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Memoria para optar al título de Químico / Los valores experimentales de los potenciales de reducción de la familia de nitroimidazoles sustituidos están en el rango de -80 y -550 mV. Estos valores fueron correlacionados con los calculados usando la teoría de funcionales de la densidad. Las estructuras optimizadas, los potenciales de reducción y los pKa calculados fueron obtenidos utilizando la funcional hibrida B3LYP y la base orbital D95. Se realizó un análisis de las estructuras obtenidas para cada etapa del proceso de reducción encontrándose una relación entre la conjugación de los dobles enlaces del sistema y el valor de los potenciales de reducción. El mecanismo propuesto en la memoria en base a los potenciales calculados difiere en dos pasos a los determinados experimentalmente por Laviron. / The experimental values of the reduction potentials of a substituted nitroimidazole family are between -80 to -550 mV. These values were correlated with the reduction potentials calculated using the density functional theory. The optimized geometries, the predicted reduction potentials and pKa were obtained using the B3LYP hybrid functional and the basis sets D95. The structural analysis of the molecules obtain for different stages of the reduction process show a relation between the double bond conjugation of the system and the calculated reduction potentials. The proposed mechanism in this thesis based on the calculated reduction potentials differs in two steps to that experimentally determinated by Laviron.

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Se realizó un estudio voltamétrico de dos compuestos 4-nitroimidazólicos los que presentan diferentes substituyentes (-H, -CH3) en la posición 1 del anillo imidazólico. Se determinó el comportamiento electroquímico en medio EtOH/Britton Robinson, DMF/Citrato y 100% DMF mediante técnicas de polarografía de pulso diferencial, polarografía tast y voltametría cíclica. La reducción en medio EtOH/Britton Robinson produce a pHs básicos una señal de carácter reversible en ambos compuestos, la cual al ser estudiada por voltametría cíclica es atribuida a la formación del anión radical nitro, posibilitando medir las constantes de decaimiento de estos radicales. Además los potenciales de reducción del compuesto con el substituyente metil en la posición 1 resultaron ser menos negativos. En medio DMF/Citrato fue posible medir las constantes de decaimiento solamente del compuesto con el substituyente metil en la posición 1, debido a la imposibilidad de aislar la señal correspondiente a la formación de anión radical nitro en el otro compuesto. Además, las constantes de decaimiento obtenidas para el compuesto en estudio resultaron ser mayores a las obtenidas por este mismo compuesto en medio EtOH/Britton Robinson.

Misonidazole (Ro 07-0582) is a nitroheterocyclic drug which sensitizes hypoxic (oxygen-deficient) cells to the lethal action of ionising radiation. Tumours contain radioresistant hypoxic cells which may limit the usefulness of radiotherapy as a modality of cancer treatment. The use of misonidazole as an adjunct to radiotherapy may improve the local control of such tumours, and clinical trials are in progress. Misonidazole is selectively toxic to hypoxic cells, even in the absence of radiation. This effect may be related to the clinical toxicity of the drug, which limits the dose of misonidazole which may be delivered safely, and, thus, limits the effectiveness of the radiosensitizer. The selective toxicity of misonidazole is believed to be related to its metabolism in hypoxic cells. Reduction of nitroaromatic compounds, such as nitrobenzene, is inhibited by oxygen; thus, reductive activation of misonidazole to a toxic species may explain the selective action of the drug against hypoxic cells. We have studied the reductive chemistry of misonidazole, and its metabolism, using a variety of chemical and in vitro biological techniques. Ascorbic acid (vitamin C) enhances the toxicity of misonidazole to hypoxic Chinese hamster ovary (CHO) cells. This marked enhancement appears to be caused by accelerated drug metabolism in the presence of ascorbate. Chemical reduction of misonidazole by zinc dust yields a mixture of azo-misonidazole and azoxy-misonidazole. These compounds were separated by preparative reversed-phase liquid chromatography, char- acterized chemically, and tested for in vitro biological activity. Azo-misonidazole is almost non-toxic, but azoxy-misonidazole is more toxic than misonidazole itself. Misonidazole was reduced by the xanthine/xanthine oxidase (XO) system, under hypoxia. This enzymatic reduction yielded a single major product, which appears to be hydroxylamino-misonidazole. The same enzyme system also reduces azo- and azoxy-misonidazole. The metabolic transformation of ¹⁴C-misonidazole was studied, using dense suspensions of CHO cells in hypoxia. Misonidazole is converted into several polar products, and binding to acid-insoluble material (presumably macromolecules) was observed. The organic-soluble metabolite fraction contains a compound with identical chromatographic properties to the xanthine/XO product, believed to be hydroxylamino-misonidazole. The significance of these results is discussed in the context of the clinical potential of misonidazole and related drugs as radiosensitizers. The possibility of exploiting hypoxic cytotoxicity as a selective chemotherapy for hypoxic tumour cells is considered. / Science, Faculty of / Zoology, Department of / Graduate

Despite the clinical importance of anaerobic bacteria in otitis media and the uncertainty regarding the proper treatment of the anaerobic focal infection, few experimental studies focused upon the role of these microorganisms in otitis media have been publis­hed. In the present investigation a guinea-pig model for the induc­tion of anaerobic monoinfections in the middle ear was described. Bacteroides fragilis and Propionibacterium acnes (4.0-10x10 colony forming units) injected via the tympanic membrane were capable of inducing clinical and histological otitis media with persistent seguele in the middle ear cavity. Bacteroides asacc-harolyticus, Peptostreptococcus micros and Peptost repto- coccus anaerobius failed to induce otitis media. B. fragilis otitis was accompanied by increased serum IgG and IgM antibody titres against the challenge organism, whereas P. acnes and P. anaerobius did not induce a humoral immune response. The results suggested true virulence of B. fragilis in guinea-pig middle ear monoinfections. Metronidazole was found to accelerate the elimination of B.fragilis from the middle ear. However, even high doses of metro­nidazole were nojt fully effective perhaps reflecting an incomplete anaerobiosis at the site of infection in some instances. At pre­sent, nitroimidazoles in chronic otitis media must be regarded as a possible alternative reguiring further study, particularly with regard to the dosage. In order to gain further knowledge of the interaction between poly­morphonuclear leukocytes and bacteria under anaerobic conditions an in vitro model was established. It was shown that P. acnes was readily phagocytosed with the aid of C3 activated either via the classical or alternative pathway and that killing of P. acnes was inefficient during anaerobiosis. The results suggest that P.acnes is maintained in the pus in chronic otitis media because it sur­vives phagocytosis. Finally, the interaction between the most common pathogen in acute purulent otitis media, Streptococcus pneumoniae, and human poly­morphonuclear leukocytes under anaerobic conditions was studied. Since purulent maxillary sinus effusion (and probably also purulent middle ear effusion), invariably has a pO^ approaching zero, such studies are highly relevant with regard to the host defence in sinuitis and perhaps also in otitis media. S. pneumoniae was killed by the phagocytes under anaerobic condi­tions although at a slower rate than in air. Degradation of pneumo­coccal teichoic acid, DNA and RNA took place after phagocytosis under aerobic as well as anaerobic conditions, whereas degradation of unsaturated cell membrane lipids took place only under aerobic conditions. Furthermore, the pneumococcal autolytic system did not participate in the killing or the degradation of the bacteria. / <p>Diss. Umeå, Umeå universitet, 1984, härtill 6 uppsatser</p> / digitalisering@umu

Local control of tumours by radiotherapy may fail due to the presence of regions of hypoxic cells. Radiosensitizers, such as nitroimidazoles, enhance killing of the resistant cells by ionizing radiation. However, dose limiting side-effects have prevented the attainment of maximum sensitization. The successful chemotherapeutic drug, cis-diamminedichloroplatinum(II) (cis-DDP), and analogues show moderate radiosensitizing effects, possibly because of binding to DNA. A rationale is then to use the DNA binding property of a metal to carry a sensitizer to the target of radiation damage, DNA, thereby improving the radiosensitizing effect while reducing the toxic side-effects of nitroimidazoles. The complex cis-RuCI₂(dmso)₄ was used as a precursor for synthesis of Ru(II)-nitroimidazole complexes because of its anti-tumour and DNA binding activities. A series of Ru(II) complexes of formulation RuCI₂(dmso)₂Ln, where dmso is S-bonded dimethyl sulphoxide, L = a nitroimidazole, and n=1 or 2, has been synthesized and characterized, and their toxicities and radiosensitizing abilities examined in vitro. When L = 2-nitroimidazole or a substituted-2-nitroimidazole, n = 2, but the nitroimidazole ligands dissociate in aqueous medium. With L = the 5-nitroimidazole, metronidazole, n=2, the sensitizing ability of the six-coordinate cis complex was disappointing with sensitizer enhancement ratio (SER) of 1.2 in hypoxic Chinese hamster ovary (CHO) cells. A series of 4-nitroimidazoles ligands was then studied. With L = 4-nitroimidazole (4-NO₂-Im), 1-(1' -aziridinyl-2' -propanol)-2-methyl-4-nitroimidazole (RSU-1170), 2-(1,2-dimethyl-4-nitroimidazolyl)-2-aminoethanol (RSU-3083), and 1-methyl-4-nitro-5-phenoxyimidazole (RSU-3100), n=2 and the six coordinate complexes appear to be of all cis geometry. The NMe-4-NO₂-Im ligand (n=1) chelates through the imidazole-N and the oxygen of NO₂ group as evidenced from spectroscopic data. Coordination via the nitrito group is uncommon and other examples involving nitroimidazole ligands have not been reported. For the 1-methyl-5-(2'-thioimidazolyl)-4-nitroimidazole (RSU-3159) ligand (n=1), binding to Ru occurs through the thioether and chelation may occur through the imidazole-NCH₃. In this series of Ru(II)-4-nitroimidazole complexes studied, RuC1₂(dmso)₂-NO₂-Im)₂, 5, was the most effective radiosensitizer (SER = 1.6 at 200 ,μM) and is better than the clinically used misonidazole (SER = 1.3 at 200 μM). In addition, 5 did not sensitize oxic CHO cells. Other Ru-N-substituted-4-nitroimidazole complexes gave SER values of 1.1-1.4 at 100-200 μM. Complex 5 also produced a dose-dependent increase in genotoxic activity (as measured by the in vitro induction of chromosome aberrations in CHO cells), which is similar to that of misonidazole but much less than that of c/s-DDP. Two changes in ancillary ligands and geometry of complexes were also examined: replacement of (i) dmso by tmso (tetramethylene sulphoxide), (ii) C1⁻ by Br⁻. The Ru-nitroimidazole complexes were synthesized from the precursors RuCl₂(tmso)₄ and trans-RuBr₂(dmso)₄. In this series of complexes, only RuCl₂(tmso)₂(4-NO₂-Im)₂, 15, and RuCl₂(tmso)₂(SR-2508), 18, have significantly higher SER values (1.6 and 1.5, respectively) than their corresponding nitroimidazole ligands. The tmso complexes of 2-NO₂-Im derivatives were more stable than the dmso series in aqueous solution with respect to the dissociation of the nitroimidazole ligands, which might be due to the improved lipophilicity of tmso complexes. Complex 18. is suggested to be penta-coordinated from XPS and ir data. The RuBr₂(dmso)₂(4-NO₂-Im)₂ was a less effective sensitizer (SER = 1.3 at 200 μM) than the dichloro analogue which may result from different geometrical structures or different behaviour in aqueous solution chemistry. The enhanced radiosensitizing effect over the corresponding free nitroimidazole ligand observed for complexes 5, 15 and 18 may depend on: (a) the metal's ability to target the sensitizer to DNA; complex 5 does bind to DNA, dissociation of C1⁻ perhaps facilitating the reaction; (b) the increase in reduction potential or (c) an increase in lipophilicity of the nitroimidazole ligand on coordination. However, the enhanced radiosensitization does not result from depletion of non-protein thiols. In the present study, the Ru complexes are less toxic than their corresponding nitroimiazole ligands in vitro. The radiosensitization and toxicity of the complexes 5, 15 and 18 are better than those of the free nitroimidazole ligands and the clinically used radiosensitizer, misonidazole. The data encourage further investigations of the use of transition metal complexes as radiosensitizers to combat the hypoxic tumour cells. [Formula Omitted] / Science, Faculty of / Chemistry, Department of / Graduate

L'objectif de ce travail consiste en la synthèse de nouveaux 5-nitroimidazoles fonctionnalisés à visée thérapeutique. Dans un premier temps, l'étude de la réactivité du 4-bromo-1,2-diméthyl-5-nitro-1H-imidazole vis-à-vis du couplage de Suzuki-Miyaura sous irradiation micro-ondes a permis la synthèse de nouveaux produits substitués en position 4 par différents groupements aryle ou styryle. Dans un second temps, la réactivité LD-SRN1 a été étudiée entre le 4-[4-(chlorométhyl)phényl]-1,2-diméthyl-5-nitro-1H-imidazole et différents nucléophiles centrés sur l'atome de carbone ou de soufre. Cette étude a révélé l'importance de la température dans l'activation de la réaction par transfert monoélectronique. De nouveaux dérivés substitués en position 4 par divers groupements sulfonyles ont ensuite été synthétisés, par réactions SN2 et SNAr entre des dérivés 5-nitroimidazolés et différents anions sulfinates. Cette synthèse a été suivie par la mise au point de tests biologiques sur Trichomonas vaginalis. L'activité trichomonacide a été évaluée sur certaines de ces molécules, à l'origine de relations structure-activité montrant l'influence de la position du groupement sulfonyle substituant le noyau 5-nitroimidazole. La dernière partie de ce travail décrit une réaction de O-arylation pallado-catalysée inattendue et originale, d'un dérivé fluoré en série nitro(o-nitrophényl)imidazole impliquant des acides arylboroniques dans les conditions opératoires de la réaction de Suzuki-Miyaura. / The aim of this work consists of the synthesis of new potentially bioactive functionalized 5-nitroimidazoles. Initially, the reactivity study of the 4-bromo-1,2-dimethyl-5-nitro-1H-imidazole under microwave-assisted Suzuki-Miyaura cross-coupling conditions gave new derivatives substituted by various aryl or styryl groups in 4-position. In a second step the 4-[4-(chloromethyl)phenyl]-1,2-dimethyl-5-nitro-1H-imidazole was prepared in order to study LD-SRN1 reactivity with different carbon and sulphur centered nucleophiles. This study pointed the role of the temperature for the electron transfer reactions. Then, new 4-position sulfonyl substituted derivatives were synthesized by SN2 and SNAr reactions between sulfinate anions and three substrates in 5-nitroimidazole series. This synthesis was followed by the development of biological assays on Trichomonas vaginalis. This assay was performed on some of these molecules, which revealed a relation between the structure and the position of the sulfonyl group and the antitrichomonas activity. The last part of this work describes an unexpected and original palladium-catalyzed O-arylation in fluorinated nitro(o-nitrophenyl)imidazole series involving arylboronic acids under Suzuki-Miyaura cross-coupling reaction conditions.