Doctor of Philosophy (PhD), Wright State University, 2024, Environmental Sciences PhD

Gold has long been recognized for its medicinal applications, dating back centuries. The use of N-heterocyclic carbenes (NHCs), stable, tunable ligands, has revolutionized the development of metal complexes, particularly those involving gold. Among these, Au-NHC complexes have shown significant promise in treating various diseases, especially arthritis and cancer. More recently, our research has focused on synthesizing dual-targeting naphthoquinone-annulated NHC-based gold(I) complexes, which have demonstrated impressive therapeutic potential in cancer treatment. This emphasizes the growing importance of gold-based complexes in developing more selective and effective cancer therapies. By strategically tuning the electronic and steric properties of these complexes, we have explored a variety of functionalized naphthoquinone-annulated NHCs. In Chapter 1, we detail the synthesis of two isomers of nitro-functionalized naphthoquinone-annulated NHC precursors (imidazolium salts). The successful synthesis of these compounds was confirmed through various characterization techniques, including 1H and 13C NMR and FT-IR spectroscopy. We also investigated the electrochemical properties of these NHC precursors (imidazolium salts), to better understand their redox chemistry. In Chapter 2, we expanded our study by complexing the newly generated NHCs with iridium metal centers to examine their electronic and electrochemical properties. NHC-iridium cyclooctadiene (Ir-COD) and NHC-iridium carbonyl complexes were synthesized for this purpose. The introduction of nitro groups at two distinct positions on the ligands led to noticeable variations in their electrochemical behavior. Additionally, FT-IR spectroscopy was used to examine the carbonyl stretching frequencies of the Ir(CO)₂Cl complexes. The values obtained from IR provided significant insights into the donating abilities of newly generated NHCs. This was further quantified through Tolman Electronic Parameter (TEP) value cal (open full item for complete abstract)

Committee: Kuppuswamy Arumugam Ph.D. (Advisor); Steven R. Higgins Ph.D. (Committee Member); Jeremy Erb Ph.D. (Committee Member); Ravi P. Sahu Ph.D. (Committee Member); Ioana E. Pavel Ph.D. (Committee Member) Subjects: Biomedical Research; Chemistry; Environmental Science

PHD, Kent State University, 2024, College of Arts and Sciences / Department of Chemistry and Biochemistry

Pt(II)-based anticancer agents (e.g., cisplatin, carboplatin, and oxaliplatin) are widely used to treat various forms of cancer. Nevertheless, the efficacy of these drugs are limited in clinical settings due to the drug resistance of cancer and their side effects. To overcome these limitations, researchers have developed octahedral Pt(IV) compounds as prodrugs. Amphiphilic prodrug used to co-deliver cisplatin and doxorubicin have been designed to develop and increase the efficiency of the platinum-based anticancer treatments. This, in turn, improves cellular uptake and inhibits DNA mechanisms; thus, the combination of these agents have demonstrated the high efficacy of anticancer prodrugs. Although, the behavior of conventional Pt (IV) prodrugs are challenging to control, which can limit their efficiency. Therefore, there is a high demand within cancer therapy for the activation of these cytotoxic agents in a controlled manner. We present a new design of near infrared (NIR)-activatable Pt(IV)-based anticancer agents. The photoactivatable Pt(IV) prodrug approach is a promising strategy for engineering novel metallodrugs with high efficacy and low systematic toxicity. The major drawback of reported photoactivatable Pt(IV) prodrugs is that they require high-energy UV-vis light for activation, and such irradiation has very limited tissue penetration capability and is not suitable for phototherapy. NIR activation is highly sought-after for phototherapy, due to deep tissue penetration. In this study, we utilized a copper-free click reaction approach to develop a novel NIR-activatable Pt (IV) prodrug. This Pt (IV) prodrug can be photoactivated by NIR irradiation, triggering photoreduction to release the cytotoxic Pt (II). Moreover, The Pt (IV) complexes exhibited stability under physiological conditions in the dark and can release the payloads upon irradiation. In addition, upon NIR-irradiation, the complex readily induced DNA damage and triggered cell death in cancer (open full item for complete abstract)

Committee: Yaorong Zheng. (Advisor); Songping Huang (Committee Member); Sangeet Lamichhaney (Committee Member); Manabu Kurokawa (Committee Member); Hao Shen (Committee Member) Subjects: Chemistry

Doctor of Philosophy, The Ohio State University, 2022, Pharmaceutical Sciences

The objective of this dissertation is to develop multiple novel lipid-based nanoparticle formulations for therapeutic active compounds with different identities, including small molecular drugs with specific functional ligands or chemical functional groups, small molecular drugs with highly lipophilic properties, or co-encapsulation of hydrophobic agents along with antisense oligonucleotides or nucleic acid substances, and the efficacy evaluation and activity enhancement on antineoplastic therapeutics. Lipid-based nanoparticles, including liposomes, lipid nanoemulsions, and lipid nanoparticles for nucleic acid delivery, have been favored by numerous scientists and the pharmaceutical industry for decades. Since the FDA approval of Doxil in 1997, the popularity of nanoparticle formulations in biomedical sciences has skyrocketed due to the extinct properties that nanoparticles can provide and the ability to alter the drug pharmacokinetic/pharmacodynamic (PK/PD) profiles. Many commercialized products utilize nanoparticle formulations to achieve sustained release, prolong systemic circulation, and protect vulnerable active substances. Moreover, lipid nanoparticle applications in nucleic acid delivery have made considerable success these years, including Onpattro (or Patisiran, from Alnylam Pharmaceuticals, the first approved lipid nanoparticle formulation for siRNA delivery against hATTR amyloidosis), Comirnaty (from BioNTech & Pfizer, lipid nanoparticles delivering SARS-CoV2 spike protein mRNA), and Spikevax (from Moderna Therapeutics, lipid nanoparticles delivering SARS-CoV2 spike protein mRNA). Those novel lipid nanoparticles have been shown to enhance the delivery of nucleic acid substances to target cells with high delivery efficiency and to achieve outstanding therapeutic responses or immunization. Hence, more and more ongoing research, utilizing nanoparticles but not limited to lipid-based nanoparticles, has been shown to achieve promising results for not only (open full item for complete abstract)

Committee: Robert J. Lee (Advisor); Ly James Lee (Committee Member); Sharyn Baker (Committee Member); Mitch Phelps (Committee Member); Yizhou Dong (Committee Member) Subjects: Pharmaceuticals; Pharmacy Sciences

Master of Science in Biological Sciences, Youngstown State University, 2020, Department of Biological Sciences and Chemistry

The purpose of this research involves the study of plant compound podophyllotoxin and the potential benefits of podophyllotoxin analogues on cancer therapy. Podophyllotoxin has been found to have anticancer properties due to its role in tubulin depolymerization within the cell cycle. Cancer is a growing concern throughout the United States and across the world. The most well-known cancer therapies are synthetic in nature and can be very harmful to the body, leaving the growing need for natural product plant-derived anticancer therapies. In this study, the potential anticancer properties of structural analogues of podophyllotoxin will be evaluated for their effects on cell viability, apoptosis induction, cell-cycle control, and migration. Podophyllotoxin analogues will be screened using cell lines A549, MCF7, MDA-MB-231, SK-MEL-28, and Jurkat, with the aims of discovering more potent compounds.

Committee: Gary Walker PhD (Advisor); Séverine Van slambrouck PhD (Committee Member); Wim Steelant PhD (Committee Member) Subjects: Biochemistry; Biology; Oncology; Pathology; Pharmaceuticals; Toxicology

Master of Science in Pharmaceutical Science (MSP), University of Toledo, 2020, Pharmaceutical Sciences (Industrial Pharmacy)

IND-2 is a pyrimido pyrazolo quinoline-derivative compound that has the potential to treat colon cancer. A simple and reliable high-performance liquid chromatographic (HPLC) method was developed for the analysis of IND-2. Stability indicating studies of IND-2 were conducted via forced degradation by subjecting IND-2 to acidic/basic hydrolysis conditions, oxidation, and thermal stress. The mobile phase consisted of water and acetonitrile (80:20, v/v) both containing 0.1% formic acid. The analytical method was validated according to ICH guidelines. The developed analytical method was specific since all the IND-2 degradant peak purity angle was less than the threshold angle. The method was accurate and reliable since the intra-day and inter-day repeatability value was less than 2% and the recovery value was between 95% and 105%. The intrinsic stability of IND-2 varied among various stress conditions. IND-2 is very unstable in basic condition, whereas unstable under thermal stress. It is quite stable in acidic environment and to oxidation. BAPT-27 is a 4-pyridinyl ring containing compound with in vitro anti-colon cancer. A simple and reliable high-performance liquid chromatographic (HPLC) method was developed for the quantitative analysis of BAPT-27. Stability indicating studies of BAPT-27 was conducted via forced degradation by subjecting to BAPT-27 to acidic/basic hydrolysis, oxidation, and thermal stress. The developed method was validated according to ICH guidelines. The mobile phase consisted of water and acetonitrile (60:40, v/v) both containing 0.1% formic acid. The analytical method was specific since all the BAPT-27 degradant peak purity angle was less than the threshold angle. The method was accurate and reliable since the intra-day and inter-day repeatability value was less than 2% and the recovery value was between 95% and 105%. The intrinsic stability of drug varied among various stress conditions. BAPT-27 is unstable in acidic condition and to oxidatio (open full item for complete abstract)

Committee: Jerry Nesamony (Committee Chair); Gabriella Baki (Committee Member); Caren Steinmiller (Committee Member) Subjects: Pharmaceuticals

Doctor of Philosophy, The Ohio State University, 2020, Pharmacy

Hematological cancers are a collection of blood-borne malignancies that manifest in the bone marrow, where development of mutations in red blood cells, white blood cells, and platelets disrupts the production of healthy blood cells. Depending upon the type of blood cell affected, hematological malignancies can arise in the form of lymphoma, multiple myeloma, and leukemia, with the cancerous blood cells traveling throughout the body via the vascular system. The movement of cancerous blood cells complicates treatment, as the mutated cells can travel to and affect healthy cells throughout the blood and in the bone marrow. Treatment regiments for hematological malignancies have been and currently are being developed. Since patients can either show no response to first-line therapies or relapse even after successful first-line treatment, novel therapeutics to overcome the issue of resistance to first-line therapeutics are needed. Mainly, these novel therapeutics target key proteins that play crucial roles in the rapid growth and proliferation of cancerous blood cells. One key protein is the human 26S (also known as the 20S) proteasome, the control center for protein degradation in the ubiquitin proteasome pathway (UPP), the major pathway for protein catabolism in cells. Due to its role in controlling protein expression, proteasomal activity is upregulated in hematological cancer cells, as these cells require high levels of protein turnover to maintain growth and proliferation. This crucial role of ensuring rapid protein turnover in cancer cells makes the proteasome an advantageous target for cancer therapeutics. Chapter 1 of this thesis goes into further detail about hematological malignancies, the human 26S proteasome, and the proteasome's oncological role. This thesis also presents two therapeutic routes, both with the potential to treat hematological malignancies, that utilize the human 26S proteasome. In Chapter 2, work to synthesize the natural product scyt (open full item for complete abstract)

Committee: James Fuchs PhD (Advisor); Karl Werbovetz PhD (Committee Member); Liva Rakotondraibe PhD (Committee Member) Subjects: Pharmacy Sciences

Doctor of Philosophy, The Ohio State University, 2020, Pharmaceutical Sciences

Lichens are composite organisms consisting of multiple species of photobionts (cyanobacteria and microalgae) and mycobionts (fungi) living in symbiosis and have been found to survive under harsh conditions such as extreme temperatures or harmful UV rays. The secondary metabolites produced by these tenacious organisms have shown a wide array of biological activities, such as antimicrobial, cytotoxic, antioxidant and antiviral activities and its production has been mainly attributed to the mycobiont, or its microbial associates. In our systematic search for novel antiproliferative compounds, a fungal associate of the lichen, Niebla homalea, endemic to the U.S. has been isolated and identified as Penicillium aurantiacobrunneum. This relatively underexplored species belongs to a genus that has produced many important drugs for treatment of hyperlipidemia and infections, and has shown to exhibit cytotoxic activities against human breast (MCF-7) and human ovarian (A2780) cancer cell lines with IC50 values of 1.8 and 2.2 μg/mL respectively. From various fermentations of P. aurantiacobrunneum, one new α-pyrone polyene, 4-epi-citreoviridin (103), three new sterols, (20R)-7,8-dihydroxypaxisterol (105), auransterol (106) and (7S)-5-en-auransterol (107) and two new tetramic acids, 14-norepicoccarine A (109) and 14-norepicoccarine B (123) have been isolated alongside three known compounds, paxisterol (104), (15R*,20S*)-dihydroxyepisterol (108) and a pyridone alkaloid, PF1140 (124). Three of these isolated compounds (103, 105 and 106) were evaluated for their cytotoxic activities and compound 103 was the only compound found to be moderately active against both the cancer cell lines. (MCF-7 IC50 4.2 μg/mL and A2780 IC50 5.7 μg/mL). Of all the fermentations of this fungal strain, the extract from a brown rice culture afforded a total of six compounds (103, 105 – 109). This set of compounds served as an internal database for the development of a dereplication method by an NMR tec (open full item for complete abstract)

Committee: Liva Rakotondraibe (Advisor); Esperanza Carcache de Blanco (Committee Member); James Fuchs (Committee Member) Subjects: Pharmacy Sciences

Doctor of Philosophy, Case Western Reserve University, 2020, Pharmacology

A governing principle of cancer development is defined by a coordinate gain of oncogenic function and loss of tumor suppressor activity. To fully reverse this pathogenic process, one would want to simultaneously inhibit oncogene activity while reengaging tumor suppressor function. However, the majority of targeted therapies are directed at modulating the oncogenic gain with few therapies directed at the critical tumor suppressor proteins. This is based upon the dogma that, in a cell, it is easier to turn something off than to turn something back on. Indeed, activation of tumor suppressors using pharmaceutically tractable approaches have proven to be challenging. Yet, efforts persist to develop activators of tumor suppressor proteins. One that stands out as a therapeutic target is Protein Phosphatase 2A (PP2A). PP2A is a serine/threonine phosphatase involved in the regulation of many cellular processes and is genetically altered or functionally inactivated in many cancers highlighting its central role in cancer pathogenesis. One of the best-defined substrates of PP2A is the transcription factor c-MYC (MYC). MYC, a well-described oncogene, is activated through both genetic amplification and stabilizing post-translational modifications. Cancers associated with high MYC expression are generally more aggressive. However, MYC has remained an elusive drug target as it lacks targetable drug pockets. MYC is rapidly degraded and its activity is inhibited by active PP2A. Thus, PP2A reactivation is a proposed strategy for the treatment of MYC driven cancers. Small Molecule Activators of PP2A (SMAPs) have been recently described for their potent anti-cancer activity which is dependent upon their ability to activate PP2A, reengaging its tumor suppressor activity. This research demonstrates that activation of PP2A by SMAPs leads to MYC degradation resulting in the inhibition of cancer growth in both cellular and in vivo model systems. Biochemical and genetic tools ar (open full item for complete abstract)

Committee: Goutham Narla M.D./Ph.D (Advisor); Ruth Keri Ph.D (Committee Chair); Marvin Nieman Ph.D (Committee Member); Amar Desai Ph.D (Committee Member); David Wald M.D. /Ph.D (Committee Member) Subjects: Biomedical Research; Pharmacology

Doctor of Philosophy, The Ohio State University, 2019, Pharmacy

Natural products were once the only source of medicine and, since the dawn of modern drug discovery, have continued to serve as inspiration for the development of novel pharmaceuticals. The use of purified plant constituents greatly advanced the treatment of cancer towards the end of the 20th century. However, there remain many shortcomings with current treatment options with regards to toxicity, resistance, and overall effectiveness. The phyllanthusmin class of natural products, initially identified in 2006 to consist primarily of arylnaphthalene lignan arabinosyl glycosides, possess potent antiproliferative activity as well as a versatile pharmacophore whose exploration has recently been well studied, but not yet exploited into a known drug. The primary work described herein involves utilizing the phyllanthusmin scaffold to identify a novel anticancer lead compound, its mechanism of action, and develop novel synthetic routes in order to further streamline drug property optimization.

Committee: James Fuchs PhD (Advisor); Liva Rakotondraibe PhD (Committee Member); Mark Mitton-Fry PhD (Committee Member) Subjects: Organic Chemistry; Pharmacy Sciences

Doctor of Philosophy, The Ohio State University, 2018, Pharmaceutical Sciences

In a continued effort aimed at the discovery of potential new anticancer leads of natural origin, a root sample of Podocarpus neriifolius D. Don, collected in the Vietnam rainforest, was selected as a candidate species for phytochemical and biological investigation of its bioactive secondary metabolites. An initial small-scale bioactivity-guided isolation of this plant sample was conducted, and yielded one new (83) and four known podolactones (77-79, and 84) together with three totarane-type diterpenes (80-82), with a structural revision carried out on 79. A larger scale extraction of the remaining sample was performed to isolate a greater amount of 83 for its complete structural characterization, as well as to investigate additional secondary metabolites from this plant. A 1D-NMR spectroscopy-guided fractionation method using both 1H and selective 1D-TOCSY NMR spectroscopy was developed as a dereplication procedure in the screening of the extracts and their fractions. This method led to the detection and isolation of further known compounds (85-92) from the hexanes, EtOAc, and aqueous extracts of P. neriifolius root sample, in addition to that of the targeted compound (83). Moreover, the 1H NMR profile of the aqueous extract revealed the presence of a major compound (89), corresponding to the glucoside derivative of the cytotoxic 78, and this compound by means of its extract of origin, was subjected to fungal-assisted biotransformation procedures using two Penicillium strains, namely, P. concentricum and P. expansum. A previously reported hydrolysis of compound 89 under harsh chemical conditions led to the A-ring epoxide unit opening of this compound, resulting in an inactive product. The fungal biotransformation proved to be a useful method for the successful hydrolysis of 89 to form 78, and the present study is the first report of a podolactone chemical modification in fungal fermentation cultures. The progress of the biotransformation reaction was monitored peri (open full item for complete abstract)

Committee: A Douglas Kinghorn (Advisor) Subjects: Chemistry; Pharmacy Sciences

Doctor of Philosophy, The Ohio State University, 2017, Chemistry

Amphidinolides C, C2, C3, and F are cytotoxic secondary metabolites that occur naturally from symbiotic marine dinoflagellates Amphidinium sp. from the Okinawan flatworm. They share an identical 25-membered macrolide core that possesses 11 stereogenic centers and two trans-2,5-disubstituted tetrahydrofuran ring systems. The only structural difference resides in the appended C25–C34 triene side chain. Although the biological mode of action for these anticancer natural products has not been fully elucidated, the C29 functionality is known to significantly impact activity. Our contribution to the amphidinolide project was designed to assemble a common macrolide framework which could be elaborated with minimal synthetic manipulations to access all four target molecules. We recognized a hidden structural homology that allowed for the scalable syntheses of the southern C1–C9 and the northern C11–C25 fragments from a common starting material, D-gluconic acid delta-lactone. Z-selective Ando's modification of the Horner–Wadsworth–Emmons olefination was employed to efficiently prepare the C3–C5 acrylate. This was crucial to install the C4 methyl group via ensuing diastereoselective substrate-controlled hydrogenation. The two endocyclic trans-tetrahydrofuran scaffolds were constructed with two strategically different intramolecular transformations in high diastereoselective ratios: (1) a kinetically-driven fluoride-mediated oxy-Michael cyclization to form the southern C3–C6 ring, and (2) a thermodynamically-controlled Hartung's modification of Mukaiyama's aerobic cobalt-catalyzed cyclization to access the northern C20–C24 ring. We utilized a chelation-controlled Mukaiyama aldol reaction to form the C13–C14 bond and to concomitantly incorporate the C13 hydroxyl substituent. Subsequently, C11 terminal functionalization was accomplished with Seyferth–Gilbert homologation to complete the synthesis of the C10–C25 advanced fragment of the target amphidinolides.

Committee: Craig Forsyth (Advisor); Jovica Badjic (Committee Member); David Nagib (Committee Member) Subjects: Chemistry; Organic Chemistry

PhD, University of Cincinnati, 2017, Arts and Sciences: Chemistry

Reactive oxygen species (ROS), includes highly reactive molecules and radicals, derived from metabolism of molecular oxygen, and have important roles in cellular signaling. At high concentrations, ROS reacts with cellular macromolecules and leads to a stress condition known as oxidative stress. Several cancer cells, such as AML cancers exhibit high ROS levels to facilitate growth and adaptation signaling. Thus, this characteristic could be used for selective targeting of cancer cells. We use ROS to selectively activate reactive anticancer agents in AML cells with high ROS status. Structure activity relationship identifies a lead agent (RAP) that has 2 µM IC50 value and more than 10-fold selectivity towards AML cancer cells compared to normal blood stem cells. We show that the agent is reactive within cells and induces an electrophilic stress condition. Importantly, further studies identify that this agent targets cancer cells with high mitochondrial ROS generation. Mitochondrial metabolism of cancer cells as an anti-cancer liability, is gaining attention in recent literature. We show that the AML cells that are targeted by RAP, have high mitochondrial activity and exposure to RAP results in damage of mitochondria, and oxidative cell death. Further, RAP activity synergizes with anti-diabetic agent Metformin and natural molecule Rotenone, which exhibit anticancer properties by targeting mitochondria. Inhibition of mitochondrial complexes by agents like Metformin, lead to increased ROS leakage from mitochondria that enhances the activation of RAP. This further proves the suggested mechanism of RAP, while paving the way for future drug combination studies. The next part of this dissertation focuses on designing efficient antioxidant agents by altering the structure of RAP, in order to protect normal cells from oxidative stress mediated cell death. Though antioxidant therapy is promising strategy to treat oxidative stress caused by several disease conditions or toxi (open full item for complete abstract)

Committee: Edward Merino Ph.D. (Committee Chair); Neil Ayres Ph.D. (Committee Member); Pearl Tsang Ph.D. (Committee Member) Subjects: Biochemistry

Master of Science, Miami University, 2016, Chemistry and Biochemistry

This thesis is comprised of four chapters: Chapter zero gives a brief introduction and points to the importance of this work. Chapter one includes an introduction to Signal Transducer and Activator of Transcription 3 proteins and its activation in cancerous cells. Various inhibitors have been synthesized and will be tested in due course for their biological activity. The design and synthesis of these inhibitors derived from readily available and inexpensive starting materials are summarized in hopeful pursuit to attaining possible building blocks for anti-cancer drugs. Chapter two includes an introduction to highly aromatic and intensely absorbing heterocyclic macrocycles known as porphyrins. Synthesis of π-extended tetraphenylporphyrins with styrene derivatives from their β-β' positions using a concise three-step method is summarized. The successful synthesis of free base mono- and dibenzotetraphenylporphyrins is described using a dual catalyst system. These molecules are obtained with the hope that they can be applied in various areas such as molecular electronics and nanotechnology. Chapter three includes a summarization of this work and describes possible future work that will be carried out with results obtained from the two individual projects.

Committee: Dominik Konkolewicz (Committee Chair); Hong Wang (Advisor); Scott Hartley (Committee Member); Rick Page (Committee Member) Subjects: Chemistry; Organic Chemistry

Doctor of Philosophy, University of Akron, 2015, Chemistry

N,N'-substituted imidazolium salts are incredibly versatile compounds that have found applications across a variety of fields. They can be chemically modified through straightforward procedures, allowing for the synthesis of imidazolium salts with vastly differing properties. This dissertation explores the potential biological applications of mono- and bisimidazolium salts as new chemotherapeutic agents for the treatment of non-small cell lung carcinomas (NSCLC) and as chemical exfoliating agents for the treatment of recurrent urinary tract infections. Chapter I of this dissertation reviews the basic nomenclature and structure of imidazolium salts. Past and current research toward the biological applications of imidazolium salts and their use as precursors to N-heterocyclic carbene complexes is summarized. Chapter II explores the activity of a series of monoimidazolium salts against a panel of NSCLC cell lines. The treatment of lung cancer remains frustratingly difficult, and lung cancer maintains one of the highest mortality rates among cancer types. Current treatment options are only marginally effective and are plagued by severe side effect profiles or eventual resistance of the cancers to treatment. Therefore, there is a pressing need to develop new chemotherapeutic agents for the treatment of lung cancer. In this chapter, the in vitro antiproliferative activity of monoimidazolium salts against several NSCLC lines are determined by the MTT cell viability assay. The degree of apoptotic cell death is investigated by the use of the Annexin V-FITC/PI apoptosis detection assay, and possible imidazolium salt interactions with DNA are probed by a fluorescent intercalator displacement assay. Chapter III focuses on the synthesis of a series of bisimidazolium salts designed to mimic the activity of the bisintercalating agent echinomycin. The in vitro antiproliferative activity of these bisimidazolium salts and their potential interactions with DNA were determined (open full item for complete abstract)

Committee: Wiley Youngs Dr. (Advisor); Claire Tessier Dr. (Committee Member); Peter Rinaldi Dr. (Committee Member); Sailaja Paruchuri Dr. (Committee Member); Edward Evans Dr. (Committee Member) Subjects: Biochemistry; Chemistry

MS, Kent State University, 2014, College of Arts and Sciences / Department of Chemistry

Gallium is a main group element. After platinum, gallium was a second metal found has anticancer properties in early 1970s. Gallium is non-toxic and redox inactive. Because of similar ionic radii, electronegativity, ionization potential and electron affinity, gallium ions could be looked as a mimic of ferric ions. Thus, gallium ions are able to interference iron metabolism, especially intracellular process. Ferric ion is a cofactor of ribonucleotide reductase of DNA replication, once ferric ion is replaced by gallium ion, ribonucleotide reductase would be inhibited. This would greatly affect cell division. Due to anticancer properties, gallium compounds are developed as anticancer agent to treat solid tumor. The first generation of gallium anticancer agent was gallium nitrate as an oral drug. However, there are some problems of gallium nitrate. Gallium nitrate is a metal salts which has low efficiency and bio-availability in cancer treatment. Patents needed to take large doses of gallium nitrate to produce desired results. On one hand, free gallium ions may form hydroxide in biological pH. And it could be cleared by kidney in few hours easily. Large dose of gallium nitrate may cause some damage to kidney. On the other hand, tumor cells start to build up drug resistance by either shutting down or turning off transferrin receptor activity or excreting gallium ions through ion pump. To solve these problems, scientists are investigating gallium complexes as small molecules or nanoparticles for drug delivery. We developed gallium ferricyanide nanoparticles and gallium lawsonate nanoparticles as potential anticancer agents to treat solid tumor. Gallium ferricyanide is an analog of Prussian blue which found in 1706 by an artists' color maker, Heinrich Diesbach. It was used as a pigment in painting for a long time. It was known that Prussian blue is non-toxic. It could use to treat thallium poisoning and as cesium removal. Gallium ferricyanide nanoparticle was investiga (open full item for complete abstract)

Committee: Songping Huang (Advisor); Scott Bunge (Committee Member); Mietek Jaroniec (Committee Member) Subjects: Chemistry

MS, University of Cincinnati, 2013, Pharmacy: Pharmaceutical Sciences

Glioblastoma multiforme (GBM) is the most common and, simultaneously, most aggressive form of primary brain tumor occurring in human adults. Despite clinical application of various chemotherapy regimens, radiation, and surgical approaches, the median survival of patients after GBM diagnosis does not exceed 15 months. This underscores the urgent need for development of new synthetic or naturally-derived therapeutic agents, which not only extend median survival beyond 15 months but also offer the potential for cure. Recent advances in delineating the contributions of distinct signaling pathways and genetic alterations in tumorigenesis offer new therapeutic targets for pharmacological interventions in GBM patients. For centuries, medicinal plants were used as essential sources for the discovery of new anticancer agents. However, to rise to the level of clinically valuable adjuvants in cancer patients, it is imperative to understand the mechanisms of action associated with plant extracts or individual components purified from medicinal plants. Using contemporary molecular biology techniques, the results from this study demonstrate that pharmacologically active ingredients present in the ethanol-soluble fraction of Azadirachta Indica (Neem) leaves (Azt), including nimbolide, induce significant cytotoxicity against GBM cells in vitro and in vivo. Azt caused cell cycle arrest, most prominently at the G1-S border in GBM cells expressing the EGFRvIII oncogene, which is present in about 20-25% of glioblastomas. Azt directly inhibited kinase activity of the cyclin-dependent kinases CDK4/CDK6 leading to hypophosphorylation of the retinoblastoma (RB) protein and cell cycle arrest at G1-S. Independent of RB hypophosphorylation, Azt also significantly reduced proliferative and survival advantage of GBM cells by downregulating Bcl2 and blocking growth factor-induced phosphorylation of Akt, Erk1/2 and STAT3, respectively. In contrast, mTOR and other cell cycle regulators were not af (open full item for complete abstract)

Committee: Giovanni Pauletti Ph.D. (Committee Chair); Biplab Dasgupta Ph.D. (Committee Member); Gerald Kasting Ph.D. (Committee Member) Subjects: Oncology

PhD, University of Cincinnati, 2007, Medicine : Cell and Molecular Biology

Cancer is characterized by cells that have many genetic mutations. Chromosome instability is a hallmark of cancer, because it promotes the acquisition of the many mutations necessary for malignancy. Centrosome amplification is a major factor in chromosome instability because it leads to multipolar spindles, which directs the unequal segregation of chromosomes during mitosis. Centrosome amplification occurs when the mechanisms that regulate centrosome duplication are disrupted. Although the mechanisms that regulate centrosome duplication are not clear, it is known that the p53-p21-cyclin E pathway plays a major role in regulating centrosome duplication. p53, a tumor suppressor, induces the expression of p21, a cell cycle inhibitor, which inhibits the activity of cdk2/cyclin E. Previous work has shown that disruption of this pathway (loss of p53 or p21, or overexpression of cyclin E) can induce centrosome amplification. In this work, we study various aspects of this pathway and its effect on centrosome duplication. We show that common anti-cancer drugs that inhibit S phase uncouple centrosome duplication and DNA synthesis, leading to an increase in centrosome amplification and chromosome instability. This may help to explain why recurrent tumors are more malignant than their primary counterpart is. If some cells receive low doses of these drugs, it is possible that they can reversibly arrest in S phase, but allow centrosomes to duplicate. Once the drugs are gone, cells can re-enter the cell cycle with amplified centrosomes. As a result, chromosome instability occurs and cells can invade and destroy nearby tissues and spread to other parts of the body. p53 probably controls centrosome duplication via multiple pathways. To examine further the role of the p53-p21-cyclin E pathway in drug-induced centrosome amplification, we show that cyclin E is required for centrosome amplification to occur in drug-treated cells. Cells lacking cyclin E show minimal centrosome amplificat (open full item for complete abstract)

Committee: Dr. Kenji Fukasawa (Advisor) Subjects:

Doctor of Philosophy, The Ohio State University, 2010, Pharmacy

Natural products have played an important role in anticancer drug development for many decades. A recent review analyzing clinically approved anticancer drugs in Western countries and Japan during a twenty-five year period from 1981 to 2006 showed that, under the class of “non-biologicals/vaccines”, 63 of 81 (77.8%) anticancer drugs were either natural products or their derivatives, or synthesized molecules based on natural product pharmacophores. As part of a collaborative, multi-disciplinary approach to the discovery of new naturally occurring anticancer drugs, two medicinal plants, namely, Hyptis brevipes and Vitex quinata, collected in Indonesia, were selected for further investigation. The chloroform-soluble extract of a sample of the entire plant of H. brevipes showed activity against the MCF-7 human breast cancer cell line. Bioassay-guided fractionation and purification of the CHCl3-soluble extract of H. brevipes led to the isolation of six new 5,6-dihydropyrone derivatives, namely, brevipolides A-F (342-346), together with seven known compounds. Brevipolides A-F (342-346), and a previously known 5,6-dihydropyrone derivative (347), were assigned with the absolute configuration, 5R, 6S, 7S, and 9S, as elucidated by analysis of data obtained from their CD spectra and by Mosher ester reactions. Brevipolides B and D, as well as compound 347 exhibited ED50 values of 6.1, 6.7 and 3.6 µM against MCF-7 cells. Brevipolides A, B, and F, and compound 349 (the known 5,6,3′-trihydroxy-3,7,4′-trimethoxyflavone) gave ED50 values of 5.8, 6.1 7.5, and 3.6 µM against HT-29 cells, respectively. However, no significant cytotoxicity was found against Lu1 cells for any of the compounds isolated. When these compounds were subjected to evaluation in a panel of mechanism-based in vitro assays, compound 347 were found to be active in an enzyme-based ELISA NF-κB p50 assay, with an ED50 value of 15.3 µM. In a mitochondrial transmembrane potential assay, brevioplide C, compounds 348 and (open full item for complete abstract)

Committee: A. Douglas Kinghorn PhD (Advisor); Esperanza Carcache de Blanco PhD (Committee Member); James R. Fuchs PhD (Committee Member); Pui-Kai Li PhD (Committee Member) Subjects: Pharmaceuticals

Doctor of Philosophy, The Ohio State University, 2009, Veterinary Biosciences

Prostate cancer is the most commonly diagnosed noncutaneous cancer and the second leading cause of cancer death in men. To combat the assortment of genomic and cellular aberrations that occur with the progression of this disease, we have developed novel classes of histone deacetylase (HDAC) inhibitors, 3-phosphoinositide dependent protein kinase-1 (PDK1)/Akt inhibitors, and indole-3-carbinol analogs using phenylbutyrate, celecoxib, and indole-3-carbinol, respectively, as scaffolds. Here, we assess both the efficacy and safety of the lead compounds of these classes (OSU-HDAC42, OSU-03012, and OSU-A9) administered orally in a series of preclinical studies carried out, in part, in preparation for prevention and regression trials in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Following the acquisition of relevant in vitro and dose-ranging data, the tumor-suppressive efficacy of selected doses was evaluated in PC-3 xenograft ± TRAMP-C2 syngeneic mouse models. The oral drug formulation found to achieve the most promising benefit-risk ratio was incorporated into a diet and administered to TRAMP mice for the assessment of its morphologic and molecular effects on the development of prostatic intraepithelial neoplasia (PIN) and carcinoma. Toxicity was evaluated by histopathologic, hematologic, and body and organ weight analysis. OSU-HDAC42 achieved the most potent blockade of prostate tumorigenesis reported in the TRAMP model, suppressing the absolute and relative weights of the urogenital tracts by 86% and 85%, respectively, in association with intraprostatic modulation of biomarkers indicative of HDAC inhibition, increased apoptosis and differentiation, and decreased proliferation. This compound, while sparing body weight, caused reversible testicular degeneration and hematologic alterations. In addition to its prostate chemopreventive effects, OSU-03012 was found to induce the hepatic biotransformation enzymatic system and caused phenotypic changes p (open full item for complete abstract)

Committee: Ching-Shih Chen PhD (Advisor); Robert Brueggemeier PhD (Committee Member); Steven Clinton MD, PhD (Committee Member); Thomas Rosol DVM, PhD (Committee Member) Subjects: Animals; Biochemistry; Health Care; Molecules; Oncology; Pathology; Pharmaceuticals; Pharmacology; Therapy; Toxicology; Veterinary Services

Doctor of Philosophy, The Ohio State University, 2003, Pharmacy

(R)-Glycine-d-15N has been used to permit assignments of the prochiral a-protons of glycine residues in the FK-506 binding protein. A key and low yielding step in the synthetic route to (R)-glycine-d-15N occurred in the ruthenium tetraoxide-mediated degradation of N-t-BOC-p-methoxybenzyl amine to the N-t-BOC-glycine after both 2H and 15N are incorporated. In order to improve this step, investigation of the oxidation reaction conditions along with various aromatic ring carboxylate precursors were undertaken. It was found that using ruthenium chloride, periodic acid as the stoichiometric re-oxidant, and N-(p-methoxyphenylmethylamine)-2,2,2-trichloroethyl carbamate were the optimal conditions and substrate. This improvement was paramount for the applicability of this route for large scale production of labeled glycine that could be used in other biological applications. The retinoic acid analog N-(4-hydroxyphenyl)retinamide (4-HPR) is an effective chemopreventative and chemotherapeutic for numerous types of cancer. In vivo, 4-HPR is metabolized to 4-HPR-O-glucuronide (4-HPROG) which has been shown to be more effective than the parent molecule in rat mammary tumor models. To investigate whether 4-HPROG was an active agent, the carbon linked analog (4-HPRCG) was synthesized and subsequently found to be a more effective chemopreventative than 4-HPROG or 4-HPR. In the original synthesis of 4-HPRCG, the route to a key C-glycoside was lengthy and inefficient. In order to investigate 4-HPRCG as a chemotherapeutic, the synthesis was redesigned and significantly improved by access to a key C-benzyl-glucuronide intermediate through employment of a Suzuki coupling reaction between an exoanomeric methylene sugar and an aryl bromide. Subsequently, 4-HPRCG was tested in an animal model and shown to possess effective chemotherapeutic actions. In vivo, potential cleavage of the amide bond of 4-HPR would liberate retinoic acid, which may explain some of its side effects. This same clea (open full item for complete abstract)

Committee: Robert Curley, Jr. (Advisor) Subjects: