Chemicals and Drugs Commons^™

Application Of Mass Spectrometry For The Characterization Of Synthetic Oligomers And Natural Lignin, Poorya Kamali

Theses and Dissertations--Chemistry

As part of the ongoing effort to substitute finite fuel and chemical resources with renewable ones, biomass is emerging as one of the most promising sources. Biomass consists of three main components of cellulose, hemicellulose, and lignin. Traditionally, cellulose has been used extensively in pulping industry, while lignin has been considered waste and is burned to generate heat. Lignin, a complex aromatic polymer component of biomass, has the potential to be used as a source of aromatic chemicals and pharmaceutical synthons. The recalcitrant nature of lignin, the lack of effective lignin breakdown methods and analytical techniques to analyze it are …

Investigating The Physical Stability Of Amorphous Pharmaceutical Formulations, Travis W. Jarrells

Theses and Dissertations--Pharmacy

Amorphous formulations, including amorphous solid dispersions (ASDs), consisting of the active pharmaceutical ingredient (API) intimately mixed in a polymeric matrix, are an attractive formulation approach to improve drug delivery, dissolution, and solubility. However, an amorphous API in an ASD is in a higher energy state compared to the crystalline drug and results in most ASDs being inherently unstable. The polymer helps to stabilize the amorphous drug against crystallization such that the resulting homogenous mixture maintains its solubility advantage relative to the crystalline form. One challenge of ASDs is that the presence of impurities including crystals or residual solvent, variations in …

Design, Synthesis, And Anticancer Properties Of Ru(Ii) Complexes With Organometallic, “Expanded” Bipyridine, And O,O’-Chelating Ligands, Raphael Ryan

Theses and Dissertations--Chemistry

Cancer is a worldwide public health crisis that requires new and improved drugs to be developed to extend survival rates and improve quality of life for the patient. Platinum-based drugs are used in approximately 50% of cancer treatment regimens. These drugs are highly effective in many kinds of cancer; however, cancers can develop platinum resistance and these drugs have troubling side effects that reduced their use and efficacy. To overcome these disadvantages, many other metals have been studied for their anticancer properties. Notably, the anticancer properties of ruthenium-based agents have drawn considerable attention with multiple ruthenium complexes entering clinical trials. …

Correlating The Physicochemical Properties Of Magnesium Stearate With Tablet Dissolution And Lubrication, Julie L. Calahan

Theses and Dissertations--Pharmacy

Magnesium stearate (MgSt) is the most commonly used pharmaceutical excipient and is present in over half the tablet formulations on the market. In spite of its popularity as an effective lubricant, it has been repeatedly recognized that there is significant variability between MgSt samples, which can cause inconsistent lubrication between batches of MgSt. The hypothesis of this research is that the batch-to-batch variability in tablet lubrication and dissolution observed in tablet formulations containing different MgSt samples can be correlated with differences in MgSt physicochemical properties (fatty acid salt composition, crystal hydrate form, particle size and surface area). Developing correlations between …

Crystal Structure Of Zymonic Acid And A Redetermination Of Its Precursor, Pyruvic Acid, Dominik Heger, Alexis J. Eugene, Sean R. Parkin, Marcelo I. Guzman

Chemistry Faculty Publications

The structure of zymonic acid (systematic name: 4-hy­droxy-2-methyl-5-oxo-2,5-di­hydro­furan-2-carb­oxy­lic acid), C₆H₆O₅, which had previously eluded crystallographic determination, is presented here for the first time. It forms by intra­molecular condensation of parapyruvic acid, which is the product of aldol condensation of pyruvic acid. A redetermination of the crystal structure of pyruvic acid (systematic name: 2-oxo­propanoic acid), C₃H₄O₃, at low temperature (90 K) and with increased precision, is also presented [for the previous structure, see: Harata et al. (1977). Acta Cryst. B33, 210–212]. In zymonic acid, the hy­droxy­lactone ring …

Toward An Enzyme-Coupled, Bioorthogonal Platform For Methyltransferases: Probing The Specificity Of Methionine Adenosyltransferases, Tyler D. Huber

Theses and Dissertations--Pharmacy

Methyl group transfer from S-adenosyl-l-methionine (AdoMet) to various substrates including DNA, proteins, and natural products (NPs), is accomplished by methyltransferases (MTs). Analogs of AdoMet, bearing an alternative S-alkyl group can be exploited, in the context of an array of wild-type MT-catalyzed reactions, to differentially alkylate DNA, proteins, and NPs. This technology provides a means to elucidate MT targets by the MT-mediated installation of chemoselective handles from AdoMet analogs to biologically relevant molecules and affords researchers a fresh route to diversify NP scaffolds by permitting the differential alkylation of chemical sites vulnerable to NP MTs that are unreactive to …

Treatment Of Mci And Alzheimer's Disease, Mark A. Lovell, Bert C. Lynn

Chemistry Faculty Patents

The present invention provides, among other things, therapeutic compositions and methods that can effectively treat, slow or prevent a neurological disease (e.g., a neurodegenerative disease, e.g., mild cognitive impairment (MCI) or Alzheimer's disease (AD)), in particular, based on therapeutically effective amount of nifedipine, oxidized or nitroso nifedipine derivatives, lactam (e.g., a compound of formula (Ic) or (Ic-i), e.g., NFD-L1), thyroxine (T4), triiodothyronine (T3) and combinations thereof.

Solution Growth And Thermal Treatment Of Crystals Lead To Two New Forms Of 2-((2,6-Dimethylphenyl)Amino)Benzoic Acid, Rong Hu, Yunping Zhoujin, Meng Liu, Mingtao Zhang, Sean Parkin, Panpan Zhou, Jianzhi Wang, Faquan Yu, Sihui Long

Chemistry Faculty Publications

We report the discovery of two new forms (II and III) of a potential non-steroidal anti-inflammatory and thyroid drug, 2-((2,6-dimethylphenyl)amino)benzoic acid (HDMPA) through solution growth and thermal treatment of crystals. Form II has been discovered through crystal growth in a variety of solvents, and characterized by single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), FT-IR, and Raman spectroscopy. Form II converts into form III upon thermal treatment, as indicated by the phase behavior study of form II with differential scanning calorimetry (DSC). Form III has been characterized by IR, Raman and PXRD. Conformational flexibility of the molecule seems to lead to …

The Role Of Catalytic Residue PKA On The Hydrolysis/Transglycosylation Partition In Family 3 Β-Glucosidases, Inacrist Geronimo, Christina M. Payne, Mats Sandgren

Chemical and Materials Engineering Faculty Publications

β-Glucosidases (βgls) primarily catalyze the hydrolysis of the terminal glycosidic bond at the non-reducing end of β-glucosides, although glycosidic bond synthesis (called transglycosylation) can also occur in the presence of another acceptor. In the final reaction step, the glucose product or another substrate competes with water for transfer to the glycosyl-enzyme intermediate. The factors governing the balance between the two pathways are not fully known; however, the involvement of ionizable residues in binding and catalysis suggests that their pK_a may play a role. Through constant pH molecular dynamics simulations of a glycoside hydrolase Family 3 (GH3) βgl, we …

Regioselective Baeyer–Villiger Oxidation Of Lignin Model Compounds With Tin Beta Zeolite Catalyst And Hydrogen Peroxide, John Adam Jennings, Sean R. Parkin, Eric Munson, Sean Delaney, Julie L. Calahan, Mark Isaacs, Kunlun Hong, Mark Crocker

Chemistry Faculty Publications

Lignin depolymerization represents a promising approach to the sustainable production of aromatic molecules. One potential approach to the stepwise depolymerization of lignin involves oxidation of the benzylic alcohol group in β-O-4 and β-1 linkages, followed by Baeyer–Villiger oxidation (BVO) of the resulting ketones and subsequent ester hydrolysis. Towards this goal, BVO reactions were performed on 2-adamantanone, a series of acetophenone derivatives, and lignin model compounds using a tin beta zeolite/hydrogen peroxide biphasic system. XRD, ¹¹⁹Sn MAS NMR spectroscopy, DRUVS and XPS were used to determine tin speciation in the catalyst, the presence of both framework Sn and extra framework …

Polymer Micelle Formulation For The Proteasome Inhibitor Drug Carfilzomib: Anticancer Efficacy And Pharmacokinetic Studies In Mice, Ji Eun Park, Se-Eun Chun, Derek Alexander Reichel, Jee Sun Min, Su-Chan Lee, Songhee Han, Gongmi Ryoo, Yunseok Oh, Shin-Hyung Park, Heon-Min Ryu, Kyung Bo Kim, Ho-Young Lee, Soo Kyung Bae, Younsoo Bae, Wooin Lee

Pharmaceutical Sciences Faculty Publications

Carfilzomib (CFZ) is a peptide epoxyketone proteasome inhibitor approved for the treatment of multiple myeloma (MM). Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites are considered to be major factors limiting its efficacy against solid cancers. We previously reported that polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) can improve the metabolic stability of CFZ in vitro. Here, we prepared the CFZ-loaded PM, PEG-PCL-deoxycholic …

Dual-Functional-Tag-Facilitated Protein Labeling And Immobilization, Xinyi Zhang, Wei Lu, Kevin Kwan, Dibakar Bhattacharyya, Yinan Wei

Chemistry Faculty Publications

An important strategy in the construction of biomimetic membranes and devices is to use natural proteins as the functional components for incorporation in a polymeric or nanocomposite matrix. Toward this goal, an important step is to immobilize proteins with high efficiency and precision without disrupting the protein function. Here, we developed a dual-functional tag containing histidine and the non-natural amino acid azidohomoalanine (AHA). AHA is metabolically incorporated into the protein, taking advantage of the Met-tRNA and Met-tRNA synthetase. Histidine in the tag can facilitate metal-affinity purification, whereas AHA can react with an alkyne-functionalized probe or surface via well-established click chemistry. …

Development Of Diverse Size And Shape Rna Nanoparticles And Investigation Of Their Physicochemical Properties For Optimized Drug Delivery, Daniel L. Jasinski

Theses and Dissertations--Pharmacy

RNA nanotechnology is an emerging field that holds great promise for advancing drug delivery and materials science. Recently, RNA nanoparticles have seen increased use as an in vivo delivery system. RNA was once thought to have little potential for in vivo use due to biological and thermodynamic stability issues. However, these issues have been solved by: (1) Finding of a thermodynamically stable three-way junction (3WJ) motif; (2) Chemical modifications to RNA confer enzymatic stability in vivo; and (3) the finding that RNA nanoparticles exhibit low immunogenicity in vivo.

In vivo biodistribution and pharmacokinetics are affected by the physicochemical …

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most …

Quantification Of Factors Governing Drug Release Kinetics From Nanoparticles: A Combined Experimental And Mechanistic Modeling Approach, Kyle Daniel Fugit

Theses and Dissertations--Pharmacy

Advancements in nanoparticle drug delivery of anticancer agents require mathematical models capable of predicting in vivo formulation performance from in vitro characterization studies. Such models must identify and incorporate the physicochemical properties of the therapeutic agent and nanoparticle driving in vivo drug release. This work identifies these factors for two nanoparticle formulations of anticancer agents using an approach which develops mechanistic mathematical models in conjunction with experimental studies.

A non-sink ultrafiltration method was developed to monitor liposomal release kinetics of the anticancer agent topotecan. Mathematical modeling allowed simultaneous determination of drug permeability and interfacial binding to the bilayer from release …