<p> One of the key contributors to the pathogenesis of various diseases is "nitroxidative stress," a condition caused by the overproduction of peroxynitrite (PN). Redox-active transition metal complexes, which function as PN decomposition catalysts (PNDCs), can redirect oxidative potential of PN and are therefore able to reduce nitroxidative stress. Herein, synthetic methods for making polyfunctional trianionic dipyrromethene (DPM) ligand systems with an X-conjugation site for biomolecule coupling were studied. In addition, derivatives of PNDCs with electron donating groups were synthesized to vary the physicochemical properties and study the catalytic activity. Cross coupling of aryl bromide analogues of PNDCs with amines under Buchwald-Hartwig reaction conditions were investigated. Post-chelate conjugation of a variety of acetylene derivatives with an aryl bromide of the DPM backbone under Sonogashira coupling conditions was also studied. Finally, a succesful Suzuki cross-coupling of the key PNDC aryl bromide with a functionalized aryl boronic acid was demonstrated. Since both PNDCs and S1P antagonists are effective in treating inflammatory and neuropathic pain, hypothesized that a conjugate of our Mn(III)-DPM and a functional antagonist (FTY-720) of the sphingosine-1-phosphate receptor(s) may have synergistic activity. Synthetic routes for preparing two prototype analogues via the X-conjugation site chemistry were also developed.</p>

We describe the total syntheses of $(\pm)$-phyllanthocin (1), the aglycon of the potent antineoplastic agent phyllanthoside (2a), and of $(\pm)$-chlorovulone II (3), a halogenated marine prostanoid with high antiproliferative and cytotoxic activity.* The key step of both syntheses is a novel carbonyl ene reaction, which occurs between ordinary aldehydes and vinyl ethers that display the oxygen functionality at the central carbon of an allylic system, e.g., 2-methoxypropene, under the catalytic influence of 0.5 mol% of the 1:1 complex of Yb(fod)$\sb3$ and acetic acid (Figure I).* ftn*Please refer to dissertation for diagrams.

The presence of an extensive enterorecirculation of amino acids between the intestine and the body, allows for the removal of elevated systemic phenylalanine present in the phenylketonuric condition, by oral administration of microencapsulated phenylalanine ammonia-lyase(28). The work presented in this thesis, had the main goal of assessing the feasibility of phenylalanine ammonia-lyase (PAL) loaded collodion microcapsules, in reducing elevated plasma phenylalanine concentrations to standard levels in genetically mutated, ENU2 PKU mice, within a 30 day time frame. The distinguishing aspect from similar previous studies, originated with the available animal model. Rather than artificial induction of elevated phenylalanine plasma levels, the mice representing the human phenylketonuric condition, were mutated strains, deficient in the enzyme phenylalanine hydroxylase. / The first in vivo study established a method for orally feeding microcapsules, over 30 consecutive days, by mixing with soft, unripened cheese. The second animal study confirmed the finding in the first study that there is no significant decrease in the plasma phenylalanine levels within the first seven days of treatment. (Abstract shortened by UMI.)

Novel heteroanthracycline antitumor drugs were designed based on structure activity relationship studies and known mechanisms of drug action. Their preparation required the development of a general synthetic approach. / After extensive studies, three methodologies were developed for the general synthetic plan. The first method involved photoenolisation of 2,5-dimethoxybenzaldehyde and SO$ sb2$ entrapment of the o-quinodimethane to give 4,7-dimethoxy-1-hydroxy-1,3-dihydrobenzo(2,3-c) thiophene-2,2-dioxide. This compound served as a general intermediate towards the synthesis of several heteroanthracyclinones. It could be reduced to the oxathiin-2-oxide derivative which thermally extruded SO$ sb2$ to yield the o-quinodimethane. Reentrapment of this latter intermediate with various glyoxalates gave key isochroman derivatives. The second method is an improvement over the first. Isochromandiones with a C-1 hydroxyl functionality were prepared from oxidative demethylation of 1-hydroxyisochromans. These were obtained after acid hydrolysis of the coupling products between epoxides and the cuprate of 2,5-dimethoxy-6-methylbenzaldehydedioxane acetal. The third method involved a sequential cycloaddition routine with two o-quinodimethanes. / By combining newly developed techniques with known methods, a general synthetic plan was developed. Consequently, the total synthesis of six tetracyclic structural hybrids of the naphthoquinone(2,3-c) pyranyl class of antibiotics was accomplished; along with the total synthesis of (R) and (S) 1-(4$ sp prime$-O-p-nitrobenzoyl-N-trifluoroacetyldaunosamine)-$ 1,3$-dihydrothioxantho(2,3-c) thiophene-2,2-dioxide, p-nitrobenzyl(5,12-dihydroxy-3,4-dihydrothioxantho(2,3-c) and (3,2-c) pyran-3-yl)formate, and eight novel heteroanthracyclines with the 5,12-dioxo-2,3,5,12-tetrahydroanthraceno(2,3-c) pyranyl backbone. The diastereomeric mixture of (1$ sp prime$S, 1R, 3S) and (1$ sp prime$S, 1S, 3R) methyl(11-hydroxy-1-$(2 sp prime,3 sp prime,6 sp prime $-trideoxy-3-trifluoroacetamido-L-lyxohexopyranose)-$5,12 $-dioxo-3,4,5,12-tetrahydroanthraceno(2,3-c) pyran-3-yl) formate was found to possess equipotent antileukemic activity to doxorubicin with no cross resistance.

<p> This thesis includes many different production and research projects that can help make many positive advances in the pharmaceutical and biomedical area. The first part of my thesis describes my practical experience at Anatrace Products, LLC. Included in this chapter is the large scale synthesis of amphiphiles for biological uses. The second part of the thesis describes my attempt to build an analytical profile of polar extracts from mastic gum for the potential treatment of chronic obstructive pulmonary disease.</p>

<p> The body of this dissertation is focused on understanding the pathomechanisms and paving the way for new treatment paradigms in human metabolic disease, particularly phenylketonuria (PKU), maple syrup urine disease (MSUD), and succinic semialdehyde dehydrogenase (SSADH) deficiency.</p><p> Phenylketonuria and MSUD are heritable aminoacidopathies displaying aberrant cerebral transport of large neutral aminoacids. This work presents evidence that non-physiological amino acids (NPAAs) have pharmacodynamic efficacy in selective exclusion of phenylalanine from the brain of phenylketonuric mice. Data is presented for feeding and intraperitoneal injection studies of various NPAA's including methyl-aminoisobutyric acid (MAIB), and some selected MAIB-related alkanoic acid analogues. My data indicates that MAIB is the most selective phenylalanine transport inhibitor identified thus far. Regional brain amino acid studies in intermediate MSUD mice fed low (6%) and high (19%) protein chow suggest that despite varying improvements in the pathophysiological branched-chain amino acids (leucine, isoleucine and valine) in serum, glutamine, aspartate, glutamate, gamma-aminobutyric acid (GABA), asparagine, citrulline, and serine levels remained unchanged in the brain, demonstrating that dietary correction of MSUD monitored in blood does not accurately reveal corrections in brain biochemistry, providing important insights for human patients. Moreover, I have documented similar findings in PKU mice.</p><p> The final chapters of this work contain a review of the treatment prospects for SSADH disorder (a defect in GABA metabolism), and our collaborative work with the University of California focused on hyperphysiological GABA's on mTOR-driven selective autophagy. SSADH-deficient mouse studies utilizing electron microscopy to quantify mitochondria in liver and brain tissues suggest mitophagic inhibition may play a causal role in the findings of oxidative stress in patients and mice. The impact of these findings are discussed from a pharmacological viewpoint including the scope of treatment of hyperGABAergic disorders.</p><p> Lastly, I have included my literature characterization of hepatocyte transplantation (HTx) for inborn errors of metabolism which suggests that we can attempt therapeutic HTx in a murine model of a new disease, transaldolase deficiency, with a goal of gaining almost complete hepatic repopulation with gene-replete (wild-type) cells. My final article is a preclude to future postdoctoral work in the area of liver repopulation and novel therapeutic approaches.</p>

<p> Secondary metabolites are organic compounds that are not directly involved in the key processes (growth, reproduction and development) of an organism. They are commonly targeted in pharmaceutical science for drug discovery. Secondary metabolites that have been used in drug discovery have been derived from plants, invertebrates and microbes. Microbes, bacteria in particular, have contributed greatly and will continue to play an important role in new drug discovery. Among the bacteria from all environments, marine bacteria are a vast reservoir for many potential useful bioactive compounds. Recent studies using marine bacteria for pharmaceutical use mainly focused on the bacteria collected from near-shore sediments. However, bacteria from deep-sea sediments remain unexplored. The South Pacific Gyre (SPG) is the most oligotrophic region of the world ocean. Due to the low surface productivity and distance from land, sediments below the gyre accumulate very slowly and are characterized by very low organic carbon content and relatively high dissolved oxygen concentrations. Sediments from South Pacific Gyre were found to host a living microbial community that, compared to other marine sediments, contains very low microbial biomass and very low metabolic activity. Thus, the goal of this study is to: (1) document the cultivatable bacterial diversity; and (2) explore the pharmaceutical potential of deep-sea bacteria from South Pacific Gyre sediment. To address this, bacteria were isolated in pure culture from sediments from seven sites of the Integrated Ocean Drilling Program (IODP) Expedition 329 in the South Pacific Gyre. 16S rRNA genes from 81 bacterial isolates throughout six SPG sites (U1366, U1367, U1368, U1369, U1370 and U1371) were sequenced for phylogenetic analysis using the RDP (Ribosomal Database Project). 16S rRNA genes were amplified with bacterial primers that have been proven to amplify bacterial sequences well (27F, 1392R). Whole genomes from nine Rhodococcus isolates (with two duplicates) throughout four SPG sites (U1366, U1367, U1370 and U1371) were sequenced for secondary metabolites gene clusters discovery. By using antiSMASH (antibiotics &amp; Secondary Metabolite Analysis SHell), secondary metabolite biosynthesis gene clusters in the bacterial genome were identified, annotated and analyzed. Of the 81 16S rRNA gene clone libraries constructed, most of the clones (63%) affiliated with the genus Bacillus, 35.8% were affiliated with the genus Rhodococcus and one clone was identified as a Corynebacterium. The phylogenetic tree further indicated that all the Rhodococci were identified as Rhodococcus erythropolis. By using antiSMASH to look for the secondary metabolites gene clusters from the Rhodococcus genomes, many gene clusters, most of which were NPRS and PKS, were found in the genomes. This study suggests that deep-sea sediments harbor bacteria with the potential to produce pharmaceutically important secondary metabolites.</p>

<p> With healthcare moving rapidly toward interprofessional expectations, this study examined the perceptions of a particular population of students pursuing a degree in the healthcare field. Pharmacy students attending a free-standing pharmacy institution were interviewed over the course of the 2012 - 2013 academic year. Interviews were conducted before, during, and after the students engaged in collaborative coursework with students from a variety of health care majors attending a nearby institution. The results demonstrated the positive impact exposure to peer students pursuing degrees in health care fields can have. Results of the interview process highlighted the impact intentional interaction with a variety of students (i.e. medical, nursing, social work, physical therapy, occupational therapy, and physician assistant students) had for the students at the free-standing pharmacy institution. Results also demonstrated an increase in the perceived value of collaboration with other health care professionals. Additionally, results highlighted the importance of respect and communication as active components of interprofessional collaborations. Study participants grew in their understanding of their own role in the field of healthcare. Lastly, the depth of participants' understanding of optimal patient care grew over the course of the intentional interaction during the academic year. Along with presenting and analyzing the results of the interview process, this document makes suggestions regarding practical application of said results to the academic curriculum at an institution granting only a pharmacy degree.</p>

<p> The excessive production of peroxynitrite (ONOO^-) anion is well-known to play a significant role in numerous diseases including chronic inflammation, Type II Diabetes Mellitus (T2DM), Alzheimer's, and Parkinson's. The highly reactive peroxynitrite (PN) is known to nitrate and oxidize proteins, lipids, and nucleotides thus generating toxicity. Thus, our objective was to design and synthesize complexes that can attenuate the toxic effects of PN in vivo <i>in vivo</i> for pharmacological studies and potential therapeutic strategies. Redox-active Manganese(III) complexes of bis(hydroxyphenyl) dipyrromethenes (Mn(III)&ndash;DPMs) are able to catalytically destroy PN by converting PN to nitrite ion through a two electron mechanism. Herein, synthetic methods for preparing functionalized Mn(III)&ndash;DPMs with enhanced solubility and a conjugation site for the attachment of biomolecules were studied. Since both Mn(III)&ndash;DPMs and peroxisome proliferation-activated receptor &gamma; (PPAR&gamma;) agonist have been shown to be active and effective in treating type II diabetes mellitus, we hypothesized that the conjugate of our Mn(III)&ndash;DPM and a functional PPAR&gamma; agonist of the PPAR receptor may have a synergistic effect in this condition. In addition, if synergistic action is observed it may be possible to reduce to dose of PPAR&gamma; agonist. Structure&ndash;activity studies using boronate oxidation and the prevention-of-nitration assays were used to determine catalytic activity and the characteristics of these assays were examined and improved. In addition, the development oxidant-triggered <i><u>aza</u></i>-bis(hydroxylphenyl)dipyrromethene (<i>aza</i>&ndash;DPM) pro-catalyst systems was also explored. </p>

This study investigated plant use by Q'eqchi' Maya healers (Southern Belize) in the context of ethno-psychiatric and neurological conditions. The healers recognize eight of these disorders, which they treat with 82 identified plant species. Moreover, the Piperaceae family is the plant family most selected by the healers for these purposes. In a second section, the etiological basis of susto, a folk illness known throughout Latin America, was investigated. Some plants used by most of the healers showed anxiolytic and/or fear suppression activity. In addition, rituals surrounding the treatment process may have calming effects, and many plants used for susto are often used to treat mental/neurological disorders as well. This strengthens the basis for the inclusion of psychological/neurological factors in susto. A third section gives insights into the domestication and conservation of key medicinal species, indicating that harvesting practices are sustainable in the current context.