Thesis (M.S.)--University of Akron, Dept. of Chemical Engineering, 2006. / "December, 2006." Title from electronic thesis title page (viewed 06/02/2008) Advisor, J. Richard Elliott; Committee members, George G. Chase, Stephanie T. Lopina; Department Chair, Lu Kwang Ju; Dean of the College, George K. Haritos; Dean of the Graduate School, George R. Newkome. Includes bibliographical references.

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Breast cancer is one of the leading causes of death, with mortality rate estimates of 465 000 deaths per annum. It is estimated that 1.3 million women are diagnosed with the disease each year especially in the developing countries. Current chemotherapy relies on the use of high doses of non-specific toxic agents that possess adverse side effects and compromise patient’s compliance and adherence to treatment. Paclitaxel, one of the common drugs used in breast cancer chemotherapy results in sensory and motor neuropathy, whilst hormonal therapy e.g. Herceptin causes severe cardiovascular, gastrointestinal and cutaneous side effects. There has been a demand in developing newer cancer agents that demonstrate selective cytoxicity with minimal effect on normal body tissue. Numerous studies have shown that marine organisms produce a wide range of halogenated compounds that possess cytotoxic properties, and hence can be a source of new drug hits or leads for cancer therapy. Halomon, a polyhalogenated monoterpene from Portieria hornemannii, displayed interesting activity against brain, renal and lung cancer tumours with selective/differential cytotoxicity. This inspired us to focus our project on halogenated monoterpenes isolated from the same Rhodophyta class as P. hornemannii but with particular attention to Plocamium species. Several metabolites have been isolated from P. cornutum, P. corallorhiza and P. suhrii that possess interesting cytotoxicities against a breast cancer cell line (MCF7) and an oesophageal cancer line (WHCO1). The aim of the project was therefore centred at isolating target compounds for preliminary structure-activity studies against a breast cancer cell line, and use this information to synthesize a series of analogues that are more stable than the natural products and yet as active using a fragment-based type approach to map out pharmacophoric elements. Five metabolites were isolated from P. cornutum and five from P. corallorhiza. Cell-based assays were conducted using an MTT assay kit against MCF7 and MDA-MB-231 breast cancer cell lines and (1E,3E,5S,6R)-1,5,6-trichloro-2-(dichloromethyl)-6-methylocta-1,3,7-triene, isolated from P. cornutum was the most active with IC50 values of 3.0 μM and 6.15 μM respectively. Introduction of a terminal aromatic ring to enhance stability, together with varying substituents (H, CH3, CF3, Br, CN, CHO, CHCl2) on position 7 of the molecule, gave rise to a series of cinnamate ester derivatives inspired by (1E,3E,5S,6R)-1,5,6-trichloro-2-(dichloromethyl)-6-methylocta-1,3,7-triene. The analogues were synthesized from their benzaldehyde precursors via Aldol condensation, esterification and Wittig reactions. Their carboxylic acid counterparts were synthesized by hydrolysis of the parent esters in an attempt to promote water solubilities of the analogues. Biological activity assays were then conducted with the cinnamate analogues against the MDA-MB-231 breast cancer cell line using an MTT assay kit. Ester derivatives with -CHO and -CHCl2 functionalities had IC50 values of 43.45 μM and 100.01 μM respectively whilst the other ester derivatives were inactive. It was concluded that either an aldehyde (-CHO) or gem-dichlorides (-CHCl2) is specifically required for cytotoxic activity to be observed. None of the carboxylic acids were active which could have been due to failure of the compounds to enter the breast cancer cells and reach the target site because of their polar nature. Compounds with -CHO and -CHCl2 functionalities were therefore selected for future SARs studies.

The thermally induced reaction of halogenated ethylenes on the α-Cr₂O₃ (101̅2) single crystal surface results in the formation of gas phase hydrocarbons including acetylene, ethylene, butadiene, and dihydrogen, and deposition of surface chlorine adatoms. No surface carbon or combustion products are observed in any reactions indicating no thermally induced C-C bond cleavage occurs and surface lattice oxygen is not incorporated into surface intermediates. Thermal desorption spectroscopy indicates that in all halogenated ethylene reactions acetylene is the major product, regardless of the reaction scheme. The surface reactions of halogenated ethylenes are proposed to proceed through C-X (X=halogen) bond cleavage to form surface halogen adatoms and surface C2 hydrocarbon fragments. Halogen adatom deposition affects reaction barriers to hydrocarbon formation, and eventually shuts down surface chemistry. Photoemission and near edge x-ray absorption fine structure spectra show that all studied reactants undergo some C-X bond cleavage upon low temperature adsorption forming adsorbed C2 fragments and halogen adatoms. Photoemission for each reaction system shows at least two C1s features (283.0-286.0 eV) and two Cl2p features (2p_3/2=198.0-201.0 eV) with higher binding energy features associated with molecularly intact halogenated ethylenes and lower binding energy features associated with dissociated surface species. Near edge x-ray absorption fine structure spectra taken, corresponding to photoemission spectra, indicate the occurrence of C1s→π∗ transitions, indicating intact π-systems are present. Heating the surface results in a reduction in intensity of higher energy photoemission and near edge x-ray absorption fine structure indicative of a decrease in surface C-X bonds. / Ph. D.

Methods of determining the aqueous solubilities of twelve chlorinated benzenes were evaluated in pure and in different water matrices. In pure water, results were comparable with the calculated values. Higher chlorinated tetrachlorobenzenes (TeCBs), pentachlorobenzenes (PCBz), and hexachlorobenzenes (HCBs) gave better precision and accuracy than lower chlorinated monochlorobenzenes (MCBs), dichlorobenzenes (DCBs), or trichlorobenzenes (TCBs).

Haloalkenes were shown to react with cysteine, N-acetyl cysteine, or glutathione to form halogenated vinylthio (HVT) or saturated conjugates. When HVT were administered iv to rabbits, active transport in the renal tubules was inhibited 50% at doses as low as 20 mg/kg within 1 hr after dosing. There was sloughing of the renal brush border membrane with the injury progressing to a specific renal tubular necrosis of the S₃ segment. In vitro studies with renal tubules found that the HVT produced a dose-response related inhibition of acid/base transport, with complete inhibition of transport occurring at 1 mM. The cysteine conjugate synthesized from trichloroethylene, DCVC, inhibited tubular active transport 60 min after in vivo dosing (20-100 mg/kg), 45 min after exposure in the isolated perfused kidney (0.01-1 mM) and 15 min after incubation with isolated tubules (0.01-1 mM). All HVT conjugates had a similar potency with regard to transport inhibition in isolated tubules, with complete inhibition occurring at 1 mM within 15 min for cysteine conjugates compared to 45-60 min for the N-acetyl cysteine or glutathione conjugates. These latter conjugates are thought to be bioactivated to the cysteine conjugate prior to transport inhibition. Inhibition of tubular (gamma)-glutamyl transpeptidase by 1 mM AT-125 or 20 mM serine/borate prevented the inhibition of acid/base transport by the glutathione conjugate. In addition, the sequential formation of glutamate, glycine and the vinyl cysteine conjugate after tubule incubation with the glutathione conjugate provides further evidence for this bioactivation. The cysteine conjugates are thought to be further metabolized in tubules to a toxic intermediate by a brush border localized enzyme, C-S lyase. The inhibitor effect of this intermediate on acid/base transport is reversed in the presence of, or subsequent addition of, 6 mM exogenous glutathione. These studies provide further evidence for the nephrotoxicity of HVT, and formation of the nephrotoxic cysteine conjugates from glutathione and cysteine conjugates. The formation of saturated conjugates from CTFE was also demonstrated. These saturated and/or unsaturated conjugates may be responsible for haloalkene-induced nephrotoxicity.

by Chiu Peng Fai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 82-87). / Abstracts in English and Chinese. / Table of Contents --- p.i / Acknowledgements --- p.iv / Abbreviations --- p.v / Abstract --- p.vi / Chapter Chapter 1 --- Introduction / Chapter 1.1 --- Definition of Carbon Hydrogen Bond Activation (CHA) by Transition Metal Comple --- p.1 x / Chapter 1.2 --- The Importance of Alkane CHA and its Potential Use --- p.1 / Chapter 1.3 --- Difficulties in Alkane CHA --- p.3 / Chapter 1.4 --- The Use of Transition Metal Complexes in CHA Reactions --- p.4 / Chapter 1.5 --- Classification of CHA Reactions --- p.6 / Chapter 1.6 --- The Importance of Toluene and Benzene CHA --- p.11 / Chapter 1.7 --- Difficulties and Challenges in CHA of Toluene --- p.11 / Chapter 1.8 --- Selectivity Control and Rate Promotion --- p.12 / Chapter 1.9 --- Structural Features of Rhodium Porphyrins --- p.17 / Chapter 1.10 --- CHA by Rhodium Porphyrins --- p.19 / Chapter 1.11 --- Objective of Work --- p.21 / Chapter Chapter 2 --- CHA Reactions of Toluenes by Rhodium Porphyrin Chlorides / Chapter 2.1 --- Synthesis of Rhodium Porphyrin Chlorides --- p.22 / Chapter 2.2 --- Temperature Effects of CHA in Toluene --- p.22 / Chapter 2.3 --- Inter and Intra Molecular Exchange of Alkyl Rhodium Porphyrin Complexes --- p.24 / Chapter 2.4 --- Electronic Effect of Rhodium Porphyrin Chlorides --- p.24 / Chapter 2.5 --- Electronic Effect of Toluene Towards CHA --- p.25 / Chapter 2.6 --- X-Ray Data --- p.26 / Chapter 2.7 --- Mechanistic Studies --- p.30 / Chapter 2.8 --- Ligand and Base Effects --- p.32 / Chapter 2.9 --- Optimization of Reaction Conditions --- p.35 / Chapter 2.10 --- Electronic Effect of Toluenes --- p.36 / Chapter 2.11 --- Concentraction Effects of Toluenes (Reactions in Benzene) --- p.38 / Chapter 2.12 --- Porphyrin Effects in CHA of Toluene --- p.39 / Chapter 2.13 --- Mechanistic Studies --- p.40 / Chapter 2.14 --- Conclusion --- p.42 / Chapter 2.15 --- Reaction between Rh(ttp)Me and Toluenes --- p.42 / Chapter 2.16 --- Selective Benzylic CHA --- p.42 / Chapter 2.17 --- Isotope Effect --- p.44 / Chapter 2.18 --- Discussion --- p.44 / Chapter 2.19 --- Exploratory Studies of Other Base-Promoted Reactions --- p.45 / Chapter 2.20 --- Benzylic CHA and Aromatic Carbon Halogen Bond Activation (CXA) Reactions --- p.45 / Chapter 2.21 --- Base-Enhanced Aromatic CXA --- p.48 / Chapter 2.22 --- X-Ray Data --- p.49 / Chapter 2.23 --- Base-Enhanced Benzylic Carbon Carbon Bond Activation (CCA) Reactions --- p.51 / Chapter 2.24 --- Summary --- p.52 / Chapter Chapter 3 --- Experimental Sections --- p.53 / References --- p.82 / Appendix I Crystal Data and Processing Parameters --- p.88 / Appendix II List of Spectra --- p.123 / Spectra --- p.125

Interest in halocarbons has been sparked by experimental evidence suggesting that these compounds are potential carcinogens and teratogens. The U.S. EPA started a nationwide program in 1970 to identify and quantify trace organic compounds in public water supplies and sewage effluents. To date no detailed large-scale areal ground-water surveys delineating concentrations of these halocarbons have been reported in the literature at the part per trillion level and below. The objectives of this dissertation are twofold: (1) identification, quantification, and detailed areal mapping of several halocarbon species in ground water near the Santa Cruz River northwest of Tucson, Arizona; and (2) development of halocarbon techniques for age dating recently recharged (0-40 years old) ground water. The halocarbon compounds considered are: trichlorofluoromethane (CC1₃F), dichlorodifluoromethane (CC1₂F₂), carbon tetrachloride (CC1₄), chloroform (CHC1₃), trichloroethylene (C₂HC1₃), methyl chloroform (CH₃CC1₃), and tetrachloroethylene (C₂C1₄). Objective (1) includes discussions of the areal halocarbon distributions detected in the ground water, their sources, and a qualitative comparison of the distributions to ground-water quality and land use patterns adjacent to the Santa Cruz River. Objective (2) utilizes the exponential atmospheric concentration buildup of CCl₂F₂, CC1₃F, and CCl₄, and the ratios of CCl₂F₂ to CCl₃F and CCl₄ to CCl₃F. Water samples from wells and the Santa Cruz River were collected in glass syringes and brought to the laboratory for analysis. An electron-capture gas chromatograph coupled to a gas stripping/concentration unit was used to quantify the halocarbons. Four high concentration areas were delineated, each probably associated with a different source: the CWUA area which was irrigated with sewage effluent during the 1960's; Rillito Creek (near its confluence with the Santa Cruz) which is a major ground-water recharge source; the Ina Road treatment plant/landfill/oxidation ponds area; and the Roger Road treatment plant "sewer farm" which is irrigated with sewage effluent. The CCl₂F₂ to CCl₃F ratio distribution indicates that most ground water in the study area is at least partially mixed with recharge less than 30 years old. The ground water adjacent to the Rillito has an apparent age of less than 10 years, in agreement with the CCl₃F distribution. Ground water in the Cortaro area has an apparent age of about 25 years, correlating with the start of irrigation in the area.

Zebra mussels (Dreissena polymorpha) have invaded a great proportion of the waters of the eastern part of North America. This mollusk may be a useful sentinel species for bioaccumulation of heavy metals and organic contaminants in aquatic ecosystems. The zebra mussel's capacity to bioaccumulate cadmium at environmentally relevant exposure and to sequester metals in metal-binding proteins, metallothioneins, was investigated. Elevated (relative to control) concentrations of Cd$ sp{2+}$ were detected in Dreissena exposed to $ ge$2 $ mu$g Cd/liter suggesting that zebra mussels cannot regulate Cd$ sp{2+}$ of trace exposure concentration. More than 85% of the measured Cd$ sp{2+}$ was bound to metallothioneins. / Lesser scaup (Aythya affinis) was assessed as a model species for potential impacts of zebra mussels on higher trophic levels. The feasibility of incubating and rearing scaup in semi-natural conditions was evaluated. A series of biomarkers was assessed in 3 groups of scaup fed a contaminant-free diet or diets containing zebra mussels from the St-Lawrence River or Lake Erie. / Lesser scaup proved to be a suitable species to raise in captivity providing daily water misting through out incubation and strict hygiene conditions during brooding. A hatching success of 89% was achieved. Appropriate housing, feeding and bathing conditions yielded low (3%) post-hatching mortality. / Phagocytosis and respiratory burst activities of heterophils of scaup were suppressed after 6 weeks of feeding on zebra mussels, compared to the control group. These two heterophilic functions were negatively correlated with the incidence of pododermatitis (bacterial feet infection), suggesting a suppression of the non specific immunity. Increased liver/body mass ratio and decreased hepatic vitamin A (retinol and retinyl palmitate) concentrations were observed in scaups fed zebra mussels. Lipid accumulation and glycogen overload were found in the livers of scaups fed mussels from the St-Lawrence River and the Lake Erie groups, respectively. These immunological, biochemical and histopathological biomarkers show promise for monitoring "early" injury and may help in the understanding of health impairment of different species of waterfowl exposed to xenobiotics via contaminated food sources.

This PhD thesis investigates the transport and distribution of short-lived halogenated organic substances in the tropical tropopause layer (TTL) in the Pacific Ocean. Short-lived halocarbons are one of the major groups of the ozone depleting substances as they provide a source for the active halogens which decrease ozone in the atmosphere. The TTL serves as the primary gateway of tropospheric air to enter the stratosphere. The air which enters the stratosphere is distributed all over the globe. Thus, the research on which tropospheric air masses go into the TTL, its structure and composition and the transport within is crucial. This thesis uses the UK Meteorological Office Lagrangian particle dispersion model NAME to (i) support the flight planning activities and achieve the multi aircraft coordination in CAST, CONTRAST, ATTREX 2014 campaigns, and (ii) quantify the amount and distribution of short-lived halocarbons in the TTL, and explain differences in these vertical distributions and transport characteristics. The halocarbons of interest are methyl iodide (CH3I), bromoform (CHBr3) and dibromomethane (CH2Br2). A new NAME procedure was developed and operated successfully to provide routine simulations and near real-time products suitable for guiding the CAST, CONTRAST and ATTREX aircraft in order to achieve their mission scientific objectives, and to make coordinated measurements. NAME was used post-campaign to analyse distribution of short-lived halocarbons in the TTL, identify their source regions and transport timescales. A new approach is proposed to investigate the TTL composition in terms of the boundary layer air influence, and subsequently quantify CH3I, CHBr3 and CH2Br2 by estimating their boundary layer and background contribution. The sums of these modelled estimates are in good agreement with the ATTREX 2014 and 2013 CH3I, CHBr3 and CH2Br2 observations. The quantification of the contribution of short-lived bromocarbons to the active bromine in the TTL was achieved, and the results lie within the range of the recent literature studies. The final focus of this thesis is on how well NAME represents the particle displacement via convection. Convection is the major transport pathway for the short-lived halocarbons to reach the TTL. The role of convection in transporting CH3I, CHBr3 and CH2Br2 to the TTL is assessed using the new convection scheme in NAME. A validation of the performance of this scheme is provided, showing that it yields improved and more realistic representation of the particle displacement via convection.