A convergent synthesis of epothilone B that generates all seven of its asymmetric centers in a completely stereoselective fashion has been completed. Key reactions include an anti-Felkin aldol condensation to set the C6 and C7 stereochemistry, a directed α-hydroxylation to install the C15 (S)-hydroxyl substituent, and a Wittig condensation to join two main subunits via C-C bond formation at C9-C10. In addition, through modifications to the C9-C10 region of the macrolide, several novel and cytotoxic epothilone analogues were synthesized. Bioassay data comparing the antiproliferative activity and tubulin polymerization of the analogues with epothilone B, epothilone D, and paclitaxel showed that the synthetic analogues were less potent than their natural counterparts. / Graduation date: 2005

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This thesis is an account of my explorations into the field of natural products chemistry. These investigations led to the discovery of several novel secondary metabolites isolated from the marine cyanobacterium Lyngbya majuscula. In addition, biosynthetic investigations were undertaken using stable isotope-labeled precursors. The dominant role that NMR spectroscopy plays in the field of natural products chemistry has led to the development of several novel pulse sequences. Hectochlorin was discovered during a phytochemical investigation of a cultured L. majuscula originally collected off the coast of the Caribbean Island, Jamaica. The absolute stereochemistry was determined by X-ray crystallography. Through a series of biological evaluations, this compound was found to stimulate actin polymerization. The jamaicamide class of compound was isolated from the same organism that yielded hectochlorin. The structures were elucidated utilizing a variety of NMR methods, including a newly developed pulse sequence. Because the producing organism was in culture, a biosynthetic pathway investigation ensued to elucidate the carbon framework in jamaicamide A. The marine natural product barbamide is intriguing due to the incorporation of a trichloromethyl group into its molecular constitution. Further investigation into the timing of the chlorination reaction has been pursued. In addition, the isolation of dechlorobarbamide and the determination of the absolute stereochemistry assignment of barbamide was accomplished. A reevaluation of the stereochemistry of antillatoxin necessitated a correction in the original assignment. Four antillatoxin stereoisomers were obtained from a collaborator and found to possess differing levels of biological activity. The three dimensional solution structures of these isomers were evaluated in an effort to understand the role these stereochemical features play in the observed bioactivity. The structures were determined utilizing NMR-derived constraints applied to molecular modeling calculations. The development of two new pulse sequences for the determination of long-range heteronuclear coupling constants was also accomplished. The 1,1 ADEQUATE experiment was modified to yield an ACCORDIAN experiment which can be optimized to observe of a wide range of ��J[subscript cc] couplings. This new experiment is demonstrated for a model compound as well as for the new marine natural product jamaicamide A. / Graduation date: 2002

Thesis (Ph. D.)--Oregon State University, 2008. / Printout. Includes bibliographical references (leaves 104-124). Also available on the World Wide Web.

A novel method for determination of tetrabromobisphenol-A (TBBPA), was developed using gas chromatography-negative ion chemical ionization-mass spectrom- etry (GC-NCI-MS). Samples of municipal wastewater treatment plant (WWTP) influent were analyzed for TBBPA. Levels ranged from 1 to 41 ng/L, with an average of 20 ± 14 ng/L. Matrix effects were shown to be 30 ± 17 % in the influent and -30 ± 11 % in membrane permeate. The method limit of quantitation was 0.1 ng/L TBBPA. Sorption of TBBPA to fresh mixed-liquor suspended solids (MLSS) from a membrane bioreactor (MBR) were studied. In a kinetic study, sorption was found to be essentially complete after 12 hours of exposure to MLSS. Log Koc and log Kd were measured at 4.7 ± 0.8 and 1.9 ± 0.8 respectively (n = 22). These values were much higher than modelled estimates based on Kow (p ≥ 0.05), and higher than modelled estimates based on Kow and pKa (p ≥ 0.05). Data was successfully modelled using the Freundlich isotherm, having a Kf value of 8.5 and an n value of 1.7. TBBPA adsorbed to borosilicate glassware, with a wall-loss coefficient (Kw) of 0.15 ± 0.1 (n ≥ 3). TBBPA levels in WWTP influent varied from 13 to 29 ng/L while effluent concentrations varied from 0 to 2.2 ng/L over the same period. Three pilot-scale membrane bioreactors (MBRs) removed less TBBPA during the same time period, though MBR removal was also significant (p ≥ 0.05). Increasing MBR sludge residence time (SRT) increased removal at the 86 % confidence interval (p = 0.14). A nitrifying MABR was shown to remove TBBPA significantly when spiked with ammonia and TBBPA (p ≥ 0.05), showing that nitrifying bacteria can degrade TBBPA. An MABR hollow fibre was found to adsorb TBBPA. Various soluble microbial products (SMP) were studied from MBRs fed munici- pal influent. Using current measurement practices, SMP were shown to be sensitive to matrix effects. Use of the standard addition technique (SA) can compensate for this. Measurements using SA showed SMP degrades rapidly during storage in the fridge and due to freezing. SA was also used to compare commonly used SMP extraction techniques, and showed that extraction method influences recovery.

Thesis (Ph. D.)--Oregon State University, 2009. / Printout. Includes bibliographical references (p. 153-160) Also available on the World Wide Web.

Thesis (M.S.)--Oregon State University, 2007. / Printout. Includes bibliographical references (leaves 81-83). Also available on the World Wide Web.

Aerobic (AeMBRs) and Anaerobic Membrane Bioreactors (AnMBRs) are an essential part of the advanced wastewater treatment options, which offer advantages in terms of higher effluent discharge and smaller footprints over the traditional wastewater treatment. This study evaluates the performance of (AnMBRs) by analyzing the cumulative effect of eleven physico-chemical parameters from the data obtained from the studies conducted from year 2000 onwards. Effect of various parameters such as Solid Retention Time (SRT), Hydraulic Retention Time (HRT), Mixed Liquor Suspended Solids (MLSS), influent Chemical Oxygen Demand (COD), Organic Loading Rate (OLR), influent COD, and temperature on the COD removal, methane production and membrane fouling were evaluated. Spearman’s correlation analysis was performed to investigate the impact of environmental and operational parameters on membrane fouling, COD reduction, EPS/SMP and methane production and explain the results. It should be noted that the literature used has all needed variables; incomplete data sets were removed for the regression analysis, in this case, the fouling rate may be estimated. Of these variables, the fouling rate was significantly correlated only with flux (r = 0.291, p =

IL-36 gamma is a proinflamatory cytokine which belongs to the IL-1 family of cytokines. It is expressed in the skin and by epithelial cells (ECs) lining lung and gut tissue. We used human 3-D organotypic cells, that recapitulate either in vivo human vaginal or cervical tissue, to explore the possible role of IL-36 gamma in host defense against pathogens in the human female reproductive tract (FRT). EC were exposed to compounds derived from virus or bacterial sources and induction and regulation of IL-36 gamma and its receptor was determined. Polyinosinic-polycytidylic acid (poly I:C), flagellin, and synthetic lipoprotein (FSL-1) significantly induced expression of IL-36 gamma in a dose-dependent manner, and appeared to be TLR-dependent. Recombinant IL-36 gamma treatment resulted in self amplification of IL-36 gamma and its receptor (IL-36R) via increased gene expression, and promoted other inflammatory signaling pathways. This is the first report to demonstrate that the IL-36 receptor and IL-36 gamma are present in the human FRT EC and that they are differentially induced by microbial products at this site. We conclude that IL-36 gamma is a driver for epithelial and immune activation following microbial insult and, as such, may play a critical role in host defense in the FRT.

Thesis (M.Sc. (Biochemistry, Microbiology & Biotechnology)) - Rhodes University, 2008.