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Thesis (M.S.)--Virginia Polytechnic Institute and State University, 1994. / Vita. Abstract. Includes bibliographical references (leaves 78-82). Also available via the Internet.

Thesis (MPH (Faculty of Medicine))--University of Pretoria, 2006. / Abstract in English. Includes bibliographical references .

Thesis (M.PH (Faculty of Medicine))--University of Pretoria, 2005. / Abstract in English. Includes bibliographical references (leaves 39-40). Also available online.

The application of Baylis-Hillman methodology has afforded access to a range of β-hydroxypropionate ester-AZT conjugates as potential dual-action HIV-1 IN/RT inhibitors. Two families comprising a total of nine β-hydroxypropionate ester-AZT conjugates were synthesised. The first family was accessed using O-benzylated salicylaldehydes and methyl acrylate and the second from unprotected salicylaldehydes using tert-butyl acrylate as the activated alkene. Spectroscopic methods were employed to fully characterize the compounds. Propargylation of the respective Baylis-Hillman adducts was achieved via conjugate addition of propargylamine. The resulting products were then employed in Cu(I)-catalysed “click” reactions with azidothymidine (AZT) to yield the desired β-hydroxypropionate ester-AZT conjugates. Exploratory studies were also conducted to access 4-hydroxycoumarins from Baylis-Hillman derived adducts and to construct customized chiral Baylis-Hillman reaction sites. Many 4- hydroxycoumarins are known to exhibit a wide range of biological activities, and extending Baylis-Hillman methodology to access these systems is an important challenge. Two approaches were investigated. The first involved the formation of a 4-phthalimidocoumarin, aromatisation and hydrolysis of which was expected to lead to the 4-hydroxycoumarin target. The second, a variation of the first, involved the use of 4-(chrolomethyl)coumarin intermediates. Unfortunately, while various intermediates were prepared and characterised, neither approach led ultimately to the desired targets. N-substituted borneol-10-sulfonamides were constructed from camphor-10- sulfonyl chloride as chiral Baylis-Hillman reaction sites. In a preliminary study, however, none of the N-substituted borneol-10-sulfonamides exhibited Baylis-Hillman catalytic activity.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The synthesis of compounds that use a nucleoside as the base structure, has an intense field application. Among these compounds, the most known nowadays is azydothymidine or zidovudine, a drug which was first synthesized to work against tumor processes. However, it was discovered that it could take action to viral combat and now it is the drug of choice in the treatment of acquired immunodeficiency syndrome (AIDS). On the other hand, organochalcogens compounds have been calling the attention of the scientific community, mainly because of their potential in biological molecules containing these atoms. Considering this last factor and aiming to explore the structural basis of nucleosides and biological influences that changes in the 5' position of the deoxyribose ring of AZT would promote, it was planned through an efficient and accessible synthetic route to produce a new series of nucleosides, the 5'-arylseleno azidothymidine, which had the insertion of the selenium atom connected to different aril groups. Moreover, the series of selenium derivatives were evaluated for their toxicological potential for oxidative stress (TBARS and thiol peroxidase), where the compounds 5´-p-methylseleno azidothymidine 3b and 5´-p-chloroseleno azidothymidine (3h) had the results of this series, with potential as antioxidant agent. After this, the compounds 3b and 3h were tested against culture cell lines of bladder cancer (5637). The tests aimed to assess the cytotoxicity, cell morphology, apoptosis analysis and gene expression. The results showed that the compounds 3b and 3h present apoptotic profile, additionally they seem to modulate the expression of anti-apoptotic gene. The results obtained indicate that the compounds 3b and 3h in addition of presenting an antioxidant potential, have a pro-apoptotic profile, even more effective than AZT itself. Considering all the results presented, it was concluded that this new nucleoside serie has great antitumor potential and can be used as a chemopreventive, combined to the antioxidant potential. / A síntese de compostos que usam como base a estrutura de nucleosídeos é um campo que possui uma intensa aplicação biológica. Dentre estes compostos, o mais conhecido é a azidotimidina ou zidovudina (AZT), um fármaco que teve sua síntese inicial voltada para o combate de processos tumorais. No entanto, descobriu-se que este poderia agir no combate viral e hoje é o fármaco de primeira escolha no tratamento da síndrome da imunodeficiência adquirida. Adicionalmente, compostos organocalcogênio, principalmente compostos de selênio, despertam a atenção da comunidade científica principalmente devido as suas potencialidades biológicas. Dessa forma, a fim de explorar a base estrutural dos nucleosídeos e as influências biológicas que modificações na posição 5´ do anel da desoxirribose do AZT promoveriam, planejou-se através de uma eficiente rota sintética, a síntese de uma nova série de nucleosídeos, os 5´-arilseleno azidotimidina, que apresentaram a inserção do átomo de selênio ligados a diferentes grupamentos arílicos. Com o objetivo de realizarmos uma seleção dos melhores compostos da série de selenonuclesídeos, avaliamos o parâmetro toxicológico para o estresse oxidativo (TBARS e tiol peroxidase) destes compostos. Onde, os compostos 5´-p-metilseleno azidotimidina (3b) e 5´-p-cloroseleno azidotimidina (3h) apresentaram os resultados mais promissores, apresentando inclusive perfil como agente antioxidante. Dessa forma, após realizarmos a triagem, os compostos 3b e 3h tiveram suas atividades testadas frente à cultura celular de linhagem de câncer de bexiga (5637). Os testes buscaram avaliar os parâmetros de citotoxicidade, morfologia celular, análise apoptótica e a expressão gênica. Os resultados obtidos mostraram que os compostos 3b e 3h apresentaram perfil apoptótico, além de serem capazes de modular a expressão do gene anti-apoptótico. Por fim, os resultados obtidos, apontam que os compostos 3b e 3h além de apresentarem um perfil antioxidante, possuem ação pró-apoptótica mais eficientes do que o próprio AZT. Dessa forma, considerando todos os resultados obtidos, foi possível concluir que essa nova série de nucleosídeos apresenta potencial antitumoral, podendo ser usado quimiopreventivamente, aliado ao perfil antioxidante.

Orientador : Maria Palmira Daflon Gremião / Coorientador: Beatriz Stringhetti Ferreira Cury / Banca: Marcos Luciano Bruschi / Banca: Sergio Paulo Campana Filho / Banca: Marlus Chorilli / Banca: Marco Vinícius Chaud / Resumo: A zidovudina (AZT) é o fármaco mais utilizado isoladamente ou em associação para o tratamento da Síndrome da Imunodeficiência Adquirida (AIDS), causada pelo vírus HIV. A baixa biodisponibilidade do AZT é o grande desafio a ser vencido para otimizar seu desempenho na terapêutica por via oral, já que sua elevada taxa de metabolização e baixa permeabilidade resultam na necessidade de administração de elevadas doses do fármaco. Além disto, este fármaco ainda é substrato do mecanismo de efluxo mediado pela glicoproteína-P no intestino, o que diminui ainda mais sua biodisponibiidade. Desta forma, dispersões sólidas (DS) e nanopartículas poliméricas (NP) foram desenvolvidas por complexação polieletrolítica com diferentes proporções entre o fármaco e os polímeros quitosana (QS) e ftalato de hidroxipropilmetilcelulose (HP). O teor de incorporação de fármaco nas DSs (em torno de 98%) foi maior que nas NPs (cerca de 65%). Os ensaios de liberação in vitro realizados em HCl 0,1 mol/l (pH 1,2) demonstraram que a complexação entre os polímeros e compartimentalização do fármaco reduziu as taxas de liberação do AZT tanto para as DSs (26 a 50%) quanto nas NPs (aproximadamente 60%) e, em tampão fosfato 50 m mol/l (pH 7,4), ambos sistemas de liberação prolongaram a liberação do fármaco por até 240 minutos. A determinação da granulometria confirmou a obtenção de sistemas micro (até 100 μm) e nanoparticulados (até 400 nm) e o potencial zeta evidenciou a carga superficial negativa das DSs e positiva das NPs. Os dados de DSC e DRX mostraram que o AZT estava molecularmente disperso em ambos os sistemas e que as DSs apresentaram estrutura amorfa, enquanto as NPs apresentaram estrutura predominantemente cristalina.A espectroscopia na região do infravermelho mostrou a formação de ligações entre a QS e o HP tanto nas DSs quanto nas NPs, sem alterar a... / Abstract: Zidovudine (AZT) is the most widely used drug alone or in combination with other antiretroviral agents for the treatment of AIDS, caused by the HIV virus. The low AZT bioavailability is the great challenge to be overcome to optimize its performance in oral therapy, since its high rate of hepatic metabolism and low permeability results in the need for high doses of the drug. In addition, this drug is substrate of the efflux mechanism mediated by P-glycoprotein in the gut, which further decreases its bioavailability. Thus, solid dispersions (SD) and polymeric nanoparticles (NP) were developed by complexation polyelectrolyte with different ratios between the drug and the polymers chitosan (CS) and hydroxypropyl methylcellulose phthalate (HP). The drug content in the SDs (around 98%) was higher than in NPs (about 65%). The in vitro release assays performed in HCl 0.1 mol/l (pH 1.2) showed that polymeric complexation and drug entrapment reduced the AZT rates release in both SDs (26 to 50%) and NPs (around 60%), and in phosphate buffer 50 m mol/l (pH 7.4), both modified the drug release until 240 minutes. The particle size determination confirmed obtaining micro systems (around 100 micron) and nanoparticles (around 400 nm) and zeta potential showed the negative surface of SDs and the positive charge of NPs. DSC and XRD data showed that AZT remained molecularly dispersed in both systems and the DSs had an amorphous structure, while the NPs showed structure crystalline predominantly. The IR spectroscopy showed in both SDs and NPs the formation of bonds between CS and the HP without changing the structure of AZT. The NPs showed higher liquid absorption capacity (until 260%) relative to SDs (until 160%) in different pH values, while SDs presented higher mucin adsorption capacity. The SDs and NPs mucin adsorption occurs according to the mechanism of Freundlich and Langmuir, respectively. Intestinal permeability assay showed the influence of SD to ... / Doutor

The purpose of the study was to determine if perceived severity of the consequences of physical inactivity is an important component for exercise motivation in college students. The participants of the study were 581 college students who had enrolled in HSC 160, Fundamentals of Human Health, at Ball State University during the spring semester of 2001. Using a cross-sectional data collection process, participants completed a survey instrument consisting of the stages of change for exercise scale, the perceived severity of the consequences of physical inactivity scale, and demographic questions.The data were analyzed using both univariate and bivariate analyses. Specific descriptive and inferential statistic analyses were used to: 1) determine the degree of association between the participants' perceived severity and their identified stages of change for exercise, 2) examine the relationship between the stages of change for exercise and the participants' demographic characteristics, and 3) determine the difference between perceived severity of consequences of physical inactivity and the Participants' demographic characteristics.The results indicated that those who perceived the threat of a health condition as a result of not being physically active to be high were more likely to exercise regularly. Males and females differed in their exercise stage of change with males being more likely in the maintenance stage whereas females were more likely to be in the preparation stage. Also, perceived severity of the consequences from the lack of physical activity was greater in females than males, suggesting that those men who exercise regularly do so, but not exclusively for preventing negative health conditions.The results of this study should be useful to health and physical education instructors to assist them with organizing and tailoring appropriate physical activity lecture topics and emphasizing the severity of the consequences to those who are not physically active.Finally, additional research should be conducted in order to determine what factors affect perceived severity of a health threat as it relates to physical inactivity such as demographics, sociopsychological, and structural variables, to help identify all the possible factors that could impact future program planning efforts. / Department of Biology

Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Pharmaceutical Science." Includes bibliographical references (p. 98-107).

Thesis (Ph. D.)--Rutgers University, 2008. / "Graduate Program in Chemistry and Chemical Biology." Includes bibliographical references (p. 236-245).