Persistent organochlorines (OCs) bioaccumulate in aquatic biota and potentially impair reproduction via endocrine disruption. The present research evaluated estrogenic effects of the OCs, chlordecone (CD) and o,p'-DDT/DDE, and the antiestrogenicity of 3,4,5,3',4',5'-hexachlorobiphenyl (345-HCB) in juvenile rainbow trout, utilizing vitellogenesis as a biomarker. Vitellogenesis, estrogen regulated hepatic production of the yolk...
Recent developments in NMR hardware have extended the reach of natural products chemists to structure elucidation of compounds isolated on a nanomolar scale. In parallel with advances in hardware new NMR techniques for structure elucidation have evolved, e.g. quantitative NOEs, residual dipolar couplings (RDCs)and diffusion-ordered spectroscopy (DOSY). The application of...
A Diels-Alder approach to biaryls (DAB) has been applied towards the synthesis
of highly substituted, programmable biaryl templates. Tri- and tetra-ortho-substituted
biaryls can be produced in just three to four steps from commercially available materials
utilizing the Diels-Alder [4+2] cycloaddition. The methods described herein will
illustrate the ability of mono...
Ambifunctional axially chiral 2,2',6,6'-tetrasubstituted biphenyls containing nucleophilic (or basic) functional groups juxtaposed with hydrogen-bond donors were synthesized and their properties studied. Applications for the prepared biaryls as potential organocatalysts for enantioselective carbon-carbon bond forming reactions were examined. Processes investigated included: aldol, Michael, nitroaldol (Henry), and Baylis-Hillman reactions.
The novel amidoamine...
Aerobic organisms have evolved many sensory mechanisms that allow
response to oxidants in the environment. One area of interest is the relationship
between the activity of the tumor suppressor protein p53 and the redox state of
thioredoxin. Human p53 activity is severely compromised in budding yeast lacking
thioredoxin reductase. Evidence...
Overtly non-toxic doses of organochlorine (OC) insecticides perturb lipid homeostasis
in mice and rats. To increase understanding of how chlordecone (CD), an OC
insecticide, modulates cholesterol (CH) homeostasis, we determined the effect of CD
pretreatment on the tissue and hepatic subcellular distribution of exogenous [¹⁴C]CH. Corn oil alone or CD...
I have participated in a drug discovery program designed to screen marine algae for
inhibitors of cancer-related enzymes, antitumor compounds, antiinflammatory substances,
and other agents of potential pharmaceutical utility. Over 1,500 lipid and aqueous extracts
of marine plants and animals were surveyed for biomedical potential. Assays designed to
screen extracts...
The isoprenoid pathway is one of the major biosynthetic pathways of secondary metabolites. Isoprenoids with a C₂₀ skeleton are known as diterpenoids and are derived from the common precursor, geranylgeranyl diphosphate (GGPP). This dissertation describes approaches to discover the diterpene synthase enzymes which provide the backbone structures for pleuromutilin and...
This project describes the investigation of marine cyanobacteria collected from the Red Sea with an emphasis on the identification and prioritization of biologically active fractions for future purification and molecular structure elucidation of medicinally relevant secondary metabolites.
Five crude extracts of taxonomically unidentified Red Sea cyanobacteria supplied by Egyptian collaborators...
Quinolinate (QUIN) is an endogenous neurotoxic product of the kynurenine
pathway of tryptophan metabolism. Quinolinate is a selective agonist of the NMDA
family of glutamate receptors and, as such, may play a role in the pathology of a number
of major central nervous system (CNS) disorders. These include both chronic...
Tetracycline (Tet)-resistant strains of Chlamydia suis were isolated from swine
farms in the Midwest. The isolation of the resistant strains was significant
because Tet is an antibiotic used to treat infections by veterinarians and
doctors. One of the tetracycline (Tet)-resistant strains, R19, was able to
survive in Tet up to...
Myxobacteria represent an interesting class of Gram-negative soil bacteria. These bacteria utilize organic materials from the environment as a food source by the action of their extracellular hydrolytic enzymes. They grow vegetatively in the presence of adequate nutrients. During starvation conditions, however, they aggregate and form multicellular structures called fruiting...
Two novel and highly related C₂H₂ zinc finger proteins (CTIP1/BCL11A/EVI9 and CTIP2/BCL11B/Rit1) have been implicated in COUP-TF signaling, etiology of myeloid and lymphoid malignancies, and hematopoietic cell development. However, the precise cellular function(s) and the contribution of these proteins to neoplastic processes and hematopoietic cell development remain unknown. The goal...
Pactamycin, a potent antitumor antibiotic produced by the soil bacterium Streptomycespactum, is a structurally unique aminocyclopentitol-containing natural product. Itconsists of a highly functionalized cyclopentitol core unit, two aromatic rings [3-aminoacetophenone (3AAP) and 6-methylsalicylic acid (6MSA)], and a 1,1-dimethylurea moiety. Despite its potent biological activity, the development of thisantibiotic was hampered...
The discovery of new antibiotics reached its peak during the golden era of antibiotics in the mid 20th century and continued to thrive until the 1980s. However, after more than 50 years of fruitful exploration and exploitation of microbial natural products the discovery rate of new antibiotics has dropped drastically...
This thesis describes an investigation of the molecular basis of the substrate specificity and catalytic mechanism of a unique pseudoglycosyltransferase (PsGT) enzyme, VldE. PsGTs are a newly discovered group of glycosyltransferase (GT)-like proteins that catalyze the transfer of a pseudosugar to an acceptor molecule via a C-N bond formation. This...
Microbial natural products represent a massive repository of unique chemical scaffolds with corresponding diverse biological functions. However, in the past decade the development of natural products into new therapeutics has dwindled, in part due to the challenges posed by high rediscovery rates and low throughput associated with classical bioassay-guided fractionation...
Metagenomics has revealed that the marine microbial biosphere is immensely more diverse than originally considered, and is an almost untapped reservoir for the potential discovery of microbial natural products. Despite numerous advances in culturing, biosynthetic engineering and genomic-based screening efforts to uncover much of this diversity in relatively accessible environments,...
This thesis details my investigations of marine cyanobacterial natural products that resulted in the discovery of thirteen new secondary metabolites, the isolation of over fifteen previously reported metabolites and the biosynthetic investigation of two additional cyanobacterial compounds. Two novel lipopeptides were identified from a Lyngbya majuscula and Schizothrix sp. assemblage...
This dissertation describes studies of isoprenoid biosynthesis in the
phytoflagellate Euglena gracilis. Elucidation of a novel isoprerioid pathway, the 2-Cmethyl-D-erythritol-4-phosphate (MEP) pathway, in addition to the generally known
mevalonate (MVA) pathway, led to extensive exploration of the distribution of both pathways in a variety of organisms. To date, photosynthetic eukaryotes...
Marine organisms produce a variety of secondary metabolites for defense, communication, and reproduction. While these uses are essential for the organisms' survival, marine natural products have demonstrated their value to human society as well. Asian countries used algae for centuries to treat or prevent illnesses as wide-ranging as cough, gout,...
Cyanobacteria are rich in biologically active secondary metabolites, many of which have potential application as anticancer or antimicrobial drugs or as useful probes in cell biology studies. A Jamaican isolate of the marine cyanobacterium, Lyngbya majuscula was the source of a novel antifungal and cytotoxic secondary metabolite, hectochlorin. The structure...
Among the myriad of naturally occurring bioactive compounds are the aminocyclopentitol-containing natural products that represent a family of sugar-derived microbial secondary metabolites, such as the antibiotics pactamycin, allosamidin, and trehazolin. Pactamycin, a structurally unique aminocyclitol antibiotic isolated from Streptomyces pactum, consists of a 5-membered ring aminocyclitol (cyclopentitol) unit, two aromatic...
Wood-plastic composites (WPCs) are one of the fastest-growing sectors of the
wood composites industry. However, the strengths of WPCs are typically low
because of the poor interfacial adhesion between hydrophilic wood and
hydrophobic thermoplastics. A compatibilizer that can form bridges between wood
and plastics is required to give WPCs desirable...
Tuberculoѕiѕ (TB) iѕ a number one killer among treatable infectious diseases. It is caused by the pathogenic bacterium Mycobacterium tuberculoѕiѕ that primarily affects the lungѕ. It infects one third of the world population and kills approximately 2 million people each year (based on WHO report). Drug-reѕiѕtant TB haѕ become a...
This thesis describes the chemical investigation of marine cyanobacteria collected in Madagascar and Panama with an emphasis on the isolation and structure elucidation of medicinally relevant secondary metabolites.
A collection of the marine cyanobacterium Lyngbya majuscula from the Radames Islands, Madagascar yielded two new cyclic depsipeptides, radamamides A and B,...
7,7'-Dihydroxy-8,8'-biquinolyl (azaBINOL) was prepared from 7-hydroxyquinoline via N,N-dimethyl O-quinol-7-yl carbamate by directed ortho-metallation followed by FeCl₃-mediated oxidative coupling of the 8-lithioquinoline intermediate. Saponification of the resulting dicarbamate provided crystalline (±)-azaBINOL in 56% overall yield. 6,6'-Bis(dimethylaminocarbonyl)-7,7'-dihydroxy-8,8´-biquinolyl was prepared from the same dicarbamate by a double anionic-Fries rearrangement in 43% yield. 7,7'-Bis(diethylamino-carbonyloxy)-6,6'-diiodo-8,8´-biquinolyl...
A gene cluster responsible for the biosynthesis of the antitumor agent
cetoniacytone A was identified in Actinomyces sp. strain Lu 9419, an
endosymbiotic bacteria isolated from the intestines of the rose chafer beetle. The
nucleotide sequence analysis of the 26 Kb DNA region revealed the presence of 17
complete ORFs,...
The work presented here is focused on applying basic principles of solid-state chemistry to the study and development of new wide band-gap semiconductors and insulators for photovoltaic and electronic-device applications. Analysis of crystal structure, band structure, optical band gap, morphology and transport properties provides fundamental insight into materials performance as...
This thesis is an investigation of the natural products deriving from marine algae and cyanobacteria and has resulted in the discovery of eleven new secondary metabolites. The structure elucidations of these new molecules were performed using a variety of spectroscopic techniques. Four new macrolides were isolated and characterized from the...
Debris flow initiation is controlled by a complex interaction of geology, geomorphology, climate, and weather. In the Cascade Range of Pacific Northwest and mountainous areas globally, patterns of temperature and precipitation are being altered by climate change, which may in turn impact debris flow initiation. Temperature has increased and patterns...
Methane is a flammable gas that is the main component of natural gas. It is a highly potent greenhouse gas, and accounts for about 20% of greenhouse gas emissions. Methane is routinely flared in many industrial processes without harnessing any of its energy. The environmental impact and wasted energy potential...
Vibrio parahaemolyticus is a seafood-borne pathogen that can cause gastroenteritis in humans. This study investigated the effectiveness of refrigerated seawater (5°C) depuration on reducing V. parahaemolyticus in raw Pacific oysters (Crassostrea gigas). Raw Pacific oysters were inoculated with a mixed culture of five clinical strains of V. parahaemolyticus and depurated...
Pseudoloma neurophilia is the most common pathogen reported in zebrafish (Danio rerio) research facilities and is an important threat to the zebrafish model. This microsporidian parasite can cause clinical disease, but more importantly is a causative agent of non-protocol induced variation in research. Studies utilizing infected zebrafish, could potentially confound...
A functional test battery (FTB), which combines the use of subjective and objective functional measures, has been proposed as a potential means to distinguish anterior cruciate ligament reconstructed (ACLR) patients' that can more safely participate in activity from those at greater risk. However, no previous study has directly assessed whether...
SAR11 Alphaproteobacteria are the most abundant aerobic chemoheterotrophs in ocean surface waters. Previous studies have indicated SAR11 cells play an important role in marine carbon cycling and consume up to half of some common dissolved organic compounds, such as amino acids. During sequencing of the first SAR11 genome, genes for...
How complex traits evolve continues to be a major focus of evolutionary
investigation. A current topic of debate is the hypothesis that the phenotypic
integration of complex traits gives rise to evolutionary constraints. I studied two color
traits in the common garter snake, Thamnophis sirtalis, that show a high level...