Selenenic acids and other organoselenium compounds are important both in organic and biochemistry. In organic chemistry, syn-elemination of selenoxides is used to prepare alkenes, giving a selenenic acid by-product. In biochemistry, selenocysteine is catalytically active in a variety of selenoenzymes, which have antioxidant properties, and is oxidized to a selenenic acid intermediate. For example, glutathione peroxidase (GPx) plays a role in fighting oxidative damage by catalyzing the reduction of hydroperoxides. Previous studies have shown that the lighter chalcogen analogue of selenenic acid, sulfenic acid, is a powerful antioxidant and that the known antioxidant activity of garlic is attributable to the 2-propenesulfenic acid derived from the compound allicin. This has prompted questions concerning the role of selenenic acid in the antioxidant activity of organoselenium compounds. In order to study the physiochemical properties of selenenic acids –a functional group about which little is known—and to evaluate their potential as antioxidants, a persistent selenenic acid is needed. Herein, the model compound, 9-triptyceneselenenic acid, is prepared by a previously reported procedure and a new pathway is designed, such that its properties and reactivity can be studied. The oxidation of thiols is important in cell signalling, leading to the disulfide bonds implicated in post-translational modification, among other biological roles. While this reaction is presumed to occur through the reaction of thiol with an oxidant that forms sulfenic acid, and from a subsequent reaction of sulfenic acid with another thiol, sulfenic acids are so reactive that they are not usually seen as intermediates. Given the stability of the 9-triptycenesulfenic acid previously synthesized, preliminary kinetic study of the oxidation of 9-triptycenethiol to its corresponding sulfenic acid is made possible.

No description available.

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references. Also available in print.

The chemistry of the enzyme glutathione peroxidase and synthetic organoselenium enzyme mimics has been a significant research interest for more than three decades. In this work, the results of a computational study employing modern electronic structure methods to model the reactions of a synthetic glutathione peroxidase mimic are presented. The ability of nine density-functional theory methods and thirteen basis sets to predict both molecular geometries and bond dissociation energies in organoselenium compounds is examined. This is used to determine the best methodology to employ for the study of glutathione peroxidase mimics. The key reactions in the catalytic mechanism of the organoselenium antioxidant N,N-dimethyl-benzylamine-2-selenol are the focus of the remainder of the document. This is a three-step mechanism which includes many of the organic forms adopted by selenium compounds, including selenol, oxoacids, and selenylsulfides. In the first step of the cycle, the well-studied reduction of hydrogen peroxide by a selenol and a diselenide is modelled. The second step modelled is a substitution reaction at the selenium centre of a selenenic acid with a thiol. The final step discussed is the reduction of the selenium centre in a selenylsulfide, regenerating the selenol and forming a disulfide species. Each mechanism is evaluated by discussing both molecular geometries and reaction energetics. To close the document, the peroxide reduction reaction is revisited to determine the effects of substitution on the phenyl ring of the synthetic antioxidant. This serves as a preliminary attempt to improve the antioxidant efficiency of this compound. In addition to a discussion of the changes in reaction energetics predicted, the topology of the electron density is studied using the quantum theory of atoms in molecules to better understand how the distribution of electron density is affected by substituents.

Reevaluation of organosulfur heats of formation resulted in the conclusion that the sulfur-sulfur bond of aliphatic disulfides is nearly 15 Kcal/mole stronger than the disulfide carbon-sulfur bond energy. Semi-empirical calculations using AM1, MNDO and MINDO/3 from the AMPAC program package confirmed these results and clarified their relative impact on organosulfide and disulfide properties. / Existing organoselenium bond energy data were also reevaluated and erroneous assumptions discovered. New bond energy estimates were made via a new procedure. It was concluded that the selenium-selenium bond is also stronger than the selenium-carbon of aliphatic diselenides. / The above results led to the conclusion that loss of molecular dichalcogen from molecules such as disulfides or diselenides is favored over the stepwise loss of a single chalcogen by about 40 Kcal/mol. Loss of molecular diselenium from dibenzyl diselenide is reported. The average carbon-selenium bond energy of the latter is calculated to be only 27 Kcal/mol. / The preparation of 2-thiatriselenides (RSeSSeR) and 2,3-dithiatetraselenides (RSeSSSeR) has been achieved from selenosilanes. The products were characterized by $ sp{77}$Se NMR and the trends of chemical shifts were analyzed. / The preparation of the first selenium transfer reagents, including the first unsymmetrical chalcogen transfer reagent, is reported. Their use to effect the synthesis of 2-selenatrisulfides (RSSeSR) is also reported. Low temperature $ sp{77}$Se NMR was used to elucidate the reaction mechanism and characterize several intermediates such as selenuranes, selenonium ions and azole selenides. In addition, 2,3-diselenatetrasulfides (RSSeSeSR) were characterized by $ sp{77}$Se NMR.

Thesis (Ph. D.)--Oregon State University, 2010. / Printout. Includes bibliographical references (leaves 114-125). Also available on the World Wide Web.

No description available.

Choi, Mei Yuk. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 79-89). / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abstract --- p.iii / Abstract (Chinese) --- p.v / List of Abbreviations --- p.vii / List of Figures --- p.viii / Chapter Chapter 1 --- Introduction / Chapter 1.1. --- General introduction of cancer --- p.1 / Chapter 1.2. --- Overview of apoptosis --- p.2 / Chapter 1.2.1. --- The extrinsic death receptor pathway --- p.4 / Chapter 1.2.2. --- The intrinsic mitochondrial pathway --- p.4 / Chapter 1.2.3. --- Cross-talk between the intrinsic and extrinsic pathways --- p.5 / Chapter 1.3. --- Overview of selenium --- p.6 / Chapter 1.3.1. --- Selenium and prostate cancer --- p.7 / Chapter i. --- Epidemiological studies --- p.7 / Chapter ii. --- Clinical trials --- p.8 / Chapter iii. --- Preclinical investigations --- p.10 / Chapter a. --- in vivo studies --- p.11 / Chapter b. --- in vitro studies --- p.12 / Chapter c. --- selenocystine and prostate cancer --- p.13 / Chapter 1.4. --- Objective --- p.15 / Chapter Chapter 2 --- Materials and methods / Chapter 2.1. --- Materials --- p.18 / Chapter 2.2. --- Methods --- p.19 / Chapter 2.2.1. --- Cell culture --- p.19 / Chapter 2.2.2. --- MTT assay --- p.19 / Chapter 2.2.3. --- Cell cycle distribution analysis --- p.20 / Chapter 2.2.4. --- TUNEL assay and DAPI staining --- p.20 / Chapter 2.2.5. --- Evaluation of mitochondrial membrane potential (ΔΨm) --- p.21 / Chapter 2.2.6. --- Measurement of superoxide generation (DHE assay) --- p.22 / Chapter 2.2.7. --- Inhibition of superoxide generation --- p.22 / Chapter 2.2.8. --- Western blot analysis --- p.23 / Chapter 2.2.9. --- Statistical analysis --- p.24 / Chapter Chapter 3 --- Results / Chapter 3.1. --- The antiproliferatvie effect of SeC on LNCaP and PC-3 cells --- p.25 / Chapter 3.2. --- The role of caspases in SeC-induced apoptosis --- p.34 / Chapter 3.3. --- The effect of SeC on the mitochondrial membrane potential --- p.39 / Chapter 3.4. --- The involvement of p53 in SeC-treated LNCaP cells --- p.44 / Chapter 3.5. --- MAPK and PI3K/Akt signaling pathways --- p.47 / Chapter 3.6. --- The role of superoxide in SeC-induced apoptosis --- p.52 / Chapter Chapter 4 --- Discussion --- p.62 / Chapter Chapter 5 --- Conclusion --- p.74 / References --- p.79

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

Submitted by Gabriela Lopes (gmachadolopesufpel@gmail.com) on 2017-08-23T13:12:51Z No. of bitstreams: 2 license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Tese de doutorado Sergio Ferraz Fonseca.pdf: 3939876 bytes, checksum: 82b8a0029f316dd9c9495a7f795faf44 (MD5) / Approved for entry into archive by Aline Batista (alinehb.ufpel@gmail.com) on 2017-09-01T19:19:37Z (GMT) No. of bitstreams: 2 Tese de doutorado Sergio Ferraz Fonseca.pdf: 3939876 bytes, checksum: 82b8a0029f316dd9c9495a7f795faf44 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-09-01T19:19:37Z (GMT). No. of bitstreams: 2 Tese de doutorado Sergio Ferraz Fonseca.pdf: 3939876 bytes, checksum: 82b8a0029f316dd9c9495a7f795faf44 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-07-07 / Com a necessidade de encontrar fármacos mais potentes, são necessárias pesquisas que visam potencializar as atividades já presentes em compostos de origem natural através de metodologias que sejam as mais ecológicas e eficientes possíveis. O objetivo deste trabalho foi sintetizar compostos derivados da crisina 1 e do cardanol 3, contendo grupamentos organosselênio em suas estruturas, com o intuito de potencializar suas atividades farmacológicas. Os derivados da crisina foram sintetizados através de uma metodologia utilizando ultrassom como fonte de energia e iodeto de cobre como catalisador, obtendo-se seis novos compostos bis-selenilados., os quais foram obtidos em bons a ótimos rendimentos (60-89%) e posteriormente avaliados quanto às suas propriedades antioxidantes e antiproliferativas in vitro, onde foi possível observar que a presença de selênio aumentou ambas as propriedades da crisina. O composto com o grupo metila na posição orto apresentou os melhores resultados frente aos radicais DPPH (Imax: 39.79 µM) e ABTS+ (IC50: 6.5µM). No ensaio de Espécies Reativas (ERs), o mesmo apresentou alta atividade antioxidante no córtex de camundongos (IC50: 5.67 µM), enquanto o composto com o grupo metoxila foi mais ativo no hipocampo (IC50: 5.63 µM). Todos os compostos foram efetivos na prevenção da peroxidação lipídica, dando destaque para o composto contendo o átomo de flúor no teste com córtex (IC50: 0.54 µM) e o composto com o grupo metila no hipocampo (IC50: 0.27 µM). Além disso, o composto com flúor foi mais efetivo na inibição do crescimento de células tumorais pulmonares (A549), com um IC50 de 19.9 µM após 72 h, enquanto que o composto com grupo metoxila foi o mais efetivo após 48 h (IC50 of 41.4 µM). Em relação à síntese de derivados do cardanol 3, foi realizado um estudo para encontrar as melhores condições reacionais. Determinou-se que utilizando uma mistura de 3, disseleneto de difenila, m-CPBA como agente oxidante e ácido acético como solvente, com ultrassom como fonte de energia obteve-se o melhor resultado, com o produto desejado 37 em 25% de rendimento. A atividade antioxidante in vitro deste composto foi avaliada, e os resultados obtidos demonstram que o mesmo apresenta uma atividade antioxidante bastante promissora, com resultados superiores aos dos seus materiais de partida. / With the necessity of finding more powerful drugs, new researches are needed aiming to improve the pharmacological activities already present in natural compounds through the most ecological and efficient methodologies possible. The aim of this work was to synthesize new selenium-containing chrysin 1 and cardanol 3 derivatives in order to increase its’ biological activities. Chrysin derivatives were synthesize through a methodology using ultrasound as an energy source and cooper iodine as catalyst, achieving six new compounds with two organoselenium moieties, witch were obtained in good to excellent yields (60-90%) and after they were evaluated by their in vitro antioxidant and antiproliferative activities, where it was possible to see that the presence of selenium boosted both chrysin’s activities.The compound with a methyl group in the orto position presented the best results against the DPPH (Imax: 39.79 µM) and ABTS+ (IC50: 6.5µM) radicals. In the Reactive Species assay (RS), it presented high antioxidant activity in mice cortex (IC50: 5.67 µM), while the compound with the methoxyl group was more effective in the hippocampus (IC50: 5.63 µM). All compounds were effective against lipid peroxidation, highlighting the compound with the fluorine atom in the cortex assay (IC50: 0.54 µM) and the compound with the methyl group in the hippocampus assay (IC50: 0.27 µM). Besides, compound with the fluorine atom was more effective inhibiting lung cancer cells’ growth (A549), with an IC50 of 19.9 µM after 72 h, while the compound with the methoxyl group was more effective after 48h (IC50 of 41.4 µM). Regarding the synthesis of cardanol 3 derivatives, a study was performed in order to find the best reaction conditions. It was determined that by using a mixture of 3, diphenyl diselenide, m-CPBA as an oxidant agent and acetic acid as solvent, with ultrasound as energy source we achieved the best result, with the desired product 37 in 25% yield. The in vitro antioxidant activity of this compound was evaluated, and the obtained results reveled that this compound presents a very promising antioxidant activity, with superior results compared to its’ starting materials.