Inaugural-Dissertation--Berlin, 1897. / Vita.

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The study of some acylurea derivatives of 2-amino-3-alkylamino- and -3-arylamino-1,4-naphthoquinones was undertaken to determine the course of reaction under conditions similar to those used by J. R. Hoover and A. R. Day to prepare 2-alkyl-1H-naphth[2,3-d] imidazole-4.9-diones from 2-acylamino-3-amino-1,4-naphthoquinones.

The major forms of cytochrome P-450 protein induced by phenobarbital (P-450[b]) and 3-methylcholanthrene (P-450[c]) have been isolated, purified to electrophoretic homogeneity and fully characterised with respect to substrate specificity. The purified cytochrome P-450[c] was used as antigen in the preparation of sheep polyclonal antibodies, which were used for the immunological detection, characterisation and quantification of the haemoprotein. The N1-substituted antifungal agents, ketoconazole, miconazole and clotrimazole, have been shown to be potent in vitro inhibitors of both the phenobarbital-induced cytochrome P-450- and the 3-methylcholanthrene-induced cytochrome P-448-dependent rat hepatic mixed-function oxidases. All three drugs were more potent inhibitors of the phenobarbital-induced activities in microsomal systems, as well as in reconstituted systems comprising purified NADPH-cytochrome P-450 reductase and cytochrome P-450[b] or P-450[c]. Ketoconazole was the weakest inhibitor and the least selective for the former haemoprotein. All three antimycotic agents elicited type II difference spectra with microsomes from both phenobarbital- and 3-methylcholanthrene-induced rats, as well as with both purified haemoprotein preparations. Miconazole and clotrimazole, and to a lesser extent ketoconazole, have been shown to decrease the magnitude of the type I spectral perturbation of hexobarbital with phenobarbital-induced microsomes. These observations indicate that, although the primary mechanism of inhibition involves reversible binding to haem, an additional interaction with the apoprotein or substrate (type I) binding site is involved and may contribute to the isoenzyme selectivity displayed by all three compounds. When administered systemically to rats, all three antifungal agents stimulated the hepatic microsomal mixed-function oxidases, particularly those activities associated with the phenobarbital and/or pregnenolone-16a-carbonitrile-induced cytochromes P-450. This was confirmed by Western blotting employing anti-cytochrome P-450[p] (PB[2C]) and anti-cytochrome P-450[b]. Administration of the planar benzimidazole 2-amino-3-methylimidazo-(4,5-f)-quinoline (IQ), a food mutagen and carcinogen, in contrast to the globular antifungal agents, selectively induced the cytochromes P-448, especially the high spin form (cytochrome P-450[d]).

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Thèse--Méd.--Reims, 1972. / Bibliogr. p. 67.

<p> Nitric oxide has been implicated in a number of biological processes, the majority of them involving iron nitrosyl complexes. The urgency then is to further study and characterize these complexes to further the understanding of biological mechanisms. However, the chemical sensitivity of these species precludes the purification and isolation of these compounds which, unfortunately, has directed the trend to merely detecting the presence of these compounds rather than isolating them. To this day, a large number of Electron Paramagnetic Resonance (EPR) detectable, biological compounds have not been isolated.</p> <p> To this end, the series of biologically relevant compounds of the form Fe(NO)2(L)2 [ L = imidazole 1, 1-methylimidazole (1-MeIm) 2, 4-methylimidazole (4-MeIm) 3, benzimidazole (benzim) 4, and 5,6-dimethylbenzimidazole (56benzim) 5 ] have been synthesized by direct reaction of the appropriate imidazole ligand with Fe(NO)2(CO)2. The compounds were extremely air sensitive, both in solution and as a dry solid. This hindered attempts to purify these compounds and so, infra red (IR), nuclear magnetic resonance (NMR) and EPR spectroscopic studies were undertaken of 2:1 reaction mixtures of the appropriate imidazole ligand and Fe(NO)2(CO)2. These studies revealed that the rapid substitution of the carbonyl ligands is facilitated by a catalytic, 17-electron, electron transfer chain mechanism (ETC), where the imidazole ligand acts to oxidize the 18-electron complex into the active 17-electron Fe(NO)2(CO)2+ species.</p> <p> In the course of the EPR study of 2, crystals formed that were suitable for single-crystal, X-ray diffraction. The compound crystallizes with a monoclinic unit cell, in the C2/c space group with unit cell dimensions: a= 13.985(5) Å, b = 11.529 (5) Å, c = 15.471(4) Å, α= 90°, β= 91.72(2)°, γ = 90°, V = 2493(2) Å^3, Z = 8. During the course of study of 6, crystals suitable for single crystal X-ray diffraction were obtained. The compound crystalizes with a monoclinic unit cell, in the P2/c space group and unit cell dimensions: a= 11.707(9) Å, b = 8.1783 (5) Å, c = 17.2489 (13) Å, α= 90°, β= 106.562 (1)°, γ = 90°, V = 1583.0 (2) Å^3 A, Z = 2.</p> <p> A relatively new mass spectrometry (MS) procedure was utilized for the reaction mixtures of 1 - 5, which involved a combination of electrochemical oxidation and electrospray. The method proved very useful, yielding data that could not be obtained by other MS techniques. Oligomeric species of the form L-[(Fe(NO)2L]x (x = 2,3,4,5 or 6), were also detected by MS for each compound reaction mixture. The oligomers involved linear chains of iron dinitrosyl fragments linked via the imidazole nitrogens. However, it is believed that these oligomers are produced as a result of the conditions met by the mass spectrometer.</p> <p> A reaction of Fe(NO)2(PPh3)(CO) with 1-MeIm was also performed in hopes of producing a more stable mono-substituted complex. However, the reaction also proceeded via an Electron Transfer Chain (ETC) pathway to produce Fe(NO)2(PPh3)2 6.</p> / Thesis / Master of Science (MSc)

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Deux sujets indépendants ont été traités dans ce manuscrit.Dans une première partie a été étudiée la possibilité d'obtenir des synthons chiraux à partir de la pyridine. Pour cela nous avons dans un premier temps développé une méthode originale de quaternisation des sels de pyridium et d'imidazoliums grâce à une réaction de Mitsonubu. Par la suite, des 2-aminopyridines ont été substituées puis engagées dans une réaction de quaternisation-réduction conduisant à des composants saturés. Malheureusement, des composés n'ont pu conduire aux synthons linéaires envisagés.Dans une seconde partie, nous nous sommes intéressés au développement d'un nouveau type de peptidomimétique dans lequel le lien amide est remplacé par un cycle imidazolique, ceci dans la continuité de travaux menés dans notre équipe. Dans un premier temps, nous nous sommes focalisés sur la mise au point de conditions efficaces menant au mime considéré. Cette méthodologie nous a permis la synthèse de plusieurs dipeptides. / Two different topics will be discussed in this work.In the first part has been studied the possibility to obtain chiral building-blocks from pyridine. For this purpose, we intially developed an original method for quartenization of pyridium and imidazolium salts through a Mitsonubu reaction. Then, 2-aminopyridines were substituted and then engaged in a quaternization-reduction reaction, leading to satured compounds. Unfortunately, these compounds have not leaded to targeted linear building-blocks.In a second part, we have been interested in the deveopment of a new peptidomimetic family in which the amide bond is replaced by an imidazole ring, extension of previous work in our research group. Initially we focused on the development of conditions leading to considered mimic. This methodology has allowed us the synthesis of several dipetides incorporating our mimic with good results. The determination of acido-basic properties of these structures has also been investigated.