Academic literature on the topic 'Isoxazolones'

The first step in the photochemical decarboxylation of isoxazolones is the formation of the triplet state of the isoxazolone. We present evidence for the first time from flash laser photolysis of the lifetime of such species, and examples of their capture by solvent and by intramolecular cycloaddition.

Several approaches to the synthesis of derivatives of the antifungal antibiotic TAN-950A, which is also an agonist of glutamate at hippocampal neurons, are reported. Additions of isoxazolon-4-yl anions to methyleneoxazolidinones were not useful because addition occurred predominantly through N-2. Similarly addition of the isoxazolon-4-yl radicals to model Michael acceptors occurred predominantly through N-2. Racemic analogues of TAN-950A were prepared by reaction of isoxazolone Mannich bases with acetylaminomalonate or addition of β-ketoester anions to dehydroalanines. The best approach to enantiomerically pure analogues was by acylation of pyroglutamates, followed by reaction with hydroxylamine.

This study examined the effect influence of various factors on the extraction of Pd(II) to develop a new liquid-liquid extraction mechanism for the selective separation of palladium(II) from its acidic chloride solutions using 4-aroyl-3-phenyl-5-isoxazolones (HA), such as 3-phenyl-4-(4-fluorobenzoyl)-5- isoxazolone (HFBPI), 3-phenyl-4-benzoyl-5-isoxazolone (HPBI) and 3-phenyl-4- (4-toluoyl)-5-isoxazolone (HTPI). The extraction strength of Pd(II) with HA were in the following order: HFBPI > HPBI > HTPI, which is opposite to that observed with their pKavalues. HPBI was used to separate Pd(II) from Pt(IV), Ni(II) and Rh(III) metal ions and calculated their separation factors (S.F.) were followed in the order: Pd/Ni (40±0.4) > Pd/Pt (25±0.2) > Pd/Rh (15±0.3 > Rh/Ni (2.7±0.3) > Pt/Ni ≈ Rh/Pt (1.7±0.2). The loading and striping of Pd(II) (1.12×10-4mol L-1) were also examined using 1.0×10-3mol L-1HPBI in CHCl3and 1.0 mol L-1HCl, respectively. The results demonstrated that the maximum (97.5%) extraction and desorption (89%) of metal required at least 3.0 cycles. The developed method was applied successfully to the separation of palladium from synthetic water samples.

The development of effective, nontoxic antifungal agents is one of the most important challenges for medicinal chemistry. A series of isoxazolo [3,4-b]pyridine-3(1H)-one derivatives previously synthesized in our laboratory demonstrated promising antifungal properties. The main goal of this study was to investigate their retention behavior in a human serum proteins-high-performance liquid chromatography (HSA-HPLC) system and explore the molecular mechanism of HSA-isoxazolone interactions using a quantitative structure–retention relationship (QSRR) approach. In order to realize this goal, multiple linear regression (MLR) modeling has been performed. The proposed QSRR models presented correlation between experimentally determined lipophilicity and computational theoretical molecular descriptors derived from Dragon 7.0 (Talete, Milan, Italy) software on the affinity of isoxazolones to HSA. The calculated plasma protein binding (PreADMET software) as well as chromatographic lipophilicity (logkw) and phospholipophilicity (CHIIAM) parameters were statistically evaluated in relation to the determined experimental HAS affinities (logkHSA). The proposed model met the Tropsha et al. criteria R2 > 0.6 and Q2 > 0.5 These results indicate that the obtained model can be useful in the prediction of an affinity to HSA for isoxazolone derivatives and they can be considered as an attractive alternative to HSA-HPLC experiments.

The reaction of 1,4-dichlorophthalazine and 2,3-dichloroquinoxaline with some isoxazolones gave their mono- and bis-isoxazolinyl derivatives. The base-catalyzed rearrangement of these derivatives afforded the corresponding tri- and tetracyclic heterocycles.

The flash vacuum pyrolysis method of synthesis of acetylenes from aldehydes via isoxazolones is a convenient method for the preparation of a variety of derivatives, including kinetically unstable, sensitive compounds such as the ethynylphenols.

Sur la plateforme de thèses en ligne Tel on trouve le résumé suivant en français : La synthèse d'alcynes en utilisant des isoxazolones comme précurseurs a été une méthode développée dans notre laboratoire dans ler dernières années. Nous avons appliqué cette méthodologie pour la synthèse de 3-alkynylamides et leur utilisation pour générer des dihydropyrrolones. Nous avons aussi développé de nouvelles réactions catalysées pour complexes d'or(I): la synthèse de 4-oxazol-2-ones à partir de Boc-ynamides, une séquence de transfert 1,5 d'hydrure et cyclisation pour former des éther cycliques et la formation de dérivés de cinnolines. Nous avons aussi développé un étude mecanistique concernant l'effet de deux contre-ions usuellement utilisés dans la cycloisomérization de 1,6-enynes catalysée à l'or: le NTf2 et SbF6. L'influence de groupes loin de la partie alcène a aussi été remarquée et étudiée en plus grand détail. Également, une première investigation vers l'identification d'un catalyseur permettant l'accès à des cycles à 6-chaînons a été réalisée (Ce qui est le résultat moins souvent observé pour ce type de réaction, où le cycle à 5-chaînons est généralement obtenu)
Ur la plateforme de thèses en ligne Tel on trouve le résumé suivant en anglais : The synthesis of alkynes using isoxazolones as precursors has been one of the methods studied by our laboratory in the last years. We have applied this methodology in the synthesis of 3-alkynylamides and their use to generate dihydropyrrolones. We have also developped new reactions catalyzed by Gold(I) complexes: the synthesis of 4-oxazol-2-ones from Boc-ynamides, a 1,5hydride/cyclization sequence affording carbocyclic ether structures and the formation of cinnoline derivatives. We have also developped a mechanistic study concerning the effect of two common counter-ions employed in gold-mediated cycloisomerization of 1,6-enynes: NTf2 and SbF6. The remote influence of the substituent on the alkene moiety was identified and studied in more detail. In the same way, a first investigation towards the identification of a catalyst allowing access to 6-membered cycles was performed (This outcome is less frequently observed, as 5-membered rings are usually obtained in these processes)

La synthèse d'alcynes en utilisant des isoxazolones comme précurseurs a été une méthode développée dans notre laboratoire dans ler dernières années. Nous avons appliqué cette méthodologie pour la synthèse de 3-alkynylamides et leur utilisation pour générer des dihydropyrrolones. Nous avons aussi développé de nouvelles réactions catalysées pour complexes d'or(I): la synthèse de 4-oxazol-2-ones à partir de Boc-ynamides, une séquence de transfert 1,5 d'hydrure et cyclisation pour former des éther cycliques et la formation de dérivés de cinnolines. Nous avons aussi développé un étude mecanistique concernant l'effet de deux contre-ions usuellement utilisés dans la cycloisomérization de 1,6-enynes catalysée à l'or: le NTf2 et SbF6. L'influence de groupes loin de la partie alcène a aussi été remarquée et étudiée en plus grand détail. Également, une première investigation vers l'identification d'un catalyseur permettant l'accès à des cycles à 6-chaînons a été réalisée (Ce qui est le résultat moins souvent observé pour ce type de réaction, où le cycle à 5-chaînons est généralement obtenu).

碩士
國立臺灣科技大學
纖維及高分子工程系
90
In this study, the reaction of Hydroxylamine hydrochloride with Benzoylacetic acid ethyl ester and Ethyl acetoacetate was shown to give compounds 3 and 6. First, a solution of compound 3 and 6 in ethanol was condensed with aromatic aldehyde derivatives by presence of basic catalyst was shown to give compounds 8a~8f and 9a~9b. Second, a solution of compound 3 and 6 were coupled with aromatic benzylamine derivatives. Finally, these compound were determined the structure by spectrometry（UV、FTIR、1H-NMR） and element analysis（EA）.

DESIGN AND SYNTHESIS OF HUMAN NEUTROPHIL ELASTASE (HNE) INHIBITORS Dottorato in area del Farmaco e Trattamenti Innovativi PhD student: Antonella Iacovone Scientific tutor: Prof.ssa Maria Paola Giovannoni Theoretical tutor: Prof.ssa Elisabetta Teodori Human Neutrophil Elastase (HNE) is an enzyme belonging to the family of serine proteases. It is a small, soluble and basic glycoprotein of approximately 30 kDa containing 218 amino acid residues that are stabilized by four disulfide bridges. HNE carries out its activity through the catalytic triad, consisting of Ser195, His57 and Asp102. It is involved in the killing of pathogens, in the regulation of inflammation and tissue homeostasis due to its proteolytic action against a variety of extracellular matrix proteins, such as elastin, collagen, fibronectin, laminin, and proteoglycans. In physiological conditions, HNE proteolytic activity is regulated by endogenous inhibitors belonging to the serpins family, including α1-antitripsin (α1-AT), α2-macroglobuline, elafin and secretory leucocyte protease inhibitor (SLPI). Alteration of the balance between HNE and serpins activity can contribute to the develop or the worsening of certain pathologies, especially affecting the respiratory system. The main pulmonary diseases involving HNE are chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), acute respiratory distress syndrome (ARDS) and acute lung injury (ALI). Additionally, HNE is also involved in other inflammatory disorders including psoriasis, dermatitis, atherosclerosis, rheumatoid arthritis and various types of cancer. Many examples of peptide and non-peptide HNE inhibitors have been reported in the literature, however, only two drugs are currently available for clinical use: Prolastin (purified α1-AT), a peptide drug synthetized by recombinant DNA techniques and used for the treatment of α1-antitripsin deficiency (AATD) and Sivelestat (Elaspol®100), a low molecular weight non-peptide molecule. The use of Sivelestat for the treatment of acute lung injury associated with systemic inflammation is approved only in Japan and Korea. The research performed in this period as a PhD student consisted in the design and synthesis of new potential HNE inhibitors. In particular, on one side we focused on the synthesis of compounds with 7-azaindole structure, as isomers of the potent indazoles, previously investigated in our research group. On the other side, we moved our attention on the investigation of new small and flexible compounds with isoxazol-5(2H)-one scaffold; additionally we synthetized some products with benzo[c]isoxazol-3(1H)-one nucleus, as elaboration of the isoxazolone derivatives. All new products were tested as HNE inhibitors in the laboratory of Prof. Quinn, Montana University, and many of these compounds have proved to be very potent inhibitors, recording activity values in the nanomolar range. On selected isoxazolones derivatives molecular modeling studies were performed to clarify the interaction with the target enzyme, as well as studies on stability in aqueous buffer and on kinetic of HNE inhibition. References 1. Hoenderdos, K.; Condliffe, A. The neutrophil in chronic obstructive pulmonary diseases. Am. J. Respir. Cell. Mol. Biol. 2013, 48, 531-539. 2. Cools-Lartigue, J.; Spicer, J.; Najmeh, S.; Ferri, L. Neutrophil extracellular traps in cancer progression. Cell. Mol. Life Sci. 2014, 71, 4179-4194. 3. Pham, C. T. Neutrophil serine proteases: specific regulators of inflammation. Nat. Rev. Immunol. 2006, 6, 541-550. 4. Crocetti, L.; Giovannoni, M. P.; Schepetkin, I. A.; Quinn, M. T.; Khlebnikov, A. I.; Cilibrizzi, A.; Dal Piaz, V.; Graziano, A.; Vergelli, C. Design, synthesis and evaluation of N-benzoylindazole derivatives and analogues as inhibitors of human neutrophil elastase. Bioorg. Med. Chem. 2011, 19, 4460-4472. 5. Crocetti, L.; Schepetkin, I. A.; Cilibrizzi, A.; Graziano, A.; Vergelli, C.; Giomi, D.; Khlebnikov, A. I.; Quinn, M. T.; Giovannoni, M. P. Optimization of N-benzoylindazole derivatives as inhibitors of human neutrophil elastase. J. Med. Chem. 2013, 56, 6259-6272. 6. Giovannoni, M. P.; Schepetkin, I. A.; Crocetti, L.; Ciciani, G.; Cilibrizzi, A.; Guerrini, G.; Khelebnikov, A. I.; Quinn, M. I.; Vergelli, C. Cinnoline derivatives as human neutrophil elastase inhibitors. J. Enz. Inhib. Med. Chem. 2016, 31(4), 628-639. 7. Crocetti, L.; Schepetkin, I. A.; Ciciani, G.; Giovannoni, M. P.; Guerrini, G.; Iacovone, A.; Khlebnikov, A. I.; Kirpotina, L. N.; Quinn, M. T. Synthesis and farmacological evaluation of indole derivative as deaza analogues of potent human neutrophil elastase inhibitors. Drug Dev. Res. 2016, 77(6), 285-289. 8. Vergelli, C.; Schepetkin, I. A.; Crocetti, L.; Iacovone, A.; Giovannoni, M. P.; Guerrini, G.; Khlebnikov, A.I.; Ciattini, S.; Ciciani, G.; Quinn, M. T. Isoxazol-5(2H)-one: a new scaffold for potent human neutrophil elastase (HNE) inhibitors. J. Enz. Inhib. Med. Chem. 2017, 32(1), 821-831. SOLID PHASE PEPTIDE SYNTHESIS OF SMALL PEPTIDE-BASED METAL CHELATORS Supervisor: Professor Robert Hider During the last year of PhD, a visiting period at King’s College of London was spent. The host research group of Professor Robert Hider is involved for many years in the design and synthesis of Iron and Gallium chelators. In particular, as regard the Iron chelators they follow two main project. The first one concerns the synthesis of small molecules used for the treatment of the pathologies characterized by an iron overload including hemochromatosis and transfusion-dependent thalassemia; the second one concerns the synthesis of peptide as novel biosensors for the mitochondrial Labile Iron Pool (LIP) in order to better understand the role of the LIP in mitochondrial oxidative disorders. About the gallium chelators, peptide molecules have recently been developed as radiopharmaceuticals for PET imaging in particular to detect and monitor prostate cancer. In this context, the entrusted project focused on the solid-phase synthesis of tripeptide (Lys-Lys-Lys) and tetrapeptide (Lys-Lys-Lys-Lys) derivatives bearing 3,4-dihydroxy picolinic acid and the 3-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)propionic acid (as chelating groups) on the amino groups of the side chains. All final compounds will be tested in the near future as iron and gallium chelators for biological and clinical applications. References 1. Hider R. C.; Zhou T. The design of orally active iron chelators. Ann N. Y. Acad. Sci. 2005, 1054, 141-154. 2. Abbate, V.; Reelfs, O.; Hider, R. C.; Pourzand, C. Design of novel fluorescent mitochondria-targeted peptides with iron selective sensing activity. Biochem. J. 2015, 469 (3), 357-366. 3. Cusnir, R.; Imberti, C.; Hider, R. C.; Blower, P. J.; Ma, M.T. Hydroxypyridinone chelators: from iron scavenging to radiopharmaceuticals for PET imaging with Gallium-68. J. Mol. Sci. 2017, 18, 116.

Die Arbeit beschreibt neuartige Isocyanat- und Initiierungsreaktionen von speziellen Basen mit dem Imin-Strukturinkrement. Gegenstand des ersten Teils ist die Synthese und Charakterisierung neuer Imidazolin-Isocyanat-Adduksysteme, welche genutzt werden um organische Netzwerke auf der Basis von 1-Ethylimidazolin und diversen Diisocyanaten aufzubauen. Ferner wurden die unterschiedlichen Adduktsysteme hinsichtlich ihrer Anwendbarkeit als blockierte Isocyanate untersucht. Hierzu wurden thermische Analysen wie DSC- und TG-MS-Messungen durchgeführt. Durch experimentelle Ergebnisse und quantenchemische Rechnungen konnte ein neuartiger Reaktionsmechanismus einer Adduktbildung gefunden werden. Die Imidazolin-Isocyanat-Adduktnetzwerke wurden als Macroinitiatoren für die radikalische Polymerisation von Methylmethacrylat (MMA) verwendet, wodurch Adduktnetzwerk-PMMA-Kompositmaterialien erhalten wurden. Gegenstand des zweiten Teils dieser Arbeit ist die Entwicklung eines neuartigen Initiatorsystems für die radikalische Polymerisation von MMA und Styrol, auf der Grundlage der Iminbase-(Meth-)Acrylat-induzierten Polymerisation (IBA-Polymerisation). Hierzu wurden unterschiedlich substituierte Isoxazolone synthetisiert und als Starter für die Polymerisation eingesetzt. Der radikalische Charakter der Polymerisation wurde mittels Copolymerisationsexperimenten belegt.:Abkürzungsverzeichnis 1. Einleitung und Zielsetzung 1.1. Einleitung 1.2. Zielsetzung und Motivation 2. Theoretische Grundlagen 2.1. Isocyanat-Imidazolin-Adduktsysteme als blockierte Isocyanate 2.1.1. Blockierte Isocyanate 2.1.2. Iminbasen-Isocyanat-Addukte 2.2. Radikalische Polymerisation 2.2.2. Autoinitiierung von Styrol und Methylmethacrylat 2.2.3. Definition der IBA- und IBI-Polymerisation 3. Ergebnisse und Diskussion 3.1. Isocyanat-Imidazolin-Adduktsysteme als blockierte Isocyanate 3.1.1. 3 : 1-Isocyanat-Imidazolin-Addukte basierend auf 1-Ethylimidazolin 3.1.2. Organische Netzwerke basierend auf 3 : 1-Isocyanat-Imidazolin-Addukten 3.1.3. 2 : 1-Isocyanat-Imidazolin-Addukte basierend auf 1-Ethyl-2-iso-propyl-imidazolin 3.1.4. 2 : 1-Isocyanat-Imidazolin-Addukte basierend auf 1-Ethyl-2-methyl-imidazolin 3.2. IBA-Polymerisation mittels Isoxazolonen 3.2.1. Tautormerie und thermische Analysen von Isoxazolonderivaten 3.2.2. Polymerisation von Acrylatmonomeren mit Isoxazolonen 3.2.3. Kinetik der IBA-Polymerisation mit Isoxazolonen 3.2.4. IBA-Polymerisation von Styrol mit 3-Phenyl-5-isoxazolon 3.2.5. Mechanistische Studien der IBA-Polymerisation initiiert durch Isoxazolone 4. Zusammenfassung und Ausblick 5. Experimenteller Teil 5.1. Geräte und Chemikalien 5.2. Synthese der Iminbasen 5.3. Synthese der Iminbase–Isocyanat–Addukte 5.4. Synthese der 3 : 1 Adduktnetzwerke 5.5. Synthese von Isoxazolonderivaten 5.6. Polymerisationen von MMA und Styrol mit Isoxazolonen 6. Literatur 7. Anhang Danksagung Lebenslauf Liste an Veröffentlichungen Selbstständigkeitserklärung