Thesis (Ph. D.)--Illinois State University, 1976. / Title from title page screen, viewed Dec. 7, 2004. Dissertation Committee: H.E. Brockman (chair), M. Neville, A. Richardson, F. Schwalm, D. Weber. Includes bibliographical references (leaves 125-138) and abstract. Also available in print.

Typescript (photocopy) / 164 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physical and Inorganic Chemistry, 1982

3 articles published by author included in back of book / 115 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Physical and Inorganic Chemistry, 1976

Thesis (Ph. D.)--University of Wisconsin--Madison, 1940. / Typescript. Includes abstract and vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 85-87, 105).

<p> Ligand backbones based on xanthene, thioxanthene and acridine (XPB, TXPB and APB) have been targeted as scaffolds for the formation of rare compounds containing Lewis basic phosphine and Lewis acidic borane moieties. The resulting complexes with Pt(O) and Pt(II) reagents are expected to possess diverse reactivity compared to traditional platinum phosphine adducts owing to the strategically appended borane Lewis acid. </p> <p> Two ligands, 2,7-di-(tert-butyl)-4-diphenylboryl-5-diphenylphosphino-9,9dimethylthioxanthene (TXPB) and 2,7-di-(tert-butyl)-4-diphenylboryl-5diphenylphosphino-9,9-dimethylxanthene (XPB), have been synthesized and reacted with the platinum reagents [PtCl2(COD)], [PtMe2(COD)] and [Pt(nbe)3]. In the case of TXPB, two new Pt(II) compounds [PtCl(μ-Cl)(TXPB)] and [PtMePh(TXPB^(Ph,Me))] have been formed, isolated and characterized. In both compounds, X-Ray analysis shows that the S and the P atoms bind to the Pt center drawing the metal into the vicinity of the B group. In [PtCl( μ-Cl)(TXPB)], a chloride is seen to bridge between the Pt and B, whereas [PtMePh(TXPB^(Pb,Me))] shows that a methyl groups has been transferred to the boron with concomitant transfer of a phenyl group to Pt. Reaction with the platinum(O) precursor [Pt(nbe)3] led to formation of an unstable complex, tentatively assigned as [Pt(nbe)TXPB]. Analogous studies with the new xanthene-derived ligand, XPB, led to starkly different results. In the reaction with [PtCl2(COD)], an insoluble product, perhaps a dinuclear complex with bridging chlorides, was formed. No reaction occurred with [PtMe2(COD)], presumably because of non-participation of the 0 ligand. However, with [Pt(nbe)3], a stable complex, [Pt(nbe)2XPB], was observed. </p> <p> Synthesis of a third ligand scaffold APB has been initiated where the pyridine moiety is expected to allow strong chelation of Pt as observed with TXPB. An advanced intermediate AFBr has been synthesised where the backbone has been created through a ring closure reaction positioning two different halides as required for sequential addition of the phosphine and borane groups of the target compound. </p> / Thesis / Master of Science (MSc)

La carbamazépine est une molécule antiépileptique très largement utilisée au point de devenir un marqueur environnemental de l'activité humaine. Elle donne lieu à des réactions d'hypersensibilité particulières, rares mais potentiellement létales, associant manifestations cutanées, hyperéosinophilie et atteintes multi-organiques (DRESS syndrome). Les hypothèses physiopathologiques font principalement appel aux métabolites de la carbamazépine mais la voie métabolique minoritaire des dérivés acridiniques est peu explorée. Les résultats obtenus à partir de stimulations ex vivo en laboratoire indiquent d'une part que l'acridine stimule la sécrétion d'interleukine-5 (facteur de croissance principal des éosinophiles), et d'autre part que la formation d'acridine et d'acridone est possible dans le sang à partir de métabolites primaires (époxyde et iminostilbène). Les données cliniques montrent une diminution des taux sanguins du 9-hydroxyméthyl-10-carbamoylacridan et du rapport acridine/acridone au cours de l'état de DRESS. Le co-traitement par l'acide valproïque majore le taux basal d'IL-5 et oriente en partie le profil métabolique vers celui du DRESS. L'étude de l'action des procédés oxydatifs environnementaux indique que les lits bactériens et le lagunage augmentent le rejet d'acridine. Nos travaux en pharmacologie humaine positionnent l'acridine et l'acridone comme des métabolites sanguins, a minima marqueurs et a maxima acteurs de la physiopathologie du DRESS. L'établissement d'un profil métabolique apparaît justifié lors d'une co-thérapie avec l'acide valproïque chez des patients à terrain atopique. L'acridine semble également être un marqueur environnemental d'intérêt. / Carbamazepine is a very usefull antiepileptic drug, widely used at the point of becoming an environmental marker of human activity. It is giving rise to rare but potentially lethal hypersensitivity reactions, with specific combination of skin manifestations, eosinophilia and multi-organ damage (DRESS syndrome). The pathophysiological hypotheses rely primarily to metabolites of carbamazepine, but the minor pathway of acridinic derivatives is little explored.The results obtained from ex vivo stimulation in our laboratory suggest both that acridine stimulates the secretion of interleukin-5 (main growth factor of eosinophils), and that the formation of acridine and acridone is possible in blood from primary metabolites (epoxide and iminostilbene). Clinical data show a decrease in blood levels of 9-hydroxymethyl-10-carbamoylacridan and in the ratio (acridine / acridone) during the state of DRESS. Co-treatment with valproic acid increases the basal rate of IL-5 and diverts, at least in part, to the metabolic profile of DRESS. The study of the action of environmental oxidative processes indicates that the purification processes by trickling filters and stabilization ponds increase the release of acridine, while activated sludge systems have little impact.Our work in human pharmacology positions acridine and acridone as regular blood metabolites, involved as markers or actors of the pathophysiology of DRESS. The determination of the metabolic profile appears warranted for atopic patients requiring co-therapy with valproic acid. Acridine also appears to be a marker of environmental interest.

Ce travail porte sur la conception de dérivés d'aminoacridine et de quinazoline. Dans une première partie, nous avons préparé des dérivés d'aminoacridine ortho-hydroxyméthylée. Pour synthétiser ces dérivés nous avons mis au point une stratégie efficace et générale mettant en jeu la préparation d'un intermédiaire-clé qui peut ensuite être fonctionnalisé. A partir de ce dernier nous avons préparé des dérivés substitués par un motif guanidine. Nous avons également préparé un dérivé iodé afin d'étudier sa distribution cellulaire par microscopie ionique (SIMS). Les propriétés biologiques (IC50 et distribution cellulaire) de ces nouveaux composés ont été évaluées sur des cellules cancéreuses et les résultats obtenus ont confirmé l'intérêt de cette nouvelle famille d'aminoacridine comme anticancéreux.<br />Dans une seconde partie nous avons mis au point une nouvelle méthodologie de synthèse de 2-alkylamino-4(3H)-quinazolinones. Nous avons ainsi préparé différents dérivés comportant un motif quinazolinone à partir d'amines aromatiques et hétérocycliques. Certains de ces dérivés ont fait l'objet d'études biologiques préliminaires (effet cytostatique, ligand ADN-quadruplex) et les résultats obtenus sont très encourageants.

Ovarian cancer is the fifth leading cause of cancer related deaths among women. Early detection improves the chances of survival following diagnosis, and new imaging modalities have the potential to reduce deaths due to this disease. The confocal microendoscope (CME) is a non-destructive in-vivo imaging device for visualization of the ovaries that operates in real-time. Two components of the CME system are evaluated in this paper, and initial results from an ongoing clinical trial are presented.Fiber-optic imaging bundles are used in the CME imaging catheter to relay images over distances of up to 20 feet. When detecting fluorescent signals from investigated tissue, any fluorescence in the system can potentially reduce contrast in images. The emission and transmission properties of three commercially available fiber optic imaging bundles were evaluated. Emission maps of fluorescence from bundles were generated at multiple excitation wavelengths to determine the profile and amount of fluorescence present in bundles manufactured by Sumitomo, Fujikura, and Schott. Results are also presented that show the variation of transmittance as a function of illumination angle in these bundles. Users of high-resolution fiber-optic imaging bundles should be aware of these properties and take them into account during system design.Contrast is improved in images obtained with the CME through the application of topical dyes. Acridine orange (AO) and SYTO 16 are two fluorescent stains that are used to show the size, shape, and distribution of cell nuclei. Unfortunately, little is known about the effects of these dyes on living tissues. This study was undertaken to evaluate the effects of dye treatment on peritoneal tissues in mice. Seventy-five Balb/c mice were split into five groups of fifteen and given peritoneal injections of dye or saline. The proportions of negative outcomes for the control and test groups were compared using confidence intervals and the Fisher's exact test. No significant difference was determined between the groups. These data provide preliminary results on determining the effect of these dyes on living tissues.Preliminary results of a clinical trial are presented showing in-vivo use of the CME for imaging of the ovaries. This is the first portion of a two part study to demonstrate the clinical diagnosis potential of the CME system. A mobile version of the bench-top CME was modified to be used in the clinic. Fluorescein sodium is used as an initial contrast agent in these studies to demonstrate fluorescence imaging. Twenty patients were successfully imaged, and results of this study have allowed progression to a clinical validation study showing the diagnostic capabilities of the CME.

The interaction of small molecules with DNA has been extensively studied and has produced a large catalogue of molecules that non-covalently bind to DNA though groove binding, intercalation, electrostatics, or a combination of these binding modes. Anthracene, acridine, and carbocyanine-based chromophores have been examined for their DNA binding properties and photo-reactivities. Their planar aromatic structures make them ideal chromophores that can be used to probe DNA structural interactions and binding patterns. We have studied DNA binding and photocleavgage properties of a bisacridine chromophore joined by a 2,6-bis(aminomethyl)pyridine copper-binding linker (Chapter II), a series of 9-aminomethyl anthracene chromophores (Chapters III and IV), both under conditions of high and low ionic strength, as well as a series of pentamethine linked symmetrical carbocyanine dyes (Chapter V). In Chapter II we present data showing that high ionic strength efficiently increases copper(II)-dependent photocleavage of plasmid DNA by the bisacridine based chromophore (419 nm, pH 7.0). In Chapters III and IV, using an pyridine N-substituted 9-(aminomethyl)anthracene (Chapter III), a bis-9-(aminomethyl)anthracene, and its mono 9-(aminomethyl)anthracene analogue (Chapter IV), pUC19 plasmid DNA was photo-converted to highly diffuse DNA fragments (350 nm, pH 7.0) in the presence of 150 mM NaCl and 260 mM KCl. Spectroscopic analyses suggest that the combination of salts promotes a change in DNA helical structure that initiate a switch in anthracene binding mode from intercalation to an external or groove binding interactions. The alteration in DNA structure and binding mode leads to an increase in the anthracene-sensitized production of DNA damaging reactive oxygen species. Finally, in Chapter V, pUC19 plasmid DNA is converted to its nicked circular and linear forms following irradiation of a series of pentamethine linked symmetrical carbocyanines (red light, pH 7.0). The data suggest that the relative levels of photocleavage arise from the different substituents on the nitrogen alkyl side chain and the pentamethine linker.

Submitted by Jean Medeiros (jeanletras@uepb.edu.br) on 2017-10-24T13:09:10Z No. of bitstreams: 1 PDF - Rawny Galdino Gouveia.pdf: 21187770 bytes, checksum: 320540e5f560ea3cbfd7e23034f4444d (MD5) / Approved for entry into archive by Secta BC (secta.csu.bc@uepb.edu.br) on 2017-10-26T16:55:41Z (GMT) No. of bitstreams: 1 PDF - Rawny Galdino Gouveia.pdf: 21187770 bytes, checksum: 320540e5f560ea3cbfd7e23034f4444d (MD5) / Made available in DSpace on 2017-10-26T16:55:41Z (GMT). No. of bitstreams: 1 PDF - Rawny Galdino Gouveia.pdf: 21187770 bytes, checksum: 320540e5f560ea3cbfd7e23034f4444d (MD5) Previous issue date: 2017-02-24 / Among the main alternatives for cancer treatment, chemotherapy is one of them, but most chemotherapeutic agents act nonspecifically, damaging several types of body cells. DNA intercalators are standout among the existing chemotherapeutics, for example, among these compounds, acridine derivatives have inhibitory activity against nuclear regulatory enzymes, such as topoisomerase, and there is a strong interaction with pairs of DNA bases. Therefore, researchers are seeking to find new candidates intercalators of DNA drugs and a significant number of molecules have been evaluated for their antitumor and intercalators properties. This paper proposed the synthesis of novel spiro-acridines derivatives; it was conducted to evaluate their interaction with BSA, DNA, and inhibition of the enzyme topoisomerase IIα. Thus, eleven new spiro-acridínicos compounds were synthesized and were determined their physicochemical characteristics and demonstrated the possible reaction mechanisms for obtaining these compounds. The compounds were obtained in parallel and convergent manner, initially the diphenylamine suffered an acylation followed by cyclization, leading to 9-metilacridina that by successive reactions led to 9-carboxaldehyde acridine. In parallel, 2- cianoacetohidrazina reacted with aromatic aldehydes substituted in acid and ethanol, leading to N-acylhydrazones intermediates substituted, finally, the two intermediates were condensed, through a Knovenagel reaction and suffered spontaneous cyclization, leading to spiro-acridine derivates. The compounds show yields ranging from 24% to 86.75%, and melting points ranging between 3 and 5 °C. Most of the compounds were characterized and had their chemical structures elucidated by spectroscopic H-NMR and C-NMR; IR and MS. By 1^H NMR analysis were observed singlets referring to NH, protons coming from the formation of the C = N bond (imino carbon) and C = C (vinyl carbon) corroborating the structural elucidation of all compounds. The 13^C NMR spectra showed the absorptions of carbon atoms characteristic of spiro-acridine derivatives, especially the chemical shift showed by the quaternary carbon evidenced on the signals from 69.33 to 71.59, demonstrating the occurrence of spontaneous cyclization of spiro-acridine derivatives. The compounds evaluated against the enzyme Topoisomerase IIα, presented different degrees of inhibition when compared with the mAMSA standard, and AMTAC 06 presented the best capacity for inhibition. The compounds that interacted with the DNA showed binding constants (Kb) 10^5M^-1, thus suggesting that the likely mechanism of action of these compounds may be related to the formation of a ternary complex between compound, DNA and Topoisomerase. The interactions with the BSA showed that all compounds evaluated were able to cause fluorescence extinction in a dose-dependent manner, and AMTAC 14 showed the highest fluorescence extinction capacity, probably due to its electronic effects. / Uma das principais abordagens para o tratamento do câncer é a quimioterapia, porém a maioria dos agentes quimioterápicos atua de forma não específica, lesando vários tipos de células do organismo. Entre os quimioterápicos existentes, destacam-se os intercaladores de DNA, como por exemplo, os derivados de acridina que possuem atividade inibitória frente a enzimas reguladoras nucleares, como as topoisomerase, além de uma forte interação com pares de bases do DNA. Por isto, pesquisadores vêm buscando a descoberta de novos candidatos a fármacos intercaladores do DNA e um número expressivo de moléculas tem sido avaliado quanto às suas propriedades antitumorais e intercaladoras. Este trabalho propôs síntetizar novos derivados espiro-acridínicos, analisar a interação destes com o BSA, DNA e a inibição da enzima topoisomerase IIα. Assim, onze novos compostos espiro-acridínicos foram sintetizados e determinados as suas características físico-químicas e demonstrados os possíveis mecanismos reacionais para a obtenção destes compostos. Os compostos foram obtidos de forma paralela e convergente, onde inicialmente a difenilamina sofreu uma acilação seguido de ciclização, obtendo-se a 9-metilacridina que por sucessivas reações foi obtido a 9-carboxialdeido acridina. Em paralelo, a 2-cianoacetohidrazina reagiu com aldeídos aromáticos substituídos em meio ácido e etanólico, conduzindo aos intermediários N- acilidrazônicos substituídos, por fim os dois intermediários foram condensados, através de uma reação de Knovenagel e ciclizaram espontaneamente, conduzindo aos derivados espiro- acridínicos. Os compostos apresentaram rendimentos que variaram de 24% a 86,75% e as faixas de fusão oscilaram entre 3 e 5ºC. A maioria dos compostos tiveram suas estruturas químicas caracterizadas e elucidadas através de técnicas espectroscópicas de RMN de 1^H RMN de 13^C ; IV e EM. Através da análise do RMN de 1^H foram observados singletos referentes ao grupo NH, prótons oriundos da formação da ligação C=N (iminico) e C=C (vinílico) corroborando para a elucidação estrutural de todos os compostos. Os espectros de RMN de 13^C evidenciaram as absorções dos átomos de carbono característicos dos derivados espiro-acridinicos, principalmente o deslocamento que mostrou o carbono quaternário evidenciado nos sinais entre 69.33 a 71.59 o qual demonstra a ocorrência da ciclização espontânea dos derivados espiro-acridinicos. Os compostos avaliados frente a enzima Topoisomerase IIα, apresentaram diferentes graus de inibição quando comparados com o padrão mAMSA, sendo o AMTAC 06 o que apresentou a melhor capacidade de inibição. Os compostos que interagiram com o DNA apresentaram constantes de ligação (Kb) 10^5M^-1, sugerindo dessa forma que o provável mecanismo de ação desses compostos pode estar relacionado a formação de um complexo ternário entre composto, DNA e Topoisomerase. As interações com a BSA, mostraram que todos os compostos avaliados foram capazes de causar a extinção da fluorescência de forma dose-dependente, sendo o AMTAC 14 o que apresentou a maior capacidade de extinção da fluorescência, provavelmente devido aos seus efeitos eletrônicos.