Thesis--PlanA (M.S.)--University of Wisconsin--Stout, 2000. / Includes bibliographical references.

Thesis (Ph. D.)--University of North Texas, Dec., 2009. / Title from title page display. Includes bibliographical references.

Thesis (MSc)--University of Stellenbosch, 2008. / Bibliography. Also available via the Internet.

published_or_final_version / Medicine / Master / Master of Research in Medicine

The pyrrolo[3,2,1-ij]quinolin-6-one ring system was synthesised from 3-aryl-4,6-dimethoxyindoles and 2,3-disubstituted-4,6-dimethoxyindoles. The reaction of 4,6-dimethoxyindoles under Friedel-Crafts or Vilsmeier-Haack acylation gave the 2- and 7-indolyldeoxybenzoins in good yield. Cyclisation of 7-indolyldeoxybenzoins with N,N-dimethylformamide dimethyl acetal as a one carbon reagent gave the pyrroloquinolin-6-ones in high yield. Reduction of pyrroloquinolin-6-ones with hydrogen gas and 10% palladium on carbon or lithium aluminium hydride yielded the dihydropyrroloquinolin-6-ones. Demethylation of pyrroloquinolin-6-ones with 48% hydrobromic acid in glacial acetic acid gave a mixture of the monohydroxy and dihydroxy analogues in high yield. The synthesis of quinolin-4-ones using the Conrad-Limpach method was attempted using three different cyclisation conditions such as Dowtherm A, polyphosphoric acid and a mixture of diphenyl ether and methanesulfonic acid. Quinolin-2-ones such as 4-methyl-3-aryl-, 3,4-diaryl- and 3-aryl-4-benzyl-5,7-dimethoxyquinolin-2-ones could be synthesised from either the N-phenylacetylaniline or the N-trifluoroacetyl aniline strategy. Attempted reduction of the quinolin-2-ones with standard metal hydride reagents was unsuccessful. However reduction was achieved via the conversion of quinolin-2-one to the corresponding 2-chloroquinoline followed by reaction of the chloroquinoline with zinc powder and glacial acetic acid to produce a novel, highly substituted quinoline system. Demethylation was successfully carried out with 48% hydrobromic acid in glacial acetic acid to give the trihydroxyquinolin-2-one in high yield. The reactions of 4-substituted-5,7-dimethoxyquinolin-2-ones and the corresponding 2-chloroquinolines as potential organic intermediates were explored. Facile formylation of both quinolin-2-ones and 2-chloroquinolines was observed under Vilsmeier-Haack conditions while acetylation was successful under Friedel-Crafts conditions using antimony (V) pentachloride as the Lewis acid. Further reaction of 8-formyl-quinolin-2-one with 1,2-diaminobenzene in N,N-dimethylformamide led to the formation of a new 8-(benzimidazolyl)-quinolin-2-one ring system. The quinolin-2-ones exhibited selective electrophilic substitution at the C8 position for a range of reactions. However, an unexpected nitration occurred at the C3 position for the 4-methoxy and 4-phenyl-5,7-dimethoxyquinolin-2-ones with good yields. A series of novel 4,6-hydroxylindoles was successfully synthesised from the corresponding methoxy analogues in high yield using anhydrous aluminium chloride. When 3-(4-bromophenyl)-4,6-dimethoxyindole was reacted with 48% hydrobromic acid in glacial acetic acid a 2,2?-indolylindoline dimer was formed. The 5,7-dihydroxyquinolin-2-ones were similarly synthesised in high yield using anhydrous aluminium chloride in chlorobenzene.

Phytoestrogens are diphenolic, non steroidal compounds which are present in plants and are consumed by both humans and animals. Previous investigations have demonstrated that dietary phytoestrogens appear to have neurobehavioral effects on intermale aggression in male Syrian hamsters and the neural mechanisms require further exploration. In this study experiments involving a phytoestrogen (PE) and a phytoestrogen free (PE Free) diet were performed to determine whether or not diet had an effect on the expression of a and p estrogen receptors in the brain of male Syrian hamsters (Mesocricetus auratus). Twenty male hamsters were used for experimentation and animals were divided into a PE (n = 10) and a PE Free group (n = 10) for a period of 3 weeks. Animals were sacrificed, perfused and brains removed for subsequent protein extraction and immunohistochemisty. Estrogen receptors were quantified using western blot utilizing brains from both the PE and the PE Free group. Results revealed a wide spread distribution of estrogen receptors throughout the brain of male Syrian hamsters. Positive irnmunoreactive labeling was observed in the thalamus, hypothalamus, amygdala, cortex and hipoocampus. Sections were matched and comparisons were made to determine which estrogen receptor had a higher rate of expression. Results revealed higher levels of ERP binding in comparison to ERa. In addition, there appeared to be a higher expression of estrogen receptors in animals on the PE Free diet (p < 0.05). Overall, results obtained form western blots support the hypothesis that animals on the PE Free diet experienced an increase in ER expression. Moreover, immunohistochemistry revealed visual differences of estrogen receptor expression in the brain and data suggests that a diet lacking phytoestrogens can up regulate estrogen receptors in male hamsters. In summary, we have demonstrated that manipulating the diet can have neurobiological consequences and future research should consider diet as a significant factor in experimental research on the brain.

The pyrrolo[3,2,1-ij]quinolin-6-one ring system was synthesised from 3-aryl-4,6-dimethoxyindoles and 2,3-disubstituted-4,6-dimethoxyindoles. The reaction of 4,6-dimethoxyindoles under Friedel-Crafts or Vilsmeier-Haack acylation gave the 2- and 7-indolyldeoxybenzoins in good yield. Cyclisation of 7-indolyldeoxybenzoins with N,N-dimethylformamide dimethyl acetal as a one carbon reagent gave the pyrroloquinolin-6-ones in high yield. Reduction of pyrroloquinolin-6-ones with hydrogen gas and 10% palladium on carbon or lithium aluminium hydride yielded the dihydropyrroloquinolin-6-ones. Demethylation of pyrroloquinolin-6-ones with 48% hydrobromic acid in glacial acetic acid gave a mixture of the monohydroxy and dihydroxy analogues in high yield. The synthesis of quinolin-4-ones using the Conrad-Limpach method was attempted using three different cyclisation conditions such as Dowtherm A, polyphosphoric acid and a mixture of diphenyl ether and methanesulfonic acid. Quinolin-2-ones such as 4-methyl-3-aryl-, 3,4-diaryl- and 3-aryl-4-benzyl-5,7-dimethoxyquinolin-2-ones could be synthesised from either the N-phenylacetylaniline or the N-trifluoroacetyl aniline strategy. Attempted reduction of the quinolin-2-ones with standard metal hydride reagents was unsuccessful. However reduction was achieved via the conversion of quinolin-2-one to the corresponding 2-chloroquinoline followed by reaction of the chloroquinoline with zinc powder and glacial acetic acid to produce a novel, highly substituted quinoline system. Demethylation was successfully carried out with 48% hydrobromic acid in glacial acetic acid to give the trihydroxyquinolin-2-one in high yield. The reactions of 4-substituted-5,7-dimethoxyquinolin-2-ones and the corresponding 2-chloroquinolines as potential organic intermediates were explored. Facile formylation of both quinolin-2-ones and 2-chloroquinolines was observed under Vilsmeier-Haack conditions while acetylation was successful under Friedel-Crafts conditions using antimony (V) pentachloride as the Lewis acid. Further reaction of 8-formyl-quinolin-2-one with 1,2-diaminobenzene in N,N-dimethylformamide led to the formation of a new 8-(benzimidazolyl)-quinolin-2-one ring system. The quinolin-2-ones exhibited selective electrophilic substitution at the C8 position for a range of reactions. However, an unexpected nitration occurred at the C3 position for the 4-methoxy and 4-phenyl-5,7-dimethoxyquinolin-2-ones with good yields. A series of novel 4,6-hydroxylindoles was successfully synthesised from the corresponding methoxy analogues in high yield using anhydrous aluminium chloride. When 3-(4-bromophenyl)-4,6-dimethoxyindole was reacted with 48% hydrobromic acid in glacial acetic acid a 2,2?-indolylindoline dimer was formed. The 5,7-dihydroxyquinolin-2-ones were similarly synthesised in high yield using anhydrous aluminium chloride in chlorobenzene.

Thesis (M. Res.(Med.))--University of Hong Kong, 2008. / Includes bibliographical references (p. 94-104)

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: MCF-7; genistein; breast cancer; PCNA; phytoestrogens. Includes bibliographical references (p. 37-41).

The objective of this study was to evaluate the effects of orally administered soy-derived extracts on normal reproductive development in neonatal pigs as a model for infants on soy formula. Yorkshire-Landrace crossbred sows were randomly assigned to a lactating diet supplemented with either Novasoy 70 or without. Feed was top-dressed from d 100 of gestation until farrowing. Neonatal pigs (NPs) were weighed on post natal day (PND) six then randomly assigned to one of four treatments 1) control, 2) estradiol, 3) low, or 4) high genistein dose. This study demonstrates that oral exposure of NPs to estradiol but not genistein alters reproductive tract development and that this effect may be amplified from in utero exposure to sow diets with elevated concentrations of phytoestrogens. Thus, the neonatal pig may provide a useful model for assessing effects of dietary phytoestrogens on reproductive development in infants on soy-based formulas.