Thesis (Ph. D.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains x, 83 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 75-78).

Thesis (M.S.)--West Virginia University, 2003. / Title from document title page. Document formatted into pages; contains viii, 62 p. : ill. (some col.) Vita. Includes abstract. Includes bibliographical reference.

Vestibular system (VN) is involved in the spatial recognition of animals. Animals with impaired VN were observed with poor spatial navigation abilities. The purpose of this thesis is to study the effect of muscimol on the spatial recognition of rats. It was found that the neonatal diffusion of muscimol to the VN significantly affected the spatial recognition of rats during dead reckoning test. In the light probe test, which distal visual cues were available, the treated rats spent significantly less time searching for the food pellet (student’s t-test: p<0.001). The return time was significantly higher in treated group than the sham control groupwhen they were tested in in the dark probe test (student’s t-test: p<0.001), which animals were limited to idiothetic cues. Similarly, the heading angles were significantly higher in all three different conditions, light/dark probe and new location tests (light: p<0.001; dark: p<0.001; new location: p<0.01). This finding suggests that neonatal diffusion of muscimol affects the development of vestibular nuclei and that thevestibular system is important for the processing of vestibular informationin spatial recognition. / published_or_final_version / Physiology / Master / Master of Medical Sciences

Not available / text

Examination of the scope of the [Rh(CO)₂Cl]₂-catalyzed allylic substitution reaction as well as the development of a domino [Rh(CO)₂Cl]₂-catalyzed allylic alkylation/Pauson Khand reaction is described. A number of experiments were carried out in order to explore the novel regioselectivity in the [Rh(CO)₂Cl]₂-catalyzed allylic substitution reaction, and the [Rh(CO)₂Cl]₂-catalyzed allylic substitution reaction was found to give products resulting from attack of the nucleophile on the carbon bearing the leaving group in a highly regioselective fashion in most cases. Examination of allylic carbonate substrates containing similar substitution at each allylic site was carried out, and conditions that minimize equilibration of active intermediates were determined. Intramolecular [Rh(CO)₂Cl]₂-catalyzed allylic alkylation was accomplished to synthesize challenging eight-membered lactone ring systems. Nucleophile scope was explored with regards to the [Rh(CO)₂Cl]₂-catalyzed allylic substitution reaction, and malonates, substituted malonates, aliphatic amines, and ortho-substituted phenols were all determined to be effective in the reaction. A domino [Rh(CO)₂Cl]₂-catalyzed allylic alkylation/Pauson-Khand reaction was developed which allows the rapid synthesis of bicyclopentenone products from simple, readily available starting materials. The first application of the Pauson-Khand reaction to the synthesis of azabridged bicyclic structures is also described. Various cis-2,6-disubstituted piperidines were cyclized to the corresponding azabridged bicyclopentenones is high yields often in high diastereoselectivities. The effect of ring size, nitrogen substituent, and remote functionality on the Pauson-Khand substrates was studied. The methodology developed was applied to the concise, enantioselective total synthesis of the antimalarial and anticancer indole alkaloid (-)-alstonerine. Pauson-Khand reaction of a readily available enyne synthesized in four steps from L-tryptophan provided a cyclopentenone in high yield as one diastereomer. Elaboration of the Pauson-Khand product required the development of a one pot conversion of a five-membered cyclic silyl enol ether to a sixmembered lactone and the mild acylation of a glycal.

Cancer is one of the leading causes of morbidity and mortality in developed and developing nations. It is estimated that 86% of new cases and 64% of death due to cancer are from Africa and 13.1 million deaths are estimated to occur worldwide by the year 2030. Cancer death rates have not subsided despite recent advances in cancer drug development and treatment. Present cancer drug regimens are limited due to unpredictable efficiency, severe side effects ,resistance and high cost. Plants provide a vast array of natural compounds such as terpenoids, phenolics and alkaloids with antiproliferative pro-apoptotic and antioxidant effects. Plants are principal sources of compounds for drug discovery and development of several clinically proven useful anticancer drugs. The present study focused on the isolation of compounds from the Holarrhena floribunda (H. Floribunda) leaves for their potential anticancer activities. Standard methods were employed to assess the antiproliferative potential, apoptosis, cell cycle analysis and reactive oxygen species of the methanolic leaf extract (MLE) of H. floribunda. The standard methods of isolation such as column chromatography, thin layer Chromatography, high performance liquid chromatography (hplc) and nuclear magnetic Resonance (nmr) were used to isolate and purify bioactive compounds from the leaves. To Elucidate the mechanism of cytotoxicity of the isolated compounds, apoptosis effect was studied by flow cytometry analysis using the Apopercentagetm dye, Annexin-V/PI stain, induction of cspase-3 using the Caspase-3/7 glo assay kit and Parp-1 deactivation using Western blot analysis. The mode of action was further assessed by evaluating reactive oxygen species (ros), mitochondrial toxicity, light and fluorescent microscopic morphological evaluations of F-actin and topoisomerase-I relaxation assay. In addition, potential cancer prevention of the plant was also evaluated by assessing the antioxidant activity of the flavonoids compounds isolated from the mle. The results of the present study show that the MLE of H. floribunda inhibited the proliferation of the cancer cell lines (HeLa, HT-29 and MCF-7) in a dose- and timedependent manner. The anti-proliferative activity of the methanolic extract is selective towards cancer cells more than normal KMST-6 fibroblast cells used in the study. The extract showed cytotoxicity, cell cycle arrest, induced generation of ROS and apoptosis. The methanolic extract of the leaves led to the isolation of two pure steroidal alkaloid and four flavonoid compounds. The two steroidal alkaloids - holamine and funtumine were found to be selectively cytotoxic to human cancer cells more than the normal fibroblasts. The cytotoxicity of the two steroidal alkaloids was mediated through the induction of apoptosis. The apoptosis induction was found to be triggered by the activation of caspase-3, deactivation of PARP-1, increased ROS, cell cycle arrest at G0/G1 and G2/GM phases, mitochondria toxicity, F-actin disorganization and topoisomerase-I inhibition. However, four flavonoids (kaempferol-3-O-rutinoside, quercetin-3-galactoside/glucoside, quercetin-3-O-glucoside and kaempferol-3-O-glucoside) isolated were subjected to antioxidant activity assay using oxygen radical absorbance capacity (ORAC), ferric reducing/antioxidant power (FRAP), trolox equivalent antioxidant capacity (TEAC) and lipid peroxidation inhibition. Two flavonoids with a quercetin nucleus were found to be active in the entire antioxidant spectrum, except pro-oxidant activity while the remaining two compounds with a kaempferol nucleus were selective in their activity. Structure-activity relationship analysis shows that the activity of the flavonoids depends on the ortho dihydroxyl group on the B-ring of the flavonoids. The present study on H. floribunda has shown that the leaves contain bioactive compounds with potential as anticancer agents and cancer protective and preventive activity. More work is still needed to elucidate other possible anticancer mechanisms that might be relevant to the cytotoxic effects of the two isolated alkaloids. / Philosophiae Doctor - PhD

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Master / Master of Philosophy

published_or_final_version / Biochemistry / Master / Master of Philosophy

published_or_final_version / Chemistry / Master / Master of Philosophy