western Blotting for GFAP showed an ipsilateral decrease of 19% in AG490- vs vehicle-treated animals (0.82 ± 0.05 vs 1.010 ± 0.06; n=9, p<0.05). NSR was 25% higher in mice given AG490 vs controls given vehicle (0.75 ± 0.07 vs 0.60 ± 0.03; n=8, p<0.05). NI showed a decrease of 21% in AG490- vs vehicle-treated mice (1.08 ± 0.06, 1.37 ± 0.09; n=5, p<0.05). The average VDPA, measured in kilometers per day for 28 days, has not changed in animals that received intrastriatal injection of QA (30nmol) compared to animals that received PBS (3.97 ± 0.34, 3.90 ± 0.21, n = 8, p> 0.05). In conclusion, our results support a role for JAK2 in striatal neuronal death, gliosis and neurogenesis determined by QA. AG490 caused neuroprotection and reduced gliosis suggesting that astrocytic reaction may impair neuronal survival in the present experimental model
Mestrado
Fisiologia
Mestre em Biologia Funcional e Molecular
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Müller, Adrienne Carmel. "An investigation into the neuroprotective properties of acyclovir." Thesis, Rhodes University, 2006. http://hdl.handle.net/10962/d1003254.
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Accumulating evidence suggests that quinolinic acid has a role to play in disorders involving impairment of learning and memory. In the present study, the effect of the guanosine analogue antiherpetic, acyclovir, on quinolinic acid-induced spatial memory deficits was investigated, as well as some of the mechanisms which underlie this effect. Behavioural studies using a Morris water maze show that post-treatment of rats with acyclovir significantly improves spatial memory deficits induced by intrahippocampal injections of quinolinic acid. Histological analysis of the hippocampi show that the effect of acyclovir is related to its ability to alleviate quinolinic acid-induced necrotic cell death, through interference with some of the mechanisms of neurodegeneration. However, acyclovir is unable to alter a quinolinic acid-induced increase in glutamate release in the rat hippocampus, even though it alleviates quinolinic acid induced oxidative stress by scavenging the superoxide anion in vitro and in vivo in whole rat brain and hippocampus respectively. Due to the inverse relationship which exists between superoxide anion and glutathione levels, acyclovir also curtails the quinolinic acid-induced decrease in hippocampal glutathione levels. Acyclovir suppresses quinolinic acid-induced lipid peroxidation in vitro and in vivo, in whole rat brain and hippocampus respectively, through its alleviation of oxidative stress and possibly through the binding of iron (II) and / or iron (III), preventing the participation and redox recycling of iron (II) in the Fenton reaction, which quinolinic acid is thought to enhance by weak binding of ferrous ions. This argument is further strengthened by the ability of the drug to suppress iron (II)-induced lipid peroxidation in vitro directly. Inorganic studies including ultraviolet and visible spectroscopy, electrochemistry and the ferrozine assay show that acyclovir binds to iron (II) and iron (III) and that quinolinic acid forms an easily oxidisable association with iron (II). Acyclovir inhibits the endogenous biosynthesis of quinolinic acid by inhibiting the activity of liver tryptophan-2,3-dioxygenase, intestinal indoleamine-2,3-dioxygenase and rat liver 3-hydroxyanthranillic acid oxygenase in vitro and in vivo, possibly through competitive inhibition of haeme, scavenging of superoxide anion and binding of iron (II) respectively. An inverse relationship exists between tryptophan-2,3-dioxygenase activity and brain serotonin levels. Acyclovir administration in rats induces a rise in forebrain serotonin and 5-hydroxyindole acetic acid and reduces the turnover of forebrain serotonin to 5-hydroxyindole acetic acid. Furthermore, it shows that acyclovir does not alter forebrain norepinephrine levels. The results of the pineal indole metabolism study show that acyclovir increases 5-hydroxytryptophol, N-acetylserotonin and the neurohormone melatonin, but decreases 5-hydroxyindole acetic acid. The results of this study show that acyclovir has some neuroprotective properties which may make it useful in the alleviation of the anomalous neurobiology in neurodegenerative disorders.
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Alves, Catiane Bisognin. "AVALIAÇÃO DO EFEITO PROTETOR DE SINVASTATINA NA FORMA LIVRE E NANOENCAPSULADA EM CONVULSÕES INDUZIDAS POR ÁCIDO QUINOLÍNICO EM RATOS." Centro Universitário Franciscano, 2015. http://www.tede.universidadefranciscana.edu.br:8080/handle/UFN-BDTD/534.
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Statins are cholesterol-lowering agents due to the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Recent studies have shown pleiotropic effects for statins, such as anti-epileptic effect in rodents. Quinolinic acid (QA) is an endogenous glutamate analog that may be involved in the etiology of epilepsy and is related to disturbances on glutamate release and uptake. The nanoparticles have become an important focus of therapeutic research on brain because they are an especially effective form of drug delivery. Therefore, considering the therapeutic potentials of nanocapsules, in the present study the protective effect of simvastatin in nanoencapsulated (SN) or free form (SF) is evaluated in QA-induced seizures in rats. Male adult Wistar rats (250-300 g) were pretreated orally during 21 days with control formulation (drug-unloaded NCs, CF), SN or SF at 1 mg/kg/day. After pretreatment, rats were infused with 4 μL of 239.2 nmol QA at right lateral brain ventricle and observed for behavioral changes during 10 min. Twenty four hours after seizures, rats were evaluated for locomotion, balance, gait and memory. CF had pH 6.75 ± 0.19, particle diameter of 213.91 ± 19.96 nm, polydispersity index of 0.167 ± 0.05 and zeta-potential values were -16,28 ± 7,90. SN had pH 6.68 ± 0.25, particle diameter of 215.25 ± 30.58 nm, polydispersity index of 0.151 ± 0.07 and zeta potential values were -16.13 ± 8.19 mV. The body weight of rats did not change during the treatment period. The pretreatment com SN or SF did not change the seizures or number of death following QA infusion. In the group CF + QA the number of rats with fall in the Beam Balance task was higher than Naive group, effect prevented by SN and SF. The groups CF + Sal and SF + QA showed a reduced number of rearings in the Open Field test, besides the increased stride length in the Footprint test. Rats infused with SF + QA had impairment of memory in the Avoidance Inhibitory Memory task and SN or SF did not change this damage effect. Altogether, the present results exhibit that simvastatin in nanoencapsulated or free form at the dose 1 mg/kg/day administered for 21 days was not able to protect rats against the behavioral damages induced by QA in rats (with exception on balance parameter). Another strategies need to investigate to better evaluate the effect of nanocapsules against cerebral damage induced by QA.
As estatinas são agentes de redução de colesterol devido à inibição da 3-hidroxi-3-metilglutaril coenzima A (HMG-CoA) redutase. Estudos recentes demonstram que as estatinas possuem efeitos pleiotrópicos, como efeito anti-epilético em roedores. Contudo, pequenas quantidades de sinvastatina atravessam a barreira hematoencefálica, sendo necessárias elevadas quantidades do fármaco, gerando os efeitos colaterais indesejáveis, o que poderia ser um problema na sua utilização para o tratamento de doenças que afetam o sistema nervoso central. O ácido quinolínico (AQ) é um análogo endógeno do neurotransmissor glutamato, que está envolvido na etiologia da epilepsia devido a perturbações na liberação e captação de glutamato. As nanopartículas tornaram-se um importante foco de pesquisas terapêuticas para o cérebro, pois é uma forma especialmente eficaz de entrega de fármacos em locais onde há baixa permeabilidade. Portanto, considerando as potencialidades terapêuticas de nanocápsulas, no presente estudo é avaliado o efeito protetor da sinvastatina na forma nanoencapsulada (NS) e livre (SL) no modelo de convulsão induzida por AQ em ratos. Os ratos Wistar adultos machos (250-300 g) foram pré-tratados via oral por 21 dias com nanocápsulas brancas (sem fármaco, NB), NS ou SL, na dose de 1 mg/kg/dia. Após o pré-tratamento, os ratos receberam uma infusão de 4 μL de 239,2 nmol de AQ no ventrículo cerebral lateral direito. Os animais foram observados por 10 minutos para a ocorrência de alterações comportamentais. Vinte e quatro horas após as convulsões, os ratos foram testados quanto locomoção, equilíbrio, marcha e memória. As NB apresentaram um pH 6,75 ± 0,19, diâmetro de partícula de 213,91 ± 19,96 nm, índice de polidispersão de 0,167 ± 0,05 e potencial zeta -16,28 ± 7,90 mV. As NS apresentaram um pH de 6,68 ± 0,25, diâmetro de partícula de 215,25 ± 30,58 nm, índice de polidispersão de 0,151 ± 0,07 e potencial zeta -6,13 ± 8,19mV. Não houve redução do peso corporal dos animais ao longo do tratamento. O pré-tratamento com NS ou SL não causou alteração nas convulsões ou número de mortes ocasionadas pela infusão de AQ. O grupo NB + AQ possui maior número de animais com quedas na tarefa de Equilíbrio na Passarela Elevada, efeito prevenido pelo pré-tratamento com NS ou SL. Os grupos NS + Sal e SL + AQ tiveram uma redução no número de explorações verticais no Campo Aberto, além de apresentarem um aumento no padrão do comprimento da passada no teste de Impressão das Patas. Os ratos tratados com NB + AQ tiveram prejuízo de memória avaliado na tarefa da Esquiva Inibitória, e o pré-tratamento com NS ou SL não preveniu esse efeito. No geral, os resultados demonstram que a sinvastatina nanoencapsulada ou na forma livre na dose de 1 mg/kg/dia administrada por 21 dias não induziu efeitos protetores contra os danos observados após a infusão de AQ (com exceção do equilíbrio). Outras estratégias devem ser exploradas para avaliar o efeito dessas formulações no dano cerebral induzido pelo AQ.
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Zheve, Georgina Teurai. "Neuroprotective mechanisms of nevirapine and efavirenz in a model of neurodegeneration." Thesis, Rhodes University, 2008. http://hdl.handle.net/10962/d1003285.
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AIDS Dementia Complex (ADC) is a neurodegenerative disorder implicated in HIV-1 infection that is associated with elevated levels of the neurotoxin, quinolinic acid (QA) which causes a cascade of events to occur, leading to the production of reactive oxygen species (ROS), these being ultimately responsible for oxidative neurotoxicity. In clinical studies, Non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz (EFV) and nevirapine (NVP) have been shown to potentially delay the progressive degeneration of neurons, thus reducing the frequency and neurological deficits associated with ADC. Despite these neuroprotective implications, there is still no biochemical data to demonstrate the mechanisms through which these agents offer neuroprotection. The present study aims to elucidate and further characterize the possible antioxidant and neuroprotective mechanisms of NVP and EFV in vitro and in vivo, using QA-induced neurotoxicity as a model. Research has demonstrated that antioxidants and metal chelators have the ability to offer neuroprotection against free radical induced injury and may be beneficial in the prevention or treatment of neurodegeneration. Hence the antioxidant and metal binding properties of these agents were investigated respectively. Inorganic studies, including the 1, 1-diphenyl-2 picrylhydrazyl (DPPH) assay, show that these agents readily scavenge free radicals in vitro, thus postulating the antioxidant property of these agents. The enhancement of superoxide radical generation and iron mediated Fenton reaction by QA is related to lipid peroxidation in biological systems, the extent of which was assayed using the nitroblue tetrazolium and thiobarbituric acid method respectively. Both agents significantly curtail QA-induced lipid peroxidation and potentially scavenge superoxide anions generated by cyanide in vitro. Furthermore, in vivo results demonstrate the ability of NVP and EFV to protect hippocampal neurons against lipid peroxidation induced by QA and superoxide radicals generated as a consequence thereof. The alleviation of QA-induced oxidative stress in vitro possibly occurs through the binding of iron (II) and / or iron (III), and this argument is further strengthened by the ability of EFV and not NVP to reduce iron (II)-induced lipid peroxidation in vitro directly. In addition the ferrozine and electrochemistry assay were used to measure the extent of iron (II) Fe[superscript 2+] and iron (III) Fe[superscript 3+] chelation activity. Both assays demonstrate that these agents bind iron (II) and iron (III), and prevent redox recycling of iron and subsequent complexation of Fe[superscript 2+] with QA which enhances neuronal damage. Both NNRTIs inhibit the endogenous biosynthesis of QA by inhibiting liver tryptophan 2, 3-dioxygenase activity in vivo and subsequently increasing hippocampal serotonin levels. Furthermore, these agents reduce the turnover of hippocampal serotonin to 5-hydroxyindole acetic acid. NVP and not EFV increase 5-hydroxyindole acetic acid and norepinephrine levels in the hippocampus. The results of the pineal indole metabolism study show that NVP increases the synthesis of melatonin, but decreases N-acetylserotonin, 5-hydroxyindole acetic acid and 5-hydroxytryptophol levels. Furthermore, it shows that EFV decreases 5-hydroxyindole acetic acid and melatonin synthesis. Behavioural studies using a Morris water maze show that the post-treatment of rats with NVP and EFV significantly improves QA-induced spatial memory deficits in the hippocampus. This study therefore provides novel information regarding the neuroprotective mechanisms of NVP and EFV. These findings strengthen the argument that these NNRTIs not only have antiviral effects but possess potential neuroprotective properties, which may contribute to the effectiveness of these drugs in the treatment of ADC.
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Bipath, Priyesh. "Tryptophan and the kynurenine pathway in chronic renal failure patients on dialysis." Diss., Pretoria : [s.n.], 2008. http://upetd.up.ac.za/thesis/available/etd-10212008-135418.
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Velloso, Nádia Aléssio. "Efeitos da espermina sobre parâmetros motores, cognitivos e neuromorfológicos em um modelo experimental da doença de huntington." Universidade Federal de Santa Maria, 2008. http://repositorio.ufsm.br/handle/1/4402.
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Spermine (SPM) is an aliphatic amine which contains four nucleophilic centers and is found in all eukaryotic cells, including nervous cells. It belongs to the group of
polyamines, which are molecules associated with both neuroprotection and neurotoxicity. The aim of this study was to investigate the effects of spermine on some parameters of toxicity induced by striatal administration of quinolinic acid (QA), an experimental model of Huntington s disease in adult and male Wistar rats.
The intrastriatal administration of QA (180 nmol/site) induced contralateral rotations and increase the number of contralateral body swings. The previous striatal administration of SPM caused mixed effects: at the dose of 0.1 nmol/site increased the number of contralateral rotations; but at 10 nmol/site it reduced both the
number of rotations and the contralateral body swings induced by QA. The mechanism by which SPM decreases these motor alterations is probably through its interaction with the NMDA receptor, since the co-administration with arcaine
(antagonist of polyamine binding sites on this receptor) reversed its protective effect. The increase of protein carbonyl content induced by QA (180 nmol/site) in
striatum of rats was prevented by the administration of 10 nmol/site of SPM. Besides, the bilateral striatal injection of QA (180 nmol/site) impaired the
performance in the recognition memory task. The post-training striatal administration of SPM (0.1 and 1 nmol/site) reversed the QA-induced cognitive deficit. It was also evaluated whether spermine prevented QA-induced
neuromorphological alterations. QA caused striatal neuronal degeneration and reactive astrogliosis. SPM, at the dose that improved the cognitive performance
(0.1 nmol/site), had no effect on striatal neuronal degeneration but reversed the intense astrocytic reaction induced by QA. These results suggest that SPM has
neuroprotective properties, presenting a dose dependent pattern of polyamine, in this experimental model of Huntington disease.A espermina (SPM) é uma amina alifática, contendo quatro centros nucleofílicos e é encontrada em todas as células eucarióticas, incluindo células nervosas. Ela pertence ao grupo das poliaminas, moléculas responsáveis tanto por efeitos neuroprotetores quanto neurotóxicos. O objetivo do presente trabalho foi investigar os efeitos da SPM sobre alguns parâmetros de toxicidade induzidos pela administração estriatal de ácido quinolínico (AQ), um modelo experimental da doença de Huntington em ratos Wistar machos adultos. A administração intraestriatal unilateral de AQ (180 nmol/sítio) induziu o aparecimento de rotações contralaterais e aumento do percentual de balanços corporais contralaterais. A prévia administração estriatal de SPM mostrou efeitos diversos: na dose de 0,1 nmol/sítio aumentou o número de rotações; porém na dose de 10 nmol/sítio ela diminuiu tanto o número de rotações quanto o percentual de balanços corporais contralaterais induzidos pelo AQ. O mecanismo pelo qual a SPM diminui estas alterações motoras é, provavelmente, devido à sua interação com o receptor NMDA, uma vez que sua co-administração com a arcaína (antagonista do sítio das poliaminas neste receptor) reverteu o efeito protetor da mesma. A administração de 10 nmol/sítio de SPM preveniu o aumento do conteúdo de proteína carbonil induzida pela injeção de AQ (180 nmol/sítio) no estriado de ratos. Além disso, foi observado prejuízo cognitivo na tarefa de reconhecimento de objetos após a injeção estriatal bilateral de AQ (180 nmol/sítio). A administração estriatal póstreino de SPM (0,1 e 1 nmol/sítio) reverteu este déficit cognitivo induzido pelo AQ. Para avaliação das alterações neuromorfológicas neste modelo foram observadas degeneração neuronal e reação astrocitária. O AQ aumentou significativamente a degeneração de neurônios estriatais e a astrogliose reativa. A SPM, na menor dose que melhorou o desempenho cognitivo (0,1 nmol/sítio), não teve efeito sobre a degeneração neuronal estriatal; no entanto, ela foi capaz de reverter a intensa reação astrocitária induzida pela injeção de AQ. Estes resultados sugerem que a SPM tem propriedades neuroprotetoras, que apresentam um padrão dependente da dose da poliamina, neste modelo experimental da doença de Huntington.
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Puntel, Robson Luiz. "Efeito de intermediários do ciclo de krebs sobre alterações oxidativas induzidas por diferentes agentes oxidantes." Universidade Federal de Santa Maria, 2006. http://repositorio.ufsm.br/handle/1/11136.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorRecent data from the literature have suggested that some Krebs cycle intermediates could act as potent antioxidant agents, both in vitro and in vivo, against a variety of pro-oxidant agents. However, the mechanism(s) involved in the antioxidant effect of Krebs cycle intermediates are not fully understood. Additionally, there are scarce data in the literature taking into account the in vitro effect of Krebs cycle intermediates during oxidative stress conditions. Thus, the aim of this study was to determine the effect of some Krebs cycle intermediates on lipid peroxidation induced in vitro by different pro-oxidant agents, and the mechanism(s) by which they act. Firstly, we investigated the effect and the mechanism(s) by which malonate and quinolinic acid modulate the thiobarbituric acid- reactive species (TBARS) production in vitro, using rat brain S1 preparations (Article 1). The present results showed that the malonate-induced TBARS production was not changed by potassium cyanide or MK-801. However, the pro-oxidant effect of quinolinic acid was significantly prevented by MK-801. In addition we found that malonate was able to form complexes with iron ions (Fe2+), but these complexes were not able to interfere with in vitro deoxyribose degradation assays. Based on the results presented, we conclude that malonate pro-oxidant activity in vitro seems to be independent of the NMDA receptors activity. Additionally, we suggest that the malonate effect, in these conditions, is due to its ability to form complexes with iron ions, thus modulating an adequate ratio Fe2+/Fe3+ that could cause an increase in free radicals generation. In contrast, the quinolinic acid effect seems to be dependent of the NMDA receptors activation. However, we can not rule out the involvement of iron ions in quinolinic acid toxicity under our assay conditions. An other objective of this study was to investigate the effect of some Krebs cycle intermediates on quinolinic acid- or iron (Fe2+)-induced TBARS production in the rat brain S1 preparations, and the mechanism(s) by which they act (Article 2). The results showed that oxaloacetate, citrate, succinate, and malate were able to significantly prevent both basal and quinolinic acid- or iron-induced TBARS production. However, α-ketoglutarate induced per se a significant increase in basal TBARS production. The addition of potassium cyanide or the heat-treatment of S1 at 100ºC during 10 min completely abolished the antioxidant succinate activity, without change the effect of other Krebs cycle intermediates studied. Except for succinate, all intermediates used in this study were able to form complexes with iron (Fe2+) ions, however only oxaloacetate and α-ketoglutarate significantly prevented deoxyribose degradation induced by hydrogen peroxide. Based on the results presented, we concluded that oxaloacetate, malate, succinate, and citrate could act as antioxidants under basal, and under quinolinic acid- or iron- induced TBARS production, whereas α-ketoglutarate act as a pro-oxidant agent per se. The mechanism(s) by which citrate, malate, and oxaloacetate acts seems to be related to their ability to form complexes with iron (Fe2+) ions, thus modulating the iron redox cycle. In contrast, the succinate antioxidant effect seems to be dependent of the succinate dehydrogenase (SDH) activity.
Dados recentes na literatura têm relatado que alguns intermediários do ciclo de Krebs podem agir como potentes antioxidantes, tanto in vitro, quanto in vivo, em diversos sistemas pró-oxidantes. Porém, o(s) mecanismo(s) através dos qual(is) os intermediários do ciclo de Krebs exercem suas atividades antioxidantes não são completamente entendidas. Considerando a escassez de dados in vitro na literatura a respeito do efeito desses intermediários durante situações de estresse oxidativo, o presente trabalho tem como objetivo determinar o efeito de intermediários do ciclo de Krebs sob a peroxidação lipídica induzida por diferentes agentes pró-oxidantes in vitro, bem como investigar o(s) mecanismo(s) de ação dos mesmos. Primeiramente investigamos o efeito e o(s) mecanismo(s) pelo(s) qual(is) o malonato e o ácido quinolínico modulam a produção de espécies reativas ao ácido tiobarbitúrico (TBARS) em S1 de cérebro de ratos, in vitro (artigo 1). Os resultados obtidos mostraram um aumento na produção de TBARS induzido pelo malonato, o qual não foi modificado pela adição de cianeto de potássio, nem pelo MK-801. Por outro lado, o efeito pró-oxidante do ácido quinolínico foi significativamente prevenido pelo MK-801. Observamos ainda que o malonato foi capaz de formar complexos com íons ferrosos e que esses complexos não foram capazes de interferir nos ensaios da degradação da desoxirribose in vitro. Portanto, com base nos resultados encontrados, concluímos que o efeito pró-oxidante do malonato in vitro parece ser independente da atividade dos receptores NMDA. Os resultados sugerem que o efeito do malonato nessas condições deve-se principalmente a sua capacidade de interagir com íons ferro, modulando uma razão Fe2+/Fe3+ que favorece a geração de radicais livres. Por outro lado, o efeito do ácido quinolínico parece ser devido à ativação dos receptores NMDA. Porém, não podemos excluir a participação dos íons ferro para a toxicidade do mesmo nessas condições. Outro foco deste estudo foi investigar o efeito de alguns intermediários do ciclo de Krebs na produção de TBARS induzida por ácido quinolínico ou ferro em S1 de cérebro de ratos in vitro, bem como investigar o(s) mecanismo(s) de ação dos mesmos (artigo 2). Os resultados mostraram que o oxaloacetato, o citrato, o sucinato e o malato foram capazes de reduzir significativamente a produção de TBARS basal, bem como a induzida por ácido quinolínico ou ferro. Por outro lado, o α-cetoglutarato foi capaz de induzir per se um significativo aumento na produção de TBARS. A adição de cianeto de potássio, bem como o pré-tratamento do S1 por 10 min a 100ºC aboliram completamente o efeito antioxidante do sucinato, sem interferir significativamente no efeito dos demais intermediários estudados. Todos os intermediários estudados, exceto o sucinato, foram capazes de quelar íons ferro, porém somente o oxaloacetato e o α-cetoglutarato foram capazes de prevenir a degradação da desoxirribose induzida por peróxido de hidrogênio. Com base nos resultados obtidos, podemos concluir que o oxaloacetato, o malato o sucinato e o citrato agem como antioxidantes sob condições basais ou em presença do ácido quinolínico ou ferro, enquanto que o α-cetoglutarato age como um agente pró-oxidante per se. O mecanismo pelo qual o citrato, o malato e o oxaloacetato exercem seus efeitos antioxidantes parece ser devido à capacidade desses em interagir com íons ferro modulando o ciclo redox desse. Por outro lado, o efeito do sucinato parece ser devido à atividade da enzima succinato desidrogenase (SDH).
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Tan, Vanessa. "Identification of biomarkers for MND, and understanding the potential role of the cyanotoxin BMAA in neurodegeneration Involvement of Quinolinic Acid in the Neuropathogenesis of amyotrophic lateral sclerosis Detection of the Cyanotoxins L-BMAA Uptake and Accumulation in Primary Neurons and Astrocytes." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS590.
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La Sclérose Latérale Amyotrophique (SLA) est une maladie neurodégénérative dévastatrice dont les causes sont inconnues et pour laquelle il n’existe aucun traitement ni marqueur spécifique. Dans ce contexte, nous avons étudié le rôle de la voie métabolique des kynurénines impliquée dans la production de métabolites neuroactifs qui peuvent être immunomodulateurs, neuroprotecteurs ou à l’inverse neurotoxiques. Dans une étude longitudinale du sérum de 66 patients atteints de SLA, nous avons évalué le profil de 10 métabolites de la voie des kynurénines par chromatographie HPLC et spectrographie GC/MS. Nous avons mis en évidence un profil métabolique, spécifique de la progression de la SLA, qui pourrait être utilisé comme biomarqueur pour suivre l’évolution de la maladie. En collaboration avec la clinique de la SLA de l’Université Macquarie de Sydney, nous avons constitué une banque d’échantillons de patients atteints de SLA et d’autres maladies neurodégénératives (Parkinson, Alzheimer) ce qui permettra de rechercher à plus grande échelle les facteurs responsables de l’étiologie et du décours de la SLA. Dans une seconde partie, nous avons évalué le potentiel neurotoxique de la (BMAA), une cyanotoxine dont la présence dans l’environnement est corrélée avec une incidence accrue de la SLA. A l’aide de modèles cellulaires permettant de modéliser des voies neuro-anatomiques in vitro. Nous avons démontré que la BMAA provoque une déstructuration des réseaux de neurones et mis en évidence la capacité de cette biotoxine, qui s’apparente à un acide aminé, de se propager de cellule à cellule et donc potentiellement de se disperser dans le système nerveux centralMotor Neuron Disease (MND) or Amyotrophic Lateral Sclerosis (ALS) is a devastating neurological disease with no biological diagnostic markers, no effective treatment, and no cure. We investigate the immune related Kynurenine Pathway (KP) for a role in ALS. The production of neuroactive metabolites during the KP indicate that there is an overlap with the mechanisms of ALS, particularly with the neurotoxin quinolinic acid. Subsequently, we investigate the KP metabolome, analysing 10 metabolites using biochemical analyses including High Performance Liquid Chromatography and Gas Chromatography/Mass Spectrometry. Using serum from a longitudinal cohort of 66 ALS patients, we establish a potential for KP metabolomics to be used a biomarker for ALS. To increase specificity and reliability of these results, in collaboration with Macquarie University Neurology, we established a Neurodegenerative Diseases Biobank to collect patient biological samples. These samples would facilitate future investigations into the mechanisms, genetics, biomarkers, and to detect the presence of toxic compounds such as metals, or β-methylamino-L-alanine (BMAA). We describe the establishment of the biobank as a case study for future references. BMAA is known to be neurotoxic, and we investigate its role ALS. We reveal its role in promoting axonal degeneration and neuronal death, and show for the first time, its ability to spread transcellularly
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Dobrachinski, Fernando. "ASSOCIAÇÃO DO DISSELENETO DE DIFENILA E MODULADORES DO SISTEMA GLUTAMATÉRGICO FRENTE AO DANO OXIDATIVO CAUSADO POR ÁCIDO QUINOLÍNICO." Universidade Federal de Santa Maria, 2013. http://repositorio.ufsm.br/handle/1/11214.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorExcessive formation of reactive oxygen species (ROS) and disruption of glutamate uptake have been hypothesized as key mechanisms contributing to quinolinic acid (QA)- induced toxicity. Thus, here we investigate if the use of diphenyl diselenide (PhSe)2, guanosine (GUO) and MK-801, alone or in combination, could protect rat brain slices from QA-induced toxicity. QA (1 mM) increased ROS formation, thiobarbituric acid reactive substances (TBARS) and decreased cell viability after 2 h of exposure. (PhSe)2 (1 μM) protected against this ROS formation in the cortex and the striatum and also prevented decreases in cell viability induced by QA. (PhSe)2 (5 μM) prevented ROS formation in the hippocampus. GUO (10 and 100 μM) blocked the increase in ROS formation caused by QA and MK-801 (20 and 100 μM) abolished the pro-oxidant effect of QA. When the non effective concentrations were used in combination produced a decrease in ROS formation, mainly (PhSe)2 + GUO and (PhSe)2 + GUO + MK-801. These results demonstrate that this combination could be effective to avoid toxic effects caused by high concentrations of QA. Furthermore, the data obtained in the ROS formation and cellular viability assays suggest different pathways in amelioration of QA toxicity present in the neurodegenerative process.
A formação excessiva de espécies reativas de oxigênio (ROS) e alterações na captação de glutamato têm sido associadas como mecanismos chave que contribuem para toxicidade induzida pelo ácido quinolínico (AQ). Assim, nós investigamos se a utilização do disseleneto de difenila (PhSe)2, guanosina (GUO) e MK-801, isoladamente ou em combinação, podem proteger as fatias de regiões cerebrais de ratos da toxicidade induzida por AQ. AQ (1 mM) aumentou a formação de ROS, substâncias reativas ao ácido tiobarbitúrico (TBARS) e diminuiu a viabilidade celular após 2h de exposição. (PhSe)2 (1 μM) protegeu contra esta formação de ROS no córtex e no estriado e além disso preveniu a diminuição da viabilidade celular induzida pelo AQ. (PhSe)2 (5 μM) preveniu a formação de ROS no hipocampo. GUO (10 e 100 μM) bloqueou o aumento na formação de ROS causada pelo AQ e MK-801 (20 e 100 μM) aboliu o efeito pró-oxidante do AQ. Quando as concentrações não-efetivas foram usadas em combinação produziram uma diminuição na formação de ROS, principalmente (PhSe)2 + GUO e (PhSe)2 + GUO + MK-801. Estes resultados demonstram que esta combinação pode ser eficaz para evitar os efeitos tóxicos provocados por concentrações elevadas do AQ. Além disso, os dados obtidos nos ensaios de formação de ROS e viabilidade celular sugerem diferentes vias de atuação na melhora da toxicidade induzida pelo AQ presente no processo neurodegenerativo.
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Puntel, Robson Luiz. "Caracterização da atividade pró-oxidante de diferentes agentes e estudo do potencial antioxidante de intermediários do ciclo de krebs sobre alterações oxidativas induzidas in vitro." Universidade Federal de Santa Maria, 2008. http://repositorio.ufsm.br/handle/1/4400.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorPrevious data from the literature have shown that some Krebs cycle intermediates could act as antioxidant in several models, both in vitro and in vivo. However, the mechanism(s) involved in the antioxidant effect of Krebs cycle intermediates are not fully understood. Additionally, there are scarce data in the literature taking into account the in vitro effect of Krebs cycle intermediates during oxidative stress conditions. Thus, the aim of this study was to determine the effect of some Krebs cycle intermediates on lipid peroxidation induced in vitro by different pro-oxidant agents, and the mechanism(s) by which they act. Furthermore, it was necessary elucidate the mechanisms by which the different pro-oxidants acts under in vitro conditions. The present results showed that the malonate-induced TBARS production was not changed by potassium cyanide or MK-801. However, the pro-oxidant effect of quinolinic acid was significantly prevented by MK-801. In addition we found that both malonate and oxalate were able to form complexes with iron ions (Fe2+). Based on the presented results, we conclude that malonate pro-oxidant activity in vitro seems to be independent of the secondary excitotoxicity via indirect NMDA receptors activation. Additionally, we suggest that both the malonate and oxalate effect, in these experimental conditions, is due to its ability to form complexes with iron ions, thus modulating an adequate ratio Fe2+/Fe3+ that could cause an increase in free radicals generation. In contrast, the quinolinic acid effect seems to be dependent of the NMDA receptors activation. However, we can not rule out the involvement of iron ions in quinolinic acid toxicity under our assay conditions. Another objective of this study was to investigate the effect of some Krebs cycle intermediates against either basal or induced TBARS production, using rat brain S1 preparations and the mechanism(s) by which they act. The results showed that oxaloacetate, citrate, succinate, and malate were able to significantly prevent both basal and quinolinic acid-, iron- or malonate-induced TBARS production. On the other hand, fumarate prevented only malonate-induced TBARS production, without effect under basal conditions. However, α-ketoglutarate induced per se a significant increase in basal TBARS production. The antioxidant activity of fumarate and succinate were completely abolished when S1 was submitted to heat-treatment at 100ºC during 10 min. Likewise, potassium cyanide completely abolished the antioxidant effect of succinate. The effect of other Krebs cycle intermediates studied was unchanged with respect to heat-treatment, or cyanide. Except for succinate and fumarate, all intermediates used in this study were able to form complexes with iron (Fe2+) ions, however only oxaloacetate and α-ketoglutarate significantly prevented deoxyribose degradation induced by hydrogen peroxide. Based on the results presented, we concluded that oxaloacetate, malate, succinate, fumarate and citrate could act as antioxidants under such conditions, whereas α-ketoglutarate acts as a pro-oxidant agent per se. The mechanism(s) by which citrate, malate, and oxaloacetate acts seems to be related to their ability to form complexes with iron (Fe2+) ions, thus modulating the iron redox cycle. In contrast, the succinate and fumarate antioxidant effect seems to be dependent of the some enzymatic system.
Dados prévios da literatura têm mostrado que alguns intermediários do ciclo de Krebs podem agir como antioxidantes em diversos modelos, tanto in vitro, quanto in vivo. Porém, o(s) mecanismo(s) através dos qual(is) esses intermediários exercem suas atividades antioxidantes não são completamente entendidas. Considerando a escassez de dados na literatura a respeito do efeito dos intermediários do ciclo de Krebs durante situações de estresse oxidativo, o presente trabalho teve por objetivo determinar o efeito desses sob a peroxidação lipídica induzida por diferentes agentes pró-oxidantes in vitro, bem como investigar o(s) mecanismo(s) de ação dos mesmos. Além disso, faz-se necessário caracterizar o(s) mecanismos(s) pelo(s) qual(is) os diferentes pró-oxidantes agem nos sistemas in vitro. Os resultados dessa tese mostraram que a atividade pró-oxidante in vitro do malonato não foi modificada pela adição de cianeto de potássio, nem pelo MK-801. Por outro lado, o efeito pró-oxidante do ácido quinolínico foi significativamente prevenido pelo MK-801. Observamos ainda que o malonato, e também o oxalato foram capazes de formar complexos com íons ferrosos. Portanto, com base nos resultados encontrados, concluímos que o efeito pró-oxidante do malonato in vitro parece ser independente da excitotoxicidade secundária, conseqüência da ativação indireta dos receptores NMDA. Os resultados sugerem que o efeito do malonato e do oxalato nessas condições experimentais deve-se principalmente a sua capacidade de interagir com íons ferro, modulando uma razão Fe2+/Fe3+ que favorece a geração de radicais livres. Por outro lado, o efeito do ácido quinolínico parece ser devido à ativação dos receptores NMDA. Porém, não podemos excluir a participação dos íons ferro para a toxicidade do mesmo nessas condições. Outro foco deste estudo foi investigar o efeito de alguns intermediários do ciclo de Krebs na produção de TBARS basal ou induzida por diferentes pró-oxidantes em S1 de cérebro de ratos in vitro, bem como investigar o(s) mecanismo(s) de ação dos mesmos. Os resultados mostraram que o oxaloacetato, o citrato, o sucinato e o malato foram capazes de reduzir significativamente a produção de TBARS basal, bem como a induzida por ácido quinolínico, ferro ou malonato. O fumarato, por sua vez, teve efeito antioxidante somente sobre a produção de TBARS induzida. Por outro lado, o α-cetoglutarato foi capaz de induzir per se um significativo aumento na produção de TBARS. O efeito antioxidante do fumarato e do sucinato foi completamente abolido quando o S1 foi submetido a um prétratamento por 10 min a 100ºC, enquanto que o efeito dos demais intermediários permaneceu inalterado. Da mesma forma, a adição de cianeto de potássio aboliu completamente o efeito antioxidante do sucinato sem interferir significativamente no efeito dos demais intermediários estudados. Todos os intermediários estudados, exceto o sucinato e o fumarato, foram capazes de quelar íons ferro, porém somente o oxaloacetato e o α- cetoglutarato foram capazes de prevenir a degradação da desoxirribose induzida por peróxido de hidrogênio. Com base nos resultados obtidos, podemos concluir que o oxaloacetato, o malato, o sucinato, o fumarato e o citrato agem como antioxidantes sob determinadas condições, enquanto que o α-cetoglutarato age como um agente pró-oxidante per se. O mecanismo pelo qual o citrato, o malato e o oxaloacetato exercem seus efeitos antioxidantes parece ser devido à capacidade desses em interagir com íons ferro modulando o ciclo redox desse. Por outro lado, o efeito do sucinato e do fumarato parece ser devido a alguma atividade enzimática.
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Zehr, Peter S. "Synthesis of novel alkaloids using squaric acid esters." Morgantown, W. Va. : [West Virginia University Libraries], 2005. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=4411.
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Thesis (Ph. D.)--West Virginia University, 2005.Title from document title page. Document formatted into pages; contains xvii, 207 p. : ill. Includes abstract. Includes bibliographical references (p. 97-101).
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Dobson, Allison J. "X-ray diffraction investigations of quinoline and amino carboxylic acids /." The Ohio State University, 1998. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487949836206992.
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Mazzanti, Stefano. "A novel atroposelective strategy for the synthesis of quinoline substrates." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2018. http://amslaurea.unibo.it/16660/.
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Among heterocyclic compounds, quinoline scaffold has become an important motif for the development of new pharmacological active compounds. Since the discovery of their antimalarial properties, a large variety of quinolines was found to have interesting physiological activities and displayed attractive applications for pharmaceutical industries. In accordance to the above-mentioned features, a number of methods were developed for their synthesis but enantioselective versions are still lacking in the literature. In the past decades, this question has become even more complex, with the emergence of the less common axial chirality. Within the growing number of articles about atropisomers, the discovery of new synthetic pathways for the synthesis of enantioenriched atropisomers and their use in drug discovery has become a challenging topic in the organic chemistry scenario. In this work, the development of a novel atroposelective strategy for the synthesis of quinoline substrates has been achieved, and in order to obtain high values of enantioselectivity and yields a screening of the reaction conditions has been performed. The design of such strategy has been developed combining an already established methodology for the synthesis of heteroaromatic compounds such as a well-known Friedländer-type quinoline synthesis with chiral Brønsted acid catalysis to obtain the C-C bond formation in an enantioselective fashion.
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García, Aguirre Ana I. "An evaluation of cognitive deficits in a rat-model of Huntington's disease." Thesis, University of St Andrews, 2016. http://hdl.handle.net/10023/8827.
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The purpose of this thesis was to develop methodology by which treatments for the cognitive impairments in Huntington's disease (HD) could be tested. As such, the thesis focused mainly on evaluating rats with quinolinic acid (QA) lesions of the striatum, as this manipulation mimics some aspects of the neural damage in Huntington's disease, to try to identify cognitive deficits of HD resulting from cell loss in the striatum. In the first part (Chapters 3-5), the role of the striatum in implicit memory was investigated. Chapter 3 compared the performance of rats and humans on a reaction time task that evaluated implicit memory by presenting visual stimuli with differing probabilities which change over time. Although rats made higher percentage of incorrect responses and late errors, both groups showed a similar pattern of reaction times. Chapter 4 investigated whether implicit memory (the computation of probabilities to predict the location of a stimulus) was affected by selective blockade of dopaminergic transmission at the D1 or D2 receptors by SCH-23390 and raclopride, respectively. Reaction times were slower with SCH-23390 and raclopride, but only SCH-23390 reduced errors to the least probable target location. Chapter 5 used the same task to evaluate implicit memory in rats with QA lesions of the dorsomedial striatum (DMS). Implicit memory was not affected by lesions of the DMS, which suggested that once a task that requires implicit memory has been learned, the DMS was not involved in sustaining the performance of the task. The second part of this thesis (Chapter 6), explored the contribution of the DMS in habit formation. DMS lesioned rats did not show habitual responding, and were not impaired in learning a new goal-directed behaviour. The third part (Chapters 7 and 8), investigated the role of the dorsal striatum in reversal learning, attentional set-formation, and set-shifting. Dorsal striatum lesioned rats were not impaired in reversal learning, but had a diminished shift-cost, which suggested that dorsal striatum lesions disrupted the formation of attentional sets. These results showed that although QA lesions of the dorsal striatum mimic some aspects of the neural damage in HD, they did not result in the same cognitive deficits observed in patients with HD, at least using the tasks presented in this thesis. However, other animal models of HD could be evaluated using the different tasks presented in this thesis to continue the search of a reliable animal model of HD in which treatments for the disease could be evaluated.
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Zhurakovskyi, Oleksandr. "NOVEL DUAL LEWIS ACID - LEWIS BASE BINDERS AS POTENTIAL HYDROGEN AND CARBONYL ACTIVATORS." Thesis, The University of Arizona, 2010. http://hdl.handle.net/10150/193458.
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A series of new “frustrated Lewis pairs” (FLPs), including chiral versions, with a predefined spatial relationship between the basic and acidic centers is proposed. Several synthetic protocols toward the targets were investigated: through an aryllithium-haloborane coupling; using organotin reagents and a chiral diazaborolidine; and through organoboranes RBH₂ as the boron component. Further development of the project is discussed in light of the discovered data. The intermolecular system consisting of 8-bromo-2-methylquinoline and (C₆F₅)₃B was shown to exist in the form of an FLP. This FLP is not capable of heterolytic H-H bond cleavage with formation of an isolable adduct either at 1 atm or at 4 atm of H₂.
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Lu, Jianyu. "Syntheses of quinolines as neural protective reagents and progress towards total synthesis of (+) - myriceric acid A." Diss., Kansas State University, 2014. http://hdl.handle.net/2097/27652.
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Doctor of PhilosophyDepartment of Chemistry
Duy H. Hua
The first chapter of this dissertation introduces and discusses the syntheses of a series of substituted quinolines as glycogen synthase kinase-3[beta] (GSK-3[beta]) inhibitors. GSK-3[beta] is highly associated with Alzheimer’s disease (AD), and it is suggested that inhibition of this enzyme could alleviate the symptoms of AD. Total 16 novel substituted quinolines were designed and synthesized, and their bio-activities were evaluated on MC65 cell protection assay. Four of the most active compounds were selected to test their enzyme inhibitory activities on GSK-3[beta] and protein kinase C assays. Among these compounds, 4-{[6-methoxy-4-methyl-5-(3-(trifluoromethyl)phenoxy)quinolin-8-ylamino]methyl} phenol (1.5) shows the highest MC65 cell protection and GSK-3[beta] enzyme inhibitory activities and potential enzyme specificity. Structure-activity relationship (SAR) was built as well, and the binding mode was simulated via computational method to interpret the observed SAR. Although additional bio-evaluation is needed, compound 1.5 is a promising lead compound for the development of more active and less toxic drug for the conteraction of AD. The second chapter introduces the progress on the total synthesis of myriceric acid A. Myriceric acid A is a triterpene-type natural product which was isolated from the young twigs of Myrica cerifera. It is a non-peptide endotheline-1 (ET-1) receptor antagonist. The total synthesis of this natural product started from the stereoselective synthesis of bicyclic intermediate (R)-5,8a-dimethyl-3,4,8,8a-tetrahydronaphthalene-1,6(2H,7H)-dione [(-)-2.28]. Then a new method was developed to enatioselectively synthesize the tricyclic intermediate (4aR,8R,8aR)-8-(tertbutyldimethylsilyloxy)-1,4a,8a-trimethyl-4,4a,4b,5,6,7,8,8a,9,10-decahydro phenanthren-2(3H)-one [(+)-2.72] which used the synthesized optically-pure (4aR,5R)-5-(tertbutyldimethylsilyloxy)-1,4a-dimethyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one [(-)-2.53] derived from (-)-2.28 and [alpha]-trimethylsilylvinyl ethyl ketone via a cascade reductive Michael addition – aldol condensation reaction. After functional group inter-conversion, the desired tricyclic intermediate (4a'S,8a'R)-1',1',4a',8a'-tetramethyldecahydro-1'H-spiro[[1,3]dioxolane-2,2'-phenanthren]-8'(3'H)-one [(-)-2.33] was synthesized. An intramolecular cascade Michael addition-aldol condensation reaction was designed to construct the triterpene-skeleton of myriceric acid A, and the desired starting material for this reaction was prepared with the trimethyl{(4a'R,8a'R)-1',1',4a',8a'-tetramethyl-3',4',4a',4b',5',6',8a',9',10',10a'-decahydro-1'Hspiro[(1,3)dioxolane-2,2'-phenanthrene]-8'-yloxy}silane [(-)-2.81] and 3,3-dimethyl-7-oxooctanal (2.46) via Mukaiyama aldol condensation reaction. The resulting pentacyclic compound was further transformed to the desired ester (6a'R,8a'R,12a'S,12b'R,14b'R)-ethyl 4',4',6a',11',11',14b'-hexamethyl-8'-oxo-2',4',4a',5',6',6a',8',8a',9',10',11',12',12a',12b',13',14',14a',14b'-octadecahydro-1'H-spiro[(1,3) dioxolane - 2, 3 '- picene]-8a'-carboxylate (-)-2.106. The further investigation on total synthesis of myriceric acid A will be pursued in future.
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Hu, Xiaobo. "Synthèse, analyses structurales et assemblage de foldamères oligoamide hydrosolubles à base de quinolines." Thesis, Bordeaux, 2017. http://www.theses.fr/2017BORD0611/document.
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La chimie des foldamères est un domaine de recherche en pleine expansion où les chimistes explorent la construction d’architectures artificielles variées mimant les structures repliées des biopolymères naturels. Les foldamères d’oligoamides quinoline, constituent une branche importante des foldamères montrant de nombreuses caractéristiques attractives, incluant la stabilité et la prédictibilité de leurs conformations repliées, qui en font de bons candidats pour des applications biologiques. Jusqu’à présent, la plupart des études sur les foldamères d’oligoamides quinolines ont été menées dans des solvants organiques. Cette thèse a pour objectif d’étendre leur portée au milieu aqueux et présente plusieurs méthodologies pour parvenir à leur solubilité, leur repliement, la variation de leurs chaines latérales, leur agrégation et leur capacité à former des cristaux dans l’eau.Tout d’abord, une méthode de synthèse en phase solide a été développée permettant l’accès rapide aux foldamères hybrides α-amino acide/quinoline (X/Q). Leur étude dans l’eau montre que contrairement aux foldamères hybrides de type (XQ)n, ceux de type (XQ2)n sont capables d’adopter une conformation hélicoïdale présentant un alignement des chaines α-amino acides dans l’espace. Ensuite, plusieurs chaines latérales courtes ont été identifiées pour doter les foldamères aromatiques d’une solubilité et d’une capacité à cristalliser dans l’eau. Six oligoamides quinoline ont ainsi été synthétisés pour une étude modèle. Des cristaux ont été obtenus pour toutes les séquences sauf une, présentant une excessive solubilité dans l’eau. Enfin, des efforts ont été faits pour construire des faisceaux d’hélices auto-assemblés dans l’eau à base d’effets hydrophobes et d’interactions électrostatiques. Les études RMN et cristallographiques ont indiqué que les effets hydrophobes étaient plus faibles qu’attendu et ne provoquaient pas d’agrégation forteFoldamer chemistry is a rapidly expanding research field where chemists explore the construction of various artificial architectures that mimic the folded structures of biopolymers found in nature. Quinoline oligoamide foldamers, as an important branch of foldamers, have been shown to possess many desirable features, including stability and predictability of their folded conformations, and are promising candidates to achieve biological applications. Up to now, most investigations of quinoline oligoamide foldamers have been carried out in organic solvents. This thesis is aimed to expand their scope in aqueous medium and presents several methodologies to achieve solubility, folding, side-chain variation, aggregation and crystal growth ability in water.First, a solid phase synthesis method was developed to enable the fast access to α-amino acid/quinoline (X/Q) hybrid oligoamide foldamers. The study of these hybrid foldamers in water showed that contrary to (XQ)n-type foldamers the (XQ2)n-type foldamers could adopt aromatic helical conformations with α-amino acid side chains aligned in space. Then, several short side chains were identified to endow aromatic foldamers with both solubility in, and crystal growth ability from water. Six quinoline oligoamides displaying these side chains were synthesized as a case study. Crystals were obtained from aqueous medium in all cases but one, exceedingly soluble in water. At last, efforts were made to construct self-assembled aromatic helix bundles in water based on hydrophobic effects and electrostatic interactions. NMR and crystallographic studies indicated that hydrophobic effects are weaker than expected and not strongly conducive of aggregation
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Gaver, Charles Richard. "The highly preorganized ligands 8-(2-Pyridyl) Quinoline, 2,2'-dipyridyl amine and 1,10-phenanthroline-2, 9-dicarboxylic acid, and their complexing properties with metal ions." View electronic thesis, 2008. http://dl.uncw.edu/etd/2008-3/gaverc/charlesgaver.pdf.
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Stemper, Jérémie. "Développement d’une nouvelle famille d’acides phosphoriques à chiralité planaire pour l’organocatalyse." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA112260.
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Depuis les années 2000 le domaine de l’organocatalyse asymétrique est en plein développement comme le montre le nombre croissant de publications sur le sujet. Durant cet essor un grand nombre d’organocatalyseurs a été développé, ils se classent en quatre catégories : les catalyseurs de transfert de phase, les bases de Lewis, les bases de Brønsted et les acides de Brønsted. Appartenant à cette dernière catégorie, les acides phosphoriques chiraux font partie des acides de Brønsted les plus populaire. Leurs premières utilisations en organocatalyse asymétrique remontent à 2004 où des acides phosphoriques dérivés du BINOL furent utilisés par Terada et Akiyama pour catalyser des réactions de Mannich de manière hautement énantiosélective. Depuis le champ d’application des acides phosphoriques s’est considérablement étendu et aujourd’hui environ 90 réactions différentes peuvent être catalysées efficacement par ces acides. En parallèle de ce développement des équipes ont commencé à apporter des modifications structurales aux acides phosphoriques dans le but d’étendre encore leur champ d’application. L’une des approches consiste à modifier le squelette carboné afin de modifier l’organisation spatiale de l’encombrement stérique chiral autour du phosphore. Le travail présenté dans ce manuscrit décrit l’élaboration et l’utilisation en catalyse d’une nouvelle famille d’acides phosphoriques à chiralité planaire basée sur un motif [3,3]paracyclophane. L’étude commence par la modélisation par calculs DFT de différents paracyclophanes dans le but d’évaluer la tension de cycle et la barrière de rotation imprimer à la structure en fonction de l’espaceur utilisé. Trois espaceurs sont sélectionnés pour des essais en synthèse : le -CH2-NTs-CH2-, le 1,8-naphtalènediyle et le 1,1’-ferrocènediyle. Les synthèses de trois bisphénols comportant les motifs précédents sont réalisées. Les bisphénol comportant les espaceurs -CH2-NTs-CH2-, le 1,8-naphtalènediyle n’ont pas pu être transformés en acides phosphoriques. En revanche il a été possible d’obtenir une nouvelle famille d’acides phosphoriques à chiralité planaire comportant le motif 1,1’-ferrocènediyle.Par la suite une méthode de synthèse permettant la variation facile des substituants aromatiques a été mise en place ainsi qu’une méthode de séparation de diastéréoisomères à l’aide d’un auxiliaire chiral afin d’obtenir des acides phosphoriques énantiopurs. Une famille de 6 acides phosphoriques a ainsi pu être synthétisée. Ces nouveaux acides ont ensuite été testés en organocatalyse asymétrique. La réaction de réduction par des esters de Hantzsch de quinoléines substituées en position 2 a servi de réaction test. Après sélection du meilleur acide, une étude sur l’influence de l’ester de Hantzsch a été menée conduisant à une forte augmentation de l’énantiosélectivité de la réaction. Enfin le champ d’application de la réaction a été explorer et des excès énantiomériques atteignant 92% ont pu être atteints. D’autres modifications structurales peuvent être apportées à cette nouvelle structure comme par exemple le remplacement du motif 1,1’-ferrocènediyle par le motif 1,8-dibromobiphénylènyl. Une influence non négligeable de l’espaceur sur les performances du catalyseur a pu être ainsi observée.L’étude a montré le potentiel de cette nouvelle famille d’acide phosphorique en organocatalyse asymétrique. Cette nouvelle famille va donc pouvoir être utilisée pour développer de nouvelle réaction énantiosélectives et ce dans le domaine de l’organocatalyse ou bien dans celui de la catalyse organométallique en utilisant le phosphate comme contre-ion chiralDuring the first decade of the century the organocatalysis has known an intense development shown by the increasing number of publications on the subject. This development led to the apparition of a wide number of different organocatalysts. These catalysts can be sorted in three categories: the phase transfer catalysts, the Lewis bases, the Brønsted bases and the Brønsted acids. One of the most used types of organocatalysts belonging to the latter category are the chiral phosphoric acids (CPA). The first use of these CPAs as organocatalysts was published in 2004 by Terada and Akiyama. They independently reported two Mannich-type reactions catalysed by BINOL-derived CPAs with high levels of enatioselectivity. Since then CPAs appeared as versatile catalysts and to this date more than 90 different reactions can be catalysed in a highly énantiosélective manner by these acids. Meanwhile some researchers began to modify the original BINOL-based phosphoric acids so as to broaden their scope. One possible approach consists in changing the chiral backbone to change the spatial organisation of the chiral environment. The work reported in this manuscript describe the design, the synthesis and the use in organocatalysis of a new planar chiral phosphoric acids based on a [3,3]paracyclophanes scaffold. This study begins with the DFT modelling of a series of paracyclophanes in order to evaluate the ring strain and rotation barrier induced by the nature of different tethering units. Three tethers have been selected for synthesis trials: the -CH2-NTs-CH2-, the 1,8-naphtalenediyl and the 1,1’-ferrocenediyl. Three different bisphenols each one embedding one of the three tethers mentioned above have been synthesised. It was not possible to turn the -CH2-NTs-CH2- and the 1,8-naphtalenediyl-based bisphenols into the corresponding phosphoric acids. But the 1,1’-ferrocenediyl-based bisphenol was successfully cyclised into the desired planar chiral phosphoric acid. Subsequently a synthetic pathway allowing an easy variation of the aryl substituents has been developed together with the use of a chiral auxiliary to obtain the planar CPAs in an enantiopure way. By this method 6 different CPAs have been synthesised. The efficiency in asymmetric organocatalysis of these new planar CPAs was investigated. The reduction of 2-substituted quinolines by Hantzsch esters was used as a benchmark reaction. After having identified the best CPA, the role of the Hantzsch ester has been investigated leading to an important improvement of the enantioselectivity of the reaction. Eventually, the scope of the reaction has been explored and e.e.’s up to 92% have been reached. Some other structural modifications of the structure can be made such as the replacement of the 1,1’-ferrocenediyl unit by a 1,8-dibromobiphenylenyl. A non-negligible influence of the tether has been observed on the catalyst behaviour. The study has demonstrated the potential of this new class of organocatalyst in asymmetric catalysis. These planar CPAs will then be used in the developpement of new énantiosélective reaction in the domain of organocatalysis or in the domain of organometallic catalysis by using the phosphate as a chiral counter-ion
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Marques, Naiani Ferreira. "Centella asiática REDUZ PEROXIDAÇÃO LIPÍDICA INDUZIDA POR ÁCIDO QUINOLÍNICO E NITROPRUSSIATO DE SÓDIO IN VITRO EM REGIÕES DO CÉREBRO DE RATO." Universidade Federal de Santa Maria, 2014. http://repositorio.ufsm.br/handle/1/11242.
Full textAbstract:
Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorThe oxidative stress is envolved in several diseases, including neurological diseases. Centella asiatica is a medicinal plant which was has long been used to treat neurological disturbances in Ayurvedic medicine. The aim of this study was to evaluate the antioxidant potencial of different extracts of C.asiatica in vitro. Were quantified by High Performance Liquid Chromatograph (HPLC) the present compounds and examined the phenolic content of the infusion and fractions: ethyl acetate, n-butanol and dichlorometane. Furthermore, the ability of C.asiatica extracts as scavenger of DPPH., as well as, the antioxidant capacity it was analyzed, through the reduction of molybdenum (VI)(Mo6+) to molybidenum (V)(Mo5+). Finally, we determined the effect of the extracts on lipid peroxidation induced by quinolinic acid (QA) and sodium nitroprusside (SNP) in different regions of the rat brain (cerebral cortex, striatum and hippocampus). HPLC analysis showed that flavonoids, triterpene glycosides, tannins and phenolic acids were present in extracts of C.asiatica. The content of phenolic compounds showed that the ethyl acetate fraction is rich in these compounds, followed by dichloromethane fraction of butanol and of infusion. Moreover, with the first analyzes it was also found a higher antioxidant potential of ethyl acetate fraction as DPPH. radical scavenger. In agreement with in vitro assays, the ethyl acetate fraction showed the highest antioxidant effect by decreasing lipid peroxidation induced by AQ in cerebral cortex (IC50 = 11.82), striatum (IC50 = 13.91) and hippocampus (IC50 = 13. 55) from rat brain. However, when the pro-oxidant agent was NPS, potency of infusion, the ethyl acetate fraction and dichloromethane were not significantly different to the cortex and hippocampus, which highlighted a greater difference of action in the striatum between the infusion (IC50 = 16.12), the ethyl acetate (IC50 = 13.57) and dichloromethane (IC50 = 11.05) regarding the butanol fraction (IC50 = 47.94). In conclusion, the results demonstrated that the infusion of C.asiatica and other fractions exhibit antioxidant capacity in vitro, which is related to their phytochemical content. Thus, the therapeutic potential in neurological diseases of C. asiatica, could be associated with its antioxidant activity.
O estresse oxidativo está envolvido em várias patologias incluindo as doenças neurológicas. A Centella asiática é uma planta medicinal que tem sido muito utilizada para o tratamento de distúrbios neurológicos na medicina Ayurvédica. O objetivo do presente estudo foi avaliar o potencial antioxidante de diferentes extratos de C. asiática in vitro. Foi quantificado por cromatografia líquida de alta eficiência (CLAE) o conteúdo fenólico da infusão e das frações: acetato de etila, n-butanólica e diclorometano. Além disso, analisou-se a capacidade dos extratos de C. asiática como scavenger do radical DPPH., bem como, a capacidade antioxidante total através da redução do molibdênio (VI) (Mo6 +) a molibdênio (V) (Mo5 +). Finalmente, determinou-se o efeito dos extratos na peroxidação lipídica induzida por ácido quinolínico (AQ) e nitroprussiato de sódio (NPS), em diferentes regiões do cérebro de rato (córtex, estriado e hipocampo). A análise por CLAE revelou que flavonóides, glicosídeo triterpeno, taninos e ácidos fenólicos estavam presentes nos extratos de C. asiática. O teor de compostos fenólicos demonstrou que a fração acetato de etila é rica nestes compostos, seguida da fração diclorometano, da n-butanólica e por fim da infusão. Além disso, com as primeiras análises também verificamos um maior potencial antioxidante da fração acetato de etila como scavenger de radical DPPH.. Em acordo com as análises in vitro, a fração acetato de etila apresentou o maior efeito antioxidante através da diminuição da peroxidação lipídica induzidas por AQ em córtex (IC50=11,82), estriado (IC50=13,91) e hipocampo (IC50=13,55) de cérebro de rato. Por outro lado, quando o agente pró-oxidante foi NPS, a potência de infusão, das frações de acetato de etila e diclorometano não foram diferentes significativamente para córtex e hipocampo, sendo destacada uma maior diferença de ação no estriado, entre a infusão (IC50=16,12), a acetato de etila (IC50= 13,57) e a diclorometano (IC50= 11,05) em realção a fração butanólica (IC50 = 47,94). Em conclusão, os resultados encontrados demonstraram que a infusão e demais frações de C. asiática apresentam capacidade antioxidante in vitro, a qual está relacionada ao seu conteúdo fitoquímico. Assim, o potencial terapêutico de C. asiática em doenças neurológicas, poderia ser associado com a sua atividade antioxidante.
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Goes, Tiago Costa. "Efeito do enriquecimento ambiental e da lesão do cortéx pré-frontal medial nos níveis de ansiedade-traço e -estado." Universidade Federal de Sergipe, 2016. https://ri.ufs.br/handle/riufs/3614.
Full textAbstract:
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESEffect of environmental enrichment and lesion of the medial prefrontal cortex in the trait and state anxiety levels. Tiago Costa Goes, Aracaju – SE, 2016. In the study of anxiety, there are two distinct concepts: state and trait anxiety. State anxiety is the anxiety a subject experiences at a particular moment in time, it is transitory and may be affected by external stimuli; whereas trait anxiety is considered an enduring feature of an individual, it is relatively stable over time and a predisposing factor for anxiety disorders. Despite its relative stability, in animals, trait anxiety seems to be sensitive to the influence of environmental enrichment established after weaning. Whether this influence also occurs when the enrichment is established in adulthood is still unknown. The brain structures implicated in trait anxiety are also unknown, but scientific evidences point to the medial prefrontal cortex (mPFC) Thus, the aims of this study were: 1) evaluate the effect of environmental enrichment in the levels of trait anxiety and state anxiety of adult rats (Experiment I); and 2) evaluate the effect of lesion of the mPFC in the levels of trait anxiety and state anxiety of adult rats (Experiment II). As, by definition, trait anxiety modulates state anxiety, this was also evaluated. In Experiment I, seventy adult Wistar male rats were first tested in the free-exploratory paradigm (FEP – animal model of trait anxiety) in order to be categorized according to their levels of trait anxiety (high, medium and low). Subsequently, half of the animals from each category returned to their home cages (standard condition) and the other half was transferred to an enriched environment (enriched condition). After three weeks, all animals were again tested in FEP. Seven to 10 days later, 50 of the 70 animals were tested on the elevated plus-maze test (EPM – animal model of state anxiety). The data from FEP were analyzed using ANOVA and Tukey's post hoc test, while the data from EPM were analyzed using Student‟s t test. In FEP, environmental enrichment reduced locomotor activity independently of the anxiety category and, it decreased the levels of trait anxiety of highly anxious rats. In EPM, no effect of environmental enrichment was observed in the levels of state anxiety. In Experiment II, 66 adult Wistar male rats were first tested in FEP and categorized according to their levels of trait anxiety. Three to six days after this exposure, all animals were submitted to stereotaxic brain surgery. Half of the animals from each anxiety category was allocated to the mPFC-lesioned group and the other half to the Sham-lesioned group. After seven to nine days, all animals were again tested in FEP. Eight to 10 days later, the animals were tested in the hole board test (HB – animal model of state anxiety). The data from both FEP and HB were analyzed using ANOVA and Tukey's post hoc test. In FEP, the mPFC lesion, independently of the anxiety category, increased locomotor activity in the second exposition to FEP in relation to first exposition to FEP and it decreased levels of trait anxiety of highly anxious rats. In HB, the mPFC lesion reduced the state anxiety of the animals of all anxiety categories. Thus, this study showed that the environmental enrichment, established in adulthood, was able to was able to decrease the trait anxiety levels without affecting the levels of state anxiety, whereas the lesion of the CPFM decreased both levels trait anxiety and state anxiety of adult Wistar rats.
Efeito do enriquecimento ambiental e da lesão do córtex pré-frontal medial nos níveis de ansiedade-traço e -estado. Tiago Costa Goes, Aracaju – SE, 2016. No estudo da ansiedade há dois conceitos distintos: a ansiedade-estado e a ansiedade-traço. A primeira é uma emoção que o indivíduo experimenta quando confrontado com um estímulo ameaçador e, a segunda, é um traço de personalidade relativamente estável ao longo do tempo e fator predisponente para os transtornos ansiosos. Apesar da relativa estabilidade, em animais, a ansiedade-traço parece ser sensível à influência de um enriquecimento ambiental, quando este é estabelecido após o desmame. Entretanto, não se sabe se esta influência também ocorre quando o enriquecimento é estabelecido na idade adulta. Também é desconhecido o substrato neural do perfil ansioso, mas evidências científicas apontam para um possível envolvimento do córtex pré-frontal medial (CPFM). Assim sendo, os objetivos do presente estudo foram: 1) avaliar o efeito do enriquecimento ambiental nos níveis de ansiedade-traço e ansiedade-estado de ratos adultos (Experimento I); e 2) avaliar o efeito da lesão do CPFM nos níveis de ansiedade-traço e ansiedade-estado de ratos adultos (Experimento II). Como, por definição, a ansiedade-traço modula a ansiedade-estado, esta também foi avaliada. No Experimento I, 70 ratos Wistar adultos foram primeiramente avaliados no paradigma da exploração livre (PEL – modelo animal de ansiedade-traço) para serem categorizados de acordo com seus níveis de ansiedade-traço (alto, médio e baixo). Subsequentemente, metade do número de animais de cada categoria retornou para sua gaiola (grupo condição padrão) e a outra metade foi exposta a um ambiente enriquecido (grupo condição enriquecida). Após três semanas, todos os animais foram novamente avaliados no PEL. Sete a dez dias após esta avaliação, 50 dos 70 animais foram avaliados no labirinto em cruz elevado (LCE – modelo animal de ansiedade-estado). Os dados obtidos no PEL foram analisados por meio de análise de variância e teste a posteriori de Tukey, e os do LCE por teste t de Student. Os resultados mostraram que o ambiente enriquecido reduziu a atividade locomotora no PEL, independentemente da categoria de ansiedade e, diminuiu os níveis de ansiedade-traço dos animais com alto traço ansioso. Já no LCE, nenhum efeito do enriquecimento ambiental foi observado nos níveis de ansiedade-estado. No Experimento II, 66 ratos Wistar adultos foram primeiramente avaliados no PEL para serem categorizados de acordo com seus níveis de ansiedade-traço. Três a seis dias após esta exposição, todos os animais foram submetidos à cirurgia estereotáxica. Metade do número de animais de cada categoria de ansiedade foi alocada para o grupo lesão do CPFM e a outra metade constituiu o grupo falsa lesão (grupo controle). Sete a nove dias após a cirurgia, todos os animais foram novamente testados no PEL. E, oito a dez dias após esta avaliação, foram testados na placa perfurada (PP – modelo animal de ansiedade-estado). Os dados obtidos tanto no PEL quanto na PP foram analisados por meio de análise de variância e teste a posteriori de Tukey. Os resultados mostraram que a lesão do CPFM, independentemente da categoria de ansiedade, aumentou a atividade locomotora na segunda exposição ao PEL em comparação com a primeira exposição e, diminuiu os níveis de ansiedade-traço de ratos com alto traço ansioso. Já na PP, a lesão do CPFM reduziu os níveis de ansiedade-estado dos animais de todas as categorias de ansiedade. Assim sendo, o presente estudo mostrou que o enriquecimento ambiental, estabelecido na idade adulta, foi capaz de diminuir os níveis de ansiedade-traço sem afetar os níveis de ansiedade-estado, ao passo que, a lesão do CPFM diminuiu tanto os níveis de ansiedade-traço quanto de ansiedade-estado de ratos Wistar adultos.
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"Enantiospecific synthesis of valiolumine and its diastereoisomers from (-)-quinic acid." Chinese University of Hong Kong, 1994. http://library.cuhk.edu.hk/record=b5887291.
Full textAbstract:
Wan Leong Hang.Thesis (M.Phil.)--Chinese University of Hong Kong, 1994.
Includes bibliographical references (leaves 80-83).
Acknowledgments --- p.i
Bibliography --- p.ii
Contents --- p.iii
Abstract --- p.iv
Abbreviations --- p.v
Chapter I --- Introduction
Chapter I-1 --- General Background of Pseudo-sugar --- p.1
Chapter I-2 --- Monocarba-sugar --- p.2
Chapter I-3 --- Dicarba-sugar --- p.4
Chapter I-4 --- Isolation of Valiolamine and Its Related Compounds --- p.6
Chapter I-5 --- Previous Syntheses of Valiolamine --- p.8
Chapter II --- Results and Discussions
Chapter II-1 --- General Strategy --- p.17
Chapter II-2 --- "Synthesis of (lR,2R)-diol (62)" --- p.20
Chapter II-3 --- Synthesis and Reactivity of Olefin 69 --- p.24
Chapter II-4 --- "Synthesis of (1R,2S) and (lR,2R)-diastereoisomers 25 and 27" --- p.27
Chapter II-5 --- "Synthesis of (1S,2R)-diastereoisomer 26 and Valiolamine" --- p.32
Chapter II-6 --- "Comment on the Regio Chemistry of Nucleophilic Attack of 68, 65 and" --- p.85
Chapter II-7 --- Results of Biological Test --- p.43
Chapter III --- Conclusion --- p.46
Chapter IV --- Experimental --- p.48
Chapter V --- Reference --- p.80
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"Enantiospecific syntheses of cyclophellitol and its analogues from (-)-quinic acid." Chinese University of Hong Kong, 1993. http://library.cuhk.edu.hk/record=b5887850.
Full textAbstract:
by Vincent Wing-Fai Tai.Thesis (M.Phil.)--Chinese University of Hong Kong, 1993.
Includes bibliographical references (leaves 79-83).
Acknowledgements --- p.i
Contents --- p.ii
Abstract --- p.iii
Abbreviations --- p.iv
Chapter I --- Introduction
Chapter I-1 --- General Background --- p.1
Chapter I-2 --- Review on Epoxycyclohexanes --- p.2
Chapter I-3 --- Mechanistic Aspect of Glycosidase Inhibitors --- p.5
Chapter I-4 --- Previous Synthesis of cyclophellitol and its diastereoisomers 1-4 --- p.12
Chapter II --- Results and Discussion
Chapter II-l --- General Strategy --- p.19
Chapter II-2 --- Synthesis of the diol 57 --- p.21
Chapter II-3 --- Synthesis of the allylic alcohol 54 --- p.25
Chapter II-4 --- "Synthesis of Cyclophellitol 1 and its (lR,6S)-diastereoisomer 2" --- p.29
Chapter II-5 --- "Synthesis of the (2S)- and (lR,2S,6S)-diasteroeisomers 3 and 4" --- p.34
Chapter II-6 --- Comments on the MCPBA Epoxidation --- p.37
Chapter II-7 --- Synthesis of the Epoxy Analogues of Cyclophellitol 104 and 105. --- p.40
Chapter II-8 --- Results of biological assays --- p.43
Chapter III --- Conclusion --- p.48
Chapter IV --- Experimental --- p.50
Chapter V --- References --- p.79
Chapter VI --- Spectra --- p.84
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"A thesis, in two parts, entitled part A, Enantiospecific syntheses of cyclophexane oxides from (-)-quinic acid, part B, Ruthenium catalyzed cis-dihydroxylation of alkenes." Chinese University of Hong Kong, 1996. http://library.cuhk.edu.hk/record=b5888854.
Full textAbstract:
by Eric Kwok Wai Tam.Thesis (Ph.D.)--Chinese University of Hong Kong, 1996.
Includes bibliographical references.
Table of Contents --- p.i
Acknowledgement --- p.iv
Abstract --- p.v
Abbreviation --- p.vii
Part A
Enantiospecific Syntheses of Cyclohexane Oxides from (-)-Quinic Acid
Chapter 1. --- Synthetic Application of (-)-Quinic Acid --- p.1
Chapter 1.1 --- Introduction --- p.1
Chapter 1.2 --- Syntheses of Cyclohexane Derivatives --- p.2
Chapter 1.2.1 --- Syntheses of Shikimic Acid (2) and its Derivatives --- p.2
Chapter 1.2.2 --- "Syntheses of D-myo-Inositol 1,4,5-Trisphosphate (52) & its analog" --- p.15
Chapter 1.2.3 --- Syntheses of Mycosporins --- p.17
Chapter 1.2.4 --- Synthesis of (+)-Palitantin (76) --- p.19
Chapter 1.2.5 --- "Synthesis of 2-Crotonyloxy-(4R,5R,6R)-4,5,6-trihydroxy- cyclohex-2-enone (COTC) (82)" --- p.20
Chapter 1.2.6 --- Syntheses of Cyclophellitol (83) and its Diastereomers --- p.21
Chapter 1.2.7 --- Syntheses of Pseudo-sugars and its Derivatives --- p.24
Chapter 1.2.8 --- Syntheses of Aminocyclitol Antibiotics --- p.34
Chapter 1.2.9 --- Syntheses of A-ring Precursor of Daunomycin --- p.36
Chapter 1.2.10 --- "Synthesis of 19-nor-lα,25-Dihydroxyvitamin D3" --- p.38
Chapter 1.2.11 --- Synthesis of Isoquinuclidines --- p.41
Chapter 1.2.12 --- Synthesis of Cyclohexenyl Iodide: Taxol CD-ring Precursor --- p.44
Chapter 1.2.13 --- Synthesis of C-20 to C-34 Segment of FK-506 --- p.46
Chapter 1.2.14 --- Synthesis of the Hexahydrobenzofuran Subunit of Avermectins --- p.49
Chapter 1.2.15 --- Synthesis of Bicyclic Core of Enediyne --- p.50
Chapter 1.2.16 --- Syntheses of Two Enantiopure Derivatives of 4-Hydroxy-2-cyclohexone --- p.53
Chapter 1.3 --- Synthesis of Homochiral Linear Molecules --- p.57
Chapter 1.3.1 --- Syntheses of (3S)-Mevalonolactone and its Derivatives --- p.57
Chapter 1.3.2 --- Synthesis of the Subunit in Maytansinoids --- p.58
Chapter 1.3.3 --- Synthesis of (+)-Negamycin --- p.59
Chapter 1.3.4 --- Syntheses of Hepoxilins B3 and its Stereoisomers --- p.61
Chapter 1.3.5 --- Synthesis of C-21 to C-25 Fragment of FK-506 --- p.62
Chapter 1.4 --- Synthesis of Cyclopentane Derivatives --- p.63
Chapter 1.4.1 --- Synthesis of 11 α-Hydroxy-13-oxaprostanoic Acid --- p.65
Chapter 1.4.2 --- Synthesis of (-)-Pentenomycin I --- p.66
Chapter 1.4.3 --- Syntheses of Carbovir and its Derivatives --- p.66
Chapter 1.5 --- Synthesis of Cycloheptane Derivatives --- p.68
Chapter 1.6 --- Conclusion --- p.70
References --- p.71
Chapter 2. --- Introduction of Cyclohexane Oxides --- p.81
Chapter 2.1 --- General Background --- p.81
Chapter 2.2 --- Previous Syntheses of Cyclohexane Oxides --- p.86
Chapter 2.2.1 --- Racemic Syntheses of Crotepoxide --- p.86
Chapter 2.2.2 --- Racemic Syntheses of Senepoxide --- p.89
Chapter 2.2.3 --- A Racemic Synthesis of Pipoxide --- p.92
Chapter 2.2.4 --- Syntheses of Enantiopure Cyclohexane Oxides --- p.93
References --- p.96
Chapter 3. --- Retrosynthetic Analysis and Strategy --- p.99
Chapter 3.1 --- Antithetic Analysis of Cyclohexane Oxides --- p.99
Chapter 3.2 --- Problems Encounter in the Conversion of Diene into Cyclohexane Oxides --- p.100
Chapter 3.3 --- Photo-oxygenation Approach to Cyclohexane Oxides --- p.102
Chapter 3.4 --- Reasons for Choosing the Silyl Ether as Blocking Group --- p.104
Chapter 3.5 --- Strategy for Synthesis of Diene 373 from Quinic acid --- p.105
References --- p.106
Chapter 4. --- Results and discussion --- p.108
Chapter 4.1 --- Synthesis of Silyl Benzoate381 --- p.108
Chapter 4.2 --- Synthesis of Alkene373 --- p.111
Chapter 4.3 --- Syntheses of (+)-Crotepoxide (289)，(+)-Bosenepoxide (290) and (-)-iso-Crotepoxide (304) --- p.115
Chapter 4.4 --- "Syntheses of the (+)-β-Senepoxide (295)，(+)-Pipoxide Acetate (365), (-) Tintanoxide (294) and (-)-Senepoxide (291)" --- p.121
References --- p.124
Chapter 5. --- Conclusion --- p.126
Chapter 6. --- Experimental Section --- p.128
References --- p.142
Part B
Ruthenium Catalyzed cis-Dihydroxylation of Alkene
Chapter 1. --- Introduction --- p.143
Chapter 1.1 --- Background --- p.143
Chapter 1.2 --- General cis-Dihydroxylation Methods --- p.144
Chapter 1.2.1 --- Potassium Permanganate (KMnO4) --- p.144
Chapter 1.2.2 --- Osmium Tetraoxide (OsO4) --- p.146
Chapter 1.3 --- Ruthenium Tetraoxide Oxidations --- p.148
Chapter 1.4 --- Previous Reports of Using Ruthenium Tetraoxide (RuO4) Mediated syn-Dihydroxylation of Olefins --- p.149
Chapter 1.4.1 --- The Snatzke and Fehlhaber Work --- p.149
Chapter 1.4.2 --- The Sharpless and Akashi Work --- p.150
Chapter 1.4.3 --- The Sica and Co-workers Work --- p.150
References --- p.152
Chapter 2. --- Ruthenium-Catalyzed cis-Dihydroxylation of Alkenes --- p.155
Chapter 2.1 --- """Flash"" Dihydroxylation" --- p.155
Chapter 2.2 --- "Stereochemical Outcome of ""Flash"" Dihydroxylation" --- p.155
References --- p.157
Chapter 3. --- Results and Discussion --- p.158
Chapter 3.1 --- "Scope and Limitations of ""Flash"" Dihydroxylation" --- p.158
Chapter 3.2 --- "Study of the Diastereoselectivity of ""Flash"" Dihydroxylation" --- p.168
Chapter 3.3 --- "Study of Co-oxidants for ""Flash"" Dihydroxylation" --- p.170
Chapter 3.4 --- "Solvent Effect for ""Flash"" Dihydroxylation" --- p.171
Chapter 3.5 --- "Synthetic Application of ""Flash"" Dihydroxylation" --- p.173
References --- p.175
Chapter 4. --- Conclusion --- p.176
Chapter 5. --- Experimental Section --- p.177
References --- p.185
Appendix --- p.186
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Strauss, Ian. "Proton magnetic resonance spectroscopic imaging of acute and chronic neuronal damage in the rat induced by quinolinic acid /." 1996. http://wwwlib.umi.com/dissertations/fullcit/9701375.
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Zheve, Georgina Teurai. "Neuroprotective mechanisms of nevirapine and efavirenz in a model of neurodegeneration /." 2007. http://eprints.ru.ac.za/1350/.
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Huo, Lu. "Structural and Mechanistic Studies on α-Amino β-Carboxymuconate ε-Semialdehyde Decarboxylase and α-Aminomuconate ε-Semialdehyde Dehydrogenase." 2014. http://scholarworks.gsu.edu/chemistry_diss/100.
Full textAbstract:
α-Amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD) and α-aminomuconate-ε-semialdehyde dehydrogenase (AMSDH) are two neighboring enzymes in the L-tryptophan and 2-nitrobenzoic acid degradation pathways. The substrates of the two enzymes, α-amino-β-carboxymuconate-ε-semialdehyde (ACMS) and α-aminomuconate-ε-semialdehyde (2-AMS), are unstable and spontaneously decay to quinolinic acid and picolinic acid, respectively.
ACMSD utilizes a divalent zinc metal as cofactor and is a member of the amidohydrolase superfamily. In this dissertation work, we have identified an important histidine residue in the active site that plays dual roles in tuning metal selectivity and activating a metal bound water ligand using mutagenesis, resonance Raman, EPR, crystallography, and ICP metal analysis techniques. The crystal structures of ACMSD from Pseudomonas fluorescens (PfACMSD) have been solved as homodimers in our laboratory while human ACMSD (hACMSD) was annotated as a monomer by another group. To resolve this structural difference, we used two conserved active site arginine residues as probes to study the oligomeriztion state of ACMSD and demonstrated that these two arginine residues are involved in substrate binding and that both Pf- and h- ACMSD are catalytically active only in the dimeric state. Subsequently, we solved the crystal structure of hACMSD and found it to be a homodimer in both catalytically active and inhibitor-bound forms.
AMSDH is an NAD+ dependent enzyme and belongs to the aldehyde dehydrogenase superfamily. Due to the high instability of its substrate, AMSDH has not been studied at the molecular level prior to our work. We have cloned and expressed PfAMSDH in E. coli. The purified protein has high activity towards both 2-AMS and 2-hydroxymuconate semialdehyde (2-HMS), a stable substrate analog. We have successfully crystallized AMSDH with/without NAD+ and solved the crystal structure at up to 1.95 Å resolution. Substrate bound ternary complex structures were obtained by soaking the NAD+ containing crystals with 2-AMS or 2-HMS. Notably, two covalently bound catalytic intermediates were captured and characterized using a combination of crystallography, stopped-flow, single crystal spectroscopy, and mass spectrometry. The first catalytic working model of AMSDH has been proposed based on our success in structural and spectroscopic characterization of the enzyme in five catalytically relevant states in this dissertation work.
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O'Connell, Adam Brett. "Development of an acute excitotoxic model of Huntington's disease in sheep." Thesis, 2020. http://hdl.handle.net/2440/127292.
Full textAbstract:
Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. The earliest and most severe neuropathological change in HD occurs within the striatum. Exogenous excitotoxic lesioning of the rodent and non-human primate (NHP) striatum is used to model HD. Apart from NHPs, no other excitotoxic large animal model of HD has been established. Sheep have the potential to be an important species for modelling neurodegenerative disease, primarily because of neuroanatomical similarities between the sheep and human brain. This thesis describes the development of an excitotoxic sheep model of HD using the excitotoxin, quinolinic acid (QA). QA is an N-methyl-D-aspartate (NMDA) glutamate receptor agonist that produces pathological changes within the striatum that resemble those seen in HD. Sixteen castrated-male, 18 month old, Merino-Border Leicester cross sheep underwent two surgical procedures, four weeks apart, to infuse 75 μl of 180 mM QA (experimental group) or 75 μl of saline (control group) into the left (first surgery) and then the right (second surgery) caudate nucleus of the striatum. Longitudinal magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) of the brains of the sheep was performed on a 3-Tesla scanner pre-surgically, one week after the first surgery, five weeks after the first surgery and sixteen weeks after the first surgery to investigate the neuropathological changes that occur in vivo after QA lesioning of the sheep striatum. The phenotypic consequences of lesioning the sheep striatum with QA were investigated using a veterinary neurological examination, dopamine agonist induced rotation and a two-choice discrimination task. The author / investigator was blind to the treatment group. MRI revealed QA-lesion hyperintensity and dilation of the lateral ventricles, consistent with atrophy of the caudate nucleus. MRS and DTI revealed a significant decrease in the neuronal marker N-acetylaspartate (NAA), and in fractional anisotropy (FA) in the acutely-lesioned (one week after surgery) striatae of the QA-lesioned sheep, followed by recovery in NAA and a significant increase in FA in the chronic (five to sixteen weeks) QA-lesioned striatae. NAA and FA changes are consistent with neuronal loss and structural disruption in the acute lesion, followed by recovery of reversibly impaired neurons, structural reorganisation and gliosis in the chronic lesion. Heterogeneous neuronal loss and damage and gliosis were visible on histological analysis of the QA-lesioned sheep striatae, supporting the in vivo MRS and DTI detected changes. Neurological examination of the sheep revealed evidence of laterality and mild hind limb motor paresis in seven out of eight of the QA-lesioned sheep, however the examination was not informative of lesion characteristics. A directional bias was evident in the QA-lesioned sheep during rotation studies. However, the direction and magnitude of bias in individual sheep at any one timepoint varied markedly, making identification of QA-lesioned individuals difficult. There was no difference between the QA-lesioned and saline-treated sheep in performance of the acquisition and reversal phases of the two-choice discrimination task. The behavioural studies described in this thesis were not suitable for comprehensive identification and characterisation of QA lesions in the striatum of sheep. This is the first description of the development of an acute excitotoxic sheep model of HD. The experiments demonstrate that longitudinal analysis of the neuropathological changes in the QA-lesioned sheep striatum is possible using advanced magnetic resonance modalities performed on a clinically relevant 3-Tesla scanner and that neuropathological changes are consistent with HD-like pathology in other species. Furthermore, phenotypic investigation of the QA-lesioned sheep is possible, however more refined methods than those described need to be utilised. The excitotoxic sheep model of HD is clinically relevant HD model with potential for use in disease mechanism and therapy investigations.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2020
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Chang, Jia-Hen, and 張嘉恆. "Supramolecular Au(I) Compounds Containing Trithiocyanuric acid or Quinoline-8-thiolate." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/6qkcmp.
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碩士國立中正大學
化學暨生物化學研究所
105
In the literature, most of the closed-shell d10 gold(I) complexes containing phosphine or thiolate ligands, show intriguing structural and spectroscopic properties. In this thesis, we used AuClPMe3 and AuClPEt3 (PMe3 = trimethylphosphine；PEt3 = triethylphosphine) to react with thiolate ligands H3N3S3 (Trithiocyanuric acid) and H8-QNS (Quinoline-8-thiolate) to construct dinuclear, trinuclear, and hexanuclear gold(I) compounds. Crystal structures of compound 1-4 are determined by single-crystal X-ray crystallography, [(N3S3)Au(AuPMe3)2]2‧2CH2Cl2 (1), [(N3S3)Au(AuPEt3)2]2‧C2H5OH (2), [(8-QNS)2Au(AuPMe3)2]2‧2ClO4‧2CH2Cl2 (3) and [(8-QNS)2(AuPEt3)4(ClO4)2] (4). Complexes 1 and 2 are hexanuclear structure, where four Au(I) centers are arranged in the form of a parallelogram with Au(I)…Au(I) distances of 2.950(1), 2.965(1) Å and 2.990(1), 2.958(1) Å, respectively. Complex 3 is a trinuclear structure, where the central Au(I) center is bonded with two 8-QNS, and two AuPMe3 are bonded with two different 8-QNS ligands, which are further aggregated to form a hexanuclear supermolecule through intermolecular Au(I)…Au(I) contacts of 3.192(1), 3.108(1) and 3.218(1) Å. Complex 4 is a dinuclear structure, where two AuPEt3 are bonded with the same 8-QNS ligand with a weak Au(I)…Au(I) interaction of 3.314 Å, which is also aggregated to form a tetranuclear supermolecule through a close intermolecular Au(I)…Au(I) contact of 3.133(1) Å. These complexes exhibit solid-state luminescence at 500-550 nm, where 1 and 2 can be tentatively attributed to ligand-to-metal charge-transfer transition (LMCT), and 3 and 4 possibly due to a metal-centered 5d(dσ*)→6p(pσ) transition.
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Yeh, Mei-Chun. "Synthesis of quinoline-fatty acid conjugates and characterization of their immunomodulatory properties." Thesis, 2010. http://hdl.handle.net/2440/121656.
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The anti-malarial chloroquine (CQ) and derivatives are useful anti-inflammatory agents which have been useful in treating patients with rheumatoid arthritis and systemic lupus erythromytosus. Nevertheless derivatives of CQ, such as hydroxychloroquine (HCQ) have been made to reduce the toxicity and increase the potency of the drug. We have approached this challenge by synthesizing 13 quinoline based compounds bearing a saturated or un-saturated fatty acid side chain (carbon chain length of 3 to 20). Examination of their immunomodulatory properties in vitro at concentrations up to 50μM showed these compounds to have no effect on phytohaemagglutinin- and antigen, tetanus toxoid- induced human lymphocyte proliferation and interferon-γ, interleukin(IL)-2, IL-10 and lymphotoxin production. Similarly, there was no effect on the responses induced by the B cell mitogen, Staphylococcus aureus. In contrast, at the same concentrations, CQ significantly inhibited lymphoproliferation and cytokine production induced by these agents. Using bacterial lipopolyssacharide (LPS) as a stimulus for monocytes in the peripheral blood mononuclear fraction, we found that cytokine production, tumour necrosis factor alpha (TNFα), IL-1β and IL-6 was inhibited by CQ but not the NT compounds. In contrast the data demonstrated that a number of the NT compounds were effective in inhibiting human neutrophil adherence induced by TNF. However, this activity was not related to either the carbon chain length or their saturated versus un-saturated state of the fatty acid side chain. In comparison, both CQ and HCQ had no effect on this response. The compound NT8 which had lauric acid on the side chain of the quinoline structure was the most active. Further studies with this compound revealed that it was particularly effective in inhibiting TNF-induced neutrophil cytokine (IL-1β and IL-8) production but not TNF-induced neutrophil migration inhibition or TNF-induced respiratory burst. CQ and HCQ had no effect on all of these responses. At the lower concentrations of NT8 which significantly inhibited neutrophil adherence and cytokine production, the compound had no effect on adherence induced by phorbol 12-myristate 13-acetate (PMA) and calcium ionophore (A23187). These agents are known to by-pass the surface receptors and act on protein kinase C and cause an increase in intracellular calcium levels respectively, suggesting that the effects of NT8 are upstream in the signalling cascade. Interestingly we found that NT8 caused a significant decrease in surface expression of TNF receptor II (TNFRII) but not TNFRI. This selective effect of NT8 on neutrophil functions such as adherence was lost with an increase in concentration, where the neutrophil responses to the agonists, complement fragment C5a, IL-8, granulocyte macrophage-colony stimulating factor, formyl-Met-Leu-Phe, PMA, A23187 and arachidonic acid were also inhibited. A similar selectivity was seen for neutrophil responses to leukotriene B4. The anti-inflammatory effects of NT8 were confirmed in vivo in a mouse model of LPS-induced peritonitis, where both TNF and neutrophils play an important role. The research in this thesis has enabled the development and characterization of a new class of quinoline based compounds with anti-inflammation properties distinguishable from those of CQ and HCQ, thus, providing a new avenue for the development of anti-inflammatory agents.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2010
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Cheng, Lin-Chieh, and 鄭琳潔. "Cu-Catalyzed Aerobic Oxidation in the Synthesis of Quinolinium Salts from Secondary Amines, Alkynes, Formaldehyde and Acid." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/dg5crz.
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碩士國立清華大學
化學系所
106
Substituted heterocyclic nitrogen salts are versatile building blocks for a number of natural products and bioactive motifs. Herein, we report a novel and convenient process to synthesize quinolinium salt derivatives by Cu-catalyzed aerobic oxidative coupling of secondary amine, alkyne and formaldehyde. The reaction proceeds via acid induced N,N-disubstituted iminium ion formation followed by nucleophilic addition of alkyne, annulation, and copper-promoted oxidation. This method features an economical catalyst, one pot process, ambient reaction temperature and short reaction time.
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Chou, Chein-an, and 周建安. "Complexation of camphor sulfonic acid to affect the emission behavior of organic compound and polymer with quinoline moiety." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/09652709812360188133.
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碩士國立中山大學
材料與光電科學學系研究所
98
Many chromophoric organics and polymers are highly emissive in their dilute solutions but become weakly luminescent in the high concentration and solid film states due to the induced π−π interactions of the intimately-contact chromophores. Therefore, it is practically important to develop fluorescent organic and polymeric materials with enhanced emission in their aggregated states (so called aggregated-induced emission, AIE). In this study, organic compound 2,4-diphenylquinoline (DPQ) with inherent quinoline ring and polymeric poly(vinyl diphenylquinoline) (PVQ) with pendant quinoline group were prepared and their AIE-phenomena were characterized. To prove the reported point that restriction of intramolecular rotation (RIR) is the main cause for AIE effect, DPQ and PVQ were further incorporated with organic strong acid of camphorsulfonic acid (CSA). Through the favorable acid-base interaction between the sulfonic acid in CSA and the nitrogen atom of the quinoline ring in DPA (or CSA), ionic complex of DPQ-CSA (and PVQ-CSA) was easily prepared and their response toward AIE properties were studied. Through the enhanced RIR by the complexation of bulky CSA with the central quinoline ring, the resulting DPQ-CSA (and PVQ-CSA) complex was proved to have better AIE-effect compared to the pristine DPQ (and PVQ). RIR mechanism can be indirectly proved in this case. We study the AIE on micelle topics of the block copolymer. We choose the poly(styrene-block-tertbutylstyrene) (PS-b-PBS) as our block copolymer. To synthesize the PS-b-PBS, we can successfully get the new block copolymer PVQ-b-PBS. PVQ-b-PBS was similarly blended with the CSA. In the block copolymer micelles, choose the selective solvent to get the different micelles and observe the diverse on the luminescence. Finally, we analyzed compositions and conformations by atomic force microscopy (AFM) and transmission electron microscopy (TEM).
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Rong, Dawen, Victoria A. Phillips, R. S. Rubio, Castro M. Angeles, and Richard T. Wheelhouse. "A safe, convenient and efficient method for the preparation of heterocyclic N-oxides using urea-hydrogen peroxide." 2008. http://hdl.handle.net/10454/6160.
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A novel, convenient, and high-yielding method has been developed for the preparation of heterocyclic N-oxides. The reaction uses the urea·hydrogen peroxide addition complex as a peroxide source for the in situ generation of trifluoroperacetic acid. The advantages of this method are easy handling of a stable, solid oxidant; high yields and simple removal of excess reagents and by-products.
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Wang, Yi-Ju, and 王以如. "具關節炎用藥潛能之2-Quinoline-4-carboxylic Acid類似物之合成." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/59577328372717768347.
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Лагрон, Аліса Вадимівна. "Синтез і властивості 4-гідразинохінолінів та їх іліденогідразинопохідних." Магістерська робота, 2020. https://dspace.znu.edu.ua/jspui/handle/12345/4201.
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Лагрон А. В. Синтез і властивості 4-гідразинохінолінів та їх іліденогідразинопохідних : кваліфікаційна робота магістра спеціальності 102 "Хімія" / наук. керівник О. А. Бражко. Запоріжжя : ЗНУ, 2020. 72 с.UA : В роботі 72 сторінки, 2 таблиці, 38 рисунків, було використано 65 літературних джерела, 20 з них на іноземній мові. Об’єктом дослідження є (хінолін-4-ілгідразон)-карбонові кислоти та їх функціональні похідні. Предметом дослідження є синтез, ідентифікація та фізико-хімічні властивості (хінолін-4-ілгідразон)-карбонових кислот та їх солей, естерів (температура плавлення, ТШХ). Мета роботи: синтезувати та вивчити фізико-хімічні властивості (хінолін-4-ілгідразон)-карбонових кислот та їх похідних, як потенційних біорегуляторів. Методи досліджень та апаратура – теоретичний, розрахунковий, експериментальний, ваги, піщана баня, хімічний посуд, прилад для визначення температури плавлення, хроматографічна камера, програмне забезпечення ACD-і-LABS, ChemOffice, PASS Online. В результаті експериментальної було розроблено оптимальні методики синтезу 4-гідразинохінолінів та (хінолін-4-ілгідразон)-карбонових кислот і їх функціональних похідних (солей, естерів), також проведено ідентифікацію отриманих сполук. Було вивчено фізико-хімічні властивості синтезованих сполук та їх перспективність, як потенційно біологічно активних речовин.
EN : This work consists of 72 pages, 2 tables, 38 figures, 65 literary sources were used, of which 20 were in a foreign language. The object of the study is (quinolin-4-ylhydrazone)-carboxylic acids and their functional derivatives. The subject of the study is the synthesis, identification and physicochemical properties of (quinolin-4-ylhydrazone) -carboxylic acids and their salts, esters (melting point, TLC). The aim of the work was to synthesize and study the physicochemical properties (quinolin-4-ylhydrazone)-carboxylic acids and their derivatives as potential bioregulators. Research methods and equipment – theoretical, estimated, experimental, scales, sand bath, chemical utensils, melting temperature determination device, chromatographic chamber, ACD-i-LABS software, ChemOffice, PASS Online. As a result of experimental research, optimal methods for the synthesis of 4-hydrazinoquinolines and (quinolin-4-ylhydrazone) -carboxylic acids and their functional derivatives (salts, esters) were developed, and the obtained compounds were identified. The physicochemical properties of the synthesized compounds and their prospects as potentially biologically active substances were studied.