The primary aim of this project was to develop organometallic methodologies for the conversion of aryl benzyl ketones into aryl- and/or aroyl- substituted stilbenes related to Selective Estrogen Receptor Modulators (SERMs): Tamoxifen and Raloxifene, respectively. Consideration was given to target molecules that were acyclic, cyclic or heterocyclic. A secondary aim of the project was to develop methodologies that would allow combinatorial methods to be applied to the synthesis of these compounds, allowing quick access to a diverse range of SERM-candidate libraries of compounds. Primary methodologies that were examined included: Grignard, organocerium, and palladium-catalysed Negishi, Stille and Suzuki cross-coupling reactions. In addition, the rearrangement reaction of epoxides and nucleophilic ring opening of epoxides were explored as secondary means of new C-C bond construction. It was found the Grignard chemistry demanded the application of heat and suffered greatly from competing deprotonation reactions of the ketones due to the basicity of the organomagnesium reagents. The corresponding, less basic, organocerium reagents also gave low yields (0-11%). While these methodologies demonstrated some advantages, such as the direct addition of the nucleophilic components to the carbonyl groups of model ketones, they demonstrated some limitations, which were poor yields and restriction to using only carbonyl containing starting materials. Palladium-catalysed Negishi cross-coupling methodology was reliable in C-C bond formation but gave only moderate yields of isolated products. Stille reagents gave crosscoupled products readily and in high yields with sterically unhindered reactants, such as the enol triflate of ??- tetralone. However, they did not readily cross-couple with the corresponding ??-enol triflate and ??-vinyl bromide reactants. This became an insurmountable barrier to their widespread use in SERM synthesis but did provide a sequence with selectivity. The Suzuki methodology was discovered to be superior to other methods of cross-coupling and the most reliable in furnishing both ??- and ??-coupled products in high yields. The yield of the palladium-catalysed Suzuki cross-coupling reaction at the ??-position was found to follow the following order of reactivity: I &gt Br &gt OTf, in keeping with literature precedent, while the stability of the palladium-catalyst, and the choices of base and solvent affected the outcome of the reaction. The Suzuki reaction was also employed in a three-component carbonylative reaction to furnish unsymmetrical ketones, in model reactions towards Raloxifene-like structures, but the products were obtained in low to moderate yields. Initial investigations into the synthesis of closer model compounds through two-fold Suzuki cross-coupling reactions were limited by access to suitable precursors and this indicated a direction for future research.

The primary aim of this project was to develop organometallic methodologies for the conversion of aryl benzyl ketones into aryl- and/or aroyl- substituted stilbenes related to Selective Estrogen Receptor Modulators (SERMs): Tamoxifen and Raloxifene, respectively. Consideration was given to target molecules that were acyclic, cyclic or heterocyclic. A secondary aim of the project was to develop methodologies that would allow combinatorial methods to be applied to the synthesis of these compounds, allowing quick access to a diverse range of SERM-candidate libraries of compounds. Primary methodologies that were examined included: Grignard, organocerium, and palladium-catalysed Negishi, Stille and Suzuki cross-coupling reactions. In addition, the rearrangement reaction of epoxides and nucleophilic ring opening of epoxides were explored as secondary means of new C-C bond construction. It was found the Grignard chemistry demanded the application of heat and suffered greatly from competing deprotonation reactions of the ketones due to the basicity of the organomagnesium reagents. The corresponding, less basic, organocerium reagents also gave low yields (0-11%). While these methodologies demonstrated some advantages, such as the direct addition of the nucleophilic components to the carbonyl groups of model ketones, they demonstrated some limitations, which were poor yields and restriction to using only carbonyl containing starting materials. Palladium-catalysed Negishi cross-coupling methodology was reliable in C-C bond formation but gave only moderate yields of isolated products. Stille reagents gave crosscoupled products readily and in high yields with sterically unhindered reactants, such as the enol triflate of ??- tetralone. However, they did not readily cross-couple with the corresponding ??-enol triflate and ??-vinyl bromide reactants. This became an insurmountable barrier to their widespread use in SERM synthesis but did provide a sequence with selectivity. The Suzuki methodology was discovered to be superior to other methods of cross-coupling and the most reliable in furnishing both ??- and ??-coupled products in high yields. The yield of the palladium-catalysed Suzuki cross-coupling reaction at the ??-position was found to follow the following order of reactivity: I &gt Br &gt OTf, in keeping with literature precedent, while the stability of the palladium-catalyst, and the choices of base and solvent affected the outcome of the reaction. The Suzuki reaction was also employed in a three-component carbonylative reaction to furnish unsymmetrical ketones, in model reactions towards Raloxifene-like structures, but the products were obtained in low to moderate yields. Initial investigations into the synthesis of closer model compounds through two-fold Suzuki cross-coupling reactions were limited by access to suitable precursors and this indicated a direction for future research.

Academisch proefschrift - Amsterdam. / Summary in Dutch, English, and German.

Thesis--Copenhagen. / Imperfect: p. 161-176 bound after p. 198. Summaries in English and Danish. "Translated into English by C.L. Heel."--P. [8]. Bibliography: p. [190]-198.

The present investigation was undertaken in order to clarify the clinical and metabolic effects of the menopause following bilateral oophorectomy in the human female and to evaluate the role of subsequent replacement exogenous oestrogen therapy. To this end pertinent clinical and laboratory studies were carried out. It is considered that the following contributions to knowledge have been made: 1. The symptoms and clinical signs directly related to endogenous oestrogen withdrawal following bilateral oophorectomy have been clarified and defined. 2. Symptoms responding to exogenous oestrogen therapy have been differentiated from those responding to placebo (general supportive) therapy. 3. The ability of exogenous oestrogens to produce a feeling of well-being in postmenopausal females is statistically substantiated. 4. The parabasal cell is shown to be the best cytologic index of the oestrogenic status of the postmenopausal female. Claims for an increase of vaginal superficial cells with exogenous oestrogen therapy are refuted. 5. Bi lateral oophorectomy. in the female of reproductive age is shown to have no effect for up to 2 years on the total serum cholesterol level. Oestrogen therapy, however, reduced the level of serum cholesterol in oophorectomized females. 6. The effects of b i lateral oophorectomy on plasma calcium and inorganic phosphorus are shown. The ability of oestrogen to lower plasma calcium and phosphorus is demonstrated and the possible explanation and implication of these findings is discussed. 7. A controlled comparative evaluation of two different forms of oestrogen demonstrates different oestrogens to have different effects. Moreover, endogenous, and exogenous oestrogens are shown to be not entirely similar in their clinical and metabolic effects. 8. The specific short-term sequelae of oophorectomy are demonstrated and the current role of exogenous oestrogen replacement therapy in postmenopausal females is discussed.

Thesis--University of Helsinki, 1991. / Includes bibliographical references (p. 71-83).

Thesis (Ph. D.)--University of Wisconsin--Madison, 1941. / Typescript. Includes abstract and vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 61-63).

No description available.

Studies of non-human animals have shown that estrogens have a significant effect on the structure and neurochemistry of the brain and on cognitive behaviours. This study examines women with BRCA1/2 mutations who have undergone bilateral salpingo-oophorectomy (BSO), resulting in surgical menopause. In order to understand how the absence of endogenous estrogens affects cognition, women with BSO are compared to women with BRCA1/2 mutations but without BSO, as well as age-matched controls on tests of verbal, spatial and working memory. Women with BSO show decreased verbal memory and attention (logical memory) relative to controls but better performance on a measure of temporal lobe function (fluency clustering). Further, concentration of estrogen metabolites (E1G) negatively correlated with performance on a spatial memory task (object placement task) and with fluency clustering. These results indicate that endogenous estrogens are important for verbal memory and attention, but may contribute negatively to spatial memory and fluency clustering.

Studies of non-human animals have shown that estrogens have a significant effect on the structure and neurochemistry of the brain and on cognitive behaviours. This study examines women with BRCA1/2 mutations who have undergone bilateral salpingo-oophorectomy (BSO), resulting in surgical menopause. In order to understand how the absence of endogenous estrogens affects cognition, women with BSO are compared to women with BRCA1/2 mutations but without BSO, as well as age-matched controls on tests of verbal, spatial and working memory. Women with BSO show decreased verbal memory and attention (logical memory) relative to controls but better performance on a measure of temporal lobe function (fluency clustering). Further, concentration of estrogen metabolites (E1G) negatively correlated with performance on a spatial memory task (object placement task) and with fluency clustering. These results indicate that endogenous estrogens are important for verbal memory and attention, but may contribute negatively to spatial memory and fluency clustering.