Medicinal and Pharmaceutical Chemistry Commons^™

Thermodynamic Mechanisms Of Helix Stabilization In A Model Peptide And Protein, Ryan Murray

University of the Pacific Theses and Dissertations

Biologics are large, complex therapeutic agents generally produced from living organisms. One group of biologics is peptide/protein based. Biological agents offer unique advantages over traditional therapeutics including longer half-lives, higher specificity, greater efficacy, and reduced off-target effects. However, protein/peptide based drugs suffer from both delivery and stability issues. The higher order of protein structures (secondary, tertiary, etc.) derive ~80% of their conformational stability from paltry hydrophobic effects, with net stabilization of 5-15 kcal/mole observed for many proteins. Loss of conformational stability can lead to increased aggregation, precipitation, and degradation; and reduced activity and side effects. To increase stability and improve …

Optimization Of The Structure Of Ttr Ligands For Half-Life Extension (Tlhe), Guanming Jiang

University of the Pacific Theses and Dissertations

Many potential therapeutic agents face challenges for their clinical development due to short circulation half-life. As a result, prolonging the half-life of therapeutic drugs in circulation while preserving their hydrophilicity and small size will be a key step toward more effective and safe pharmacological molecules. Our lab developed a new approach for enhancing the safety and efficacy of therapeutic agents. By endowing therapeutic agents with a hydrophilic small molecule (a derivative of the clinical candidate, AG10) which reversibly binds to the serum protein transthyretin (TTR), the half-life of the therapeutic agent should be extended by binding to the TTR in …

Expression Of Mouse Full-Length Aryl Hydrocarbon Receptor And Human Aryl Hydrocarbon Receptor Ligand Binding Domain In Pichia Pastoris, Yiyuan Wang

University of the Pacific Theses and Dissertations

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates biological responses to planar aromatic hydrocarbon. AHR activates gene transcription by binding to its corresponding enhancer with its partner-aryl hydrocarbon receptor nuclear translocator (ARNT). In addition, this receptor has been shown to regulate xenobiotic-metabolizing enzymes such as cytochrome P450. AHR exists widely in body tissues and affects bioactivation of carcinogenic compounds, T cell differentiation, fatty acid synthesis, cell proliferation, hematopoietic stem cell differentiation, respiratory reactivity, and insulin sensitivity. Although the precise mechanism illustrating the endogenous AHR function remains unclear, there has been intense interest in exploring AHR as a …

Incorporating Glutamic Acid-Valine-Citrulline Linker In Trifunctional Molecules Targeting Psma Ensures Enhanced Stability, Safety, And Efficacy In Mouse Model Of Prostate Cancer, Toufiq Ul Amin

University of the Pacific Theses and Dissertations

This project describes the development of a new antitumor therapeutic platform that combines the benefits of small-molecule drug conjugates (SMDCs) and antibody drug conjugates (ADCs). Valine-citrulline (VCit) dipeptide linkers are popular cathepsin B cleavable ADC linkers. Due to its instability in mouse serum, translating efficacy data from mouse to human is more difficult. It has been reported that replacing the VCit linker with glutamic acid-valine-citrulline (EVCit) improves ADC stability in mouse serum. The effect of the EVCit linker on the stability of SMDCs has not been reported so far. In a xenograft mouse model of prostate cancer, we found that …

Gc/Ms And Lc/Ms Approaches To Chemical Communication In Plants And Marine Cyanobacteria, Carolyn Keim

University of the Pacific Theses and Dissertations

Natural products are small organic compounds synthesized by living organisms including plants, animals, and microbes. These fall into one of two categories, primary metabolites are required for survival, but secondary metabolites usually play a more accessory role. Extracts from organisms have proven to be useful to humans throughout history. Prior to evidence-based western medicine practices, natural products were the only source of medicine and remain as a treatment source for underdeveloped nations. Today, natural products have either been approved by or have served as the template for many FDA approved drugs. Based on a survey of all FDA approved drugs …

The Vagabond Flourine Atom Revisited: Dissociative Photoionization Of Tri- And Pentafluoropropene, Jessica K. De La Cruz

University of the Pacific Theses and Dissertations

Photoelectron Photoion Coincidence (PEPICO) Spectroscopy studies on two unsaturated hydrofluorocarbons (HFCs), also known as hydrofluoroolefines (HFOs), are presented here. Previously, the Sztáray group has studied the dissociation of trans-1,3,3,3-tetrafluoroprop-1-ene (ElixClean), which is a fourth-generation refrigerant and propellant and has lower global warming potential than its precursors. My study is an extension of the ElixClean study as it aims to explore how the different number of fluorine atoms impact the dissociation reactions of these molecules. Both 3,3,3-trifluoropropene (TFP) and cis-1,2,3,3,3- pentafluoropropene (PFP) are also utilized as propellants and refrigerants.Measurements were carried out with remote access to the CRF-PEPICO (combustion reactions followed …

Investigation Of Cdk8 Inhibitor Q-12 Effects On Cdk8 And Cdk8 Substrates In Triple Negative Breast Cancer Cell Line Mda-Mb-468, Shengxi Li

University of the Pacific Theses and Dissertations

Cyclin-dependent kinases (CDKs) and cyclins (Cyclins) are the core molecules in the regulation mechanism of the entire cell cycle. Cell cycle dysregulation is a common feature of human cancers, and inhibitors of cyclin-dependent kinases (CDKs) play a crucial role in cell cycle control and are one of the most promising areas of cancer therapy. We aspired to use our cyclin-dependent kinase 8 (CDK8) inhibitor, Q-12, as a probe for biomarker discovery for CDK8 inhibitor sensitive tumor types. Q-12 shows potent inhibition of cell viability and induction of apoptosis process in some triple-negative breast cancer (TNBC) and colorectal cancer cell lines …

Development Of Miriplatin-Loaded Nanoparticles Against Non-Small Cell Lung Cancer, Zhongyue Yuan, Zizhao Xu, Xin Guo

Graduate and Professional Student Research Showcase

Lung cancer claims the highest mortality and the second-most new cases among all oncological diseases. NSCLC accounts for approximately 85% of all newly diagnosed lung cancers. Although platinum-based drugs are standard first-line chemotherapy for stage IIIB/IV NSCLC, accumulating reports have shown the failure of conventional platinum-based regimens due to drug resistance. Miriplatin is a lipophilic anti-cancer drug that has been approved in Japan for transcatheter arterial chemoembolization treatment of hepatocellular carcinoma. Lipid-based nanoparticles such as liposomes, micelles, and solid lipid nanoparticles (SLNs) can encapsulate anti-cancer drugs to improve their water solubility and bioavailability.

Development Of Miriplatin-Loaded Nanoparticles Against Non-Small Cell Lung Cancer, Zhongyue Yuan

University of the Pacific Theses and Dissertations

Lung cancer claims the highest mortality and the second-most estimated new cases among all oncological diseases [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all newly diagnosed lung cancers [2]. Approximately 40% of newly diagnosed lung cancer patients are stage IV. For stage IIIB/IV NSCLC, cytotoxic combination chemotherapy is standard first-line chemotherapy. A regimen of platinum (cisplatin or carboplatin) plus paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, or pemetrexed is the recommended clinical treatment [3].

Cisplatin is the first-generation platinum-based anti-cancer drug. Although cisplatin is much more effective than other platinum drugs at the same dosage [4], accumulating reports …

Bayesian-Derived Vancomycin Auc24h Threshold For Nephrotoxicity In Special Populations, Dan Ho

University of the Pacific Theses and Dissertations

A Bayesian-derived 24-hour area under the concentration-time curve over minimum inhibitory concentration from broth microdilution (AUC24h/MICBMD) ratio of 400 to 600 is recommended as the new monitoring parameter for vancomycin to optimize efficacy and minimize nephrotoxicity. The AUC24h threshold of 600 mg*h/L for nephrotoxicity was extrapolated from studies that assessed the general population. It is unclear if this upper threshold is consistent or varies when used in special populations such as critically ill patients, obese patients, patients with preexisting renal disease, and patients on concomitant nephrotoxins.The purpose of this study is to investigate the generalizability of the proposed vancomycin AUC24h …

Impact Of 17-Beta Estradiol And Moderate-Intensity Exercise On Mesenteric Arterial Function Of Uc Davis Type-2 Diabetes Mellitus Rats, Md Rahatullah Razan

University of the Pacific Theses and Dissertations

The studies in this dissertation were designed to investigate the impacts of estrogen (17-β estradiol/E2) and moderate-intensity exercise (MIE) on the mesenteric arterial (MA) function of the University of California Davis type-2 diabetes mellitus (UCD-T2DM) Rat model. Our recent report suggests that diabetes impairs MA vasorelaxation in both sexes of the UCD-T2DM model. Particularly, we reported that MA from prediabetic male rats showed a greater impairment compared to that in prediabetic females. However, when females become diabetic, they exhibit a greater vascular dysfunction than males. Therefore, the aim of the first study was to investigate whether female sex hormone, specifically …

Elephant And Anchors ‒ Photoelectron Photoion Coincidence Spectroscopy Of Small Oxygenated Molecules, Apeter Weidner

University of the Pacific Theses and Dissertations

The dissociative photoionization reactions of two small, oxygenated organics, namely 1,3-dioxolane and methyl vinyl ketone, were studied by photoelectron photoion coincidence (PEPICO) spectroscopy. Experiments involving 1,3-dioxolane were carried out in the photon energy range of 9.5‒13.5 eV. The statistical thermodynamics model shows that a total of six dissociation channels are involved in the formation of three fragment ions, namely C3H5O2+ (m/z 73), C2H5O+ (m/z 45) and C2H4O+ (m/z 44), with two channels contributing to the formation of each. By comparing the results of ab initio quantum chemical calculations to the experimentally derived appearance energies of the fragment ions, the most …

Studies On The Size And Non-Planarity Of Aromatic Stacking Moiety On Conformation Selectivity And Thermal Stabilization Of G-Quadruplexes, Mandeep Singh

University of the Pacific Theses and Dissertations

Targeting DNA has the advantage over proteins for cancer remediation because of the fewer copies of the ligands required for the desired therapeutic effect. Traditionally, covalent DNA binders like alkylating agents have been used to induce genetic instability through the formation of DNA lesions and strand breaks, leading to cellular apoptosis. The primary drawback of this treatment is the non-specific binding that affects both cancerous and non-cancerous cells. G-quadruplexes are the DNA secondary structures that are present in abundance near the promoter regions of the oncogenes and are involved in the regulation of their activities. A ligand-mediated stabilization of G-quadruplexes …

Intrapulmonary Inoculation Of Multicellular Tumor Spheroids To Construct An Orthotopic Lung Cancer Xenograft Model That Mimics Four Clinical Stages Of Non-Small Cell Lung Cancer, Yingbo Huang

University of the Pacific Theses and Dissertations

Lung cancer leads in mortality among all types of cancer in the US and Non-small cell lung cancer (NSCLC) is the major type of lung cancer. Immuno-compromised mice bearing xenografts of human lung cancer cells represent the most common animal models for studying lung cancer biology and for evaluating potential anticancer agents. However, orthotopic lung cancer models based on intrapulmonary injection of suspended cancer cells feature premature leakage of the cancer cells to both sides of the lung within five days, which generates a quick artifact of metastasis and thus belies the development and progression of lung cancer as seen …

I3: Isomerization Of Isomer Ions, Krisztián Gabor Torma

University of the Pacific Theses and Dissertations

Photoelectron Photoion Coincidence (PEPICO) spectroscopy is a robust tool for elucidating complex unimolecular dissociation mechanisms and for determining thermochemical and kinetic data of gas-phase ion dissociations with high accuracy. In this work, the dissociative photoionization of two sets of isomeric systems were analyzed with PEPICO: 1) C7H7+ ions of toluene (Tol) and 1,3,5-cycloheptatriene (CHT), and 2) two butyl alcohol isomers, 1-butanol and isobutanol. Threshold dissociative photoionization data on these four molecules of interest were collected on the imaging PEPICO apparatus at the VUV beamline of the Swiss Light Source. Data analysis was aided by ab initio calculations and Rice-Ramsperger-Kassel-Marcus (RRKM) …

Investigating The Effect Of Rutaecarpine On The Benzo[A]Pyrene-Induced Dna Damage In Vitro, You Li

University of the Pacific Theses and Dissertations

Benzo[a]pyrene (BaP), is one of the most potent mutagens and carcinogens known. It requires metabolic activation through cytochrome P450 (CYP)1A1 to yield the ultimate carcinogenic metabolite, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE can bind to DNA and form predominantly covalent (+) trans adducts at the N2 position of guanine causing DNA damage. Rutaecarpine (RTC) is an herbal medicine that has been used to treat several diseases such as headache, hypertension, gastrointestinal disorders, amenorrhea, and anti-inflammation. It has also been reported as a potent inducer of CYP enzymes, including CYP1A1, and CYP1A2. The mechanisms underlying up-regulation of CYP1A1 by RTC is dependent on aryl …

Development And Characterization Of Ldv Peptide Targeted Nanocarriers For Paclitaxel Delivery: A Comparative Study Of Micelles, Liposomes And Solid Lipid Nanoparticles, Poonam Dattani

University of the Pacific Theses and Dissertations

Nanocarriers have been established as delivery vehicles to target cancer tumors. However, premature drug leakage is one of the major reasons for inefficient drug delivery of nanocarriers to the tumor. Drug diffusion out of the nanocarriers or destabilization of drug loaded nanocarriers by physiological interactions with blood cells, serum proteins, and cell membranes upon systemic administration contribute to premature drug release. In this study, targeted micelles, liposomes and solid lipid nanoparticles (SLNs) of similar composition were prepared and characterized to compare physicochemical characteristics, in vitro stability, in vitro release rates in release media and in vivo performance. Peptide Amphiphiles (PAs) …

Development Of A New Class Of Ligand-Targeted Chemotherapeutics With Enhanced Safety And Efficacy Profile, Arindom Pal

University of the Pacific Theses and Dissertations

The hydrophobicity of many chemotherapeutic agents usually results in their nonselective passive distribution into healthy cells and organs causing collateral toxicity. Ligand-targeted drugs (LTDs) are a promising class of targeted anticancer agents. The hydrophilicity of the targeting ligands in LTDs limits its nonselective passive tissue distribution and toxicity to healthy cells. In addition, the small size of LTDs allows for better tumor penetration, especially in the case of solid tumors. However, the short circulation half-life of LTDs, due to their hydrophilicity and small size, remains a significant challenge for achieving their full therapeutic potential. Therefore, extending the circulation half-life of …

Bimetallic Complexes: The Fundamental Aspects Of Metal-Metal Interactions, Ligand Sterics And Application, Michael Bernard Pastor

University of the Pacific Theses and Dissertations

Metal containing complexes have been used to catalyze various organic transformations for the past few decades. The success of several mononuclear catalysts led to transition metal catalysts used in pharmaceuticals, environmental, and industrial processes. While mononuclear complexes have been used extensively, bimetallic systems have received far less attention. Bimetallic or polynuclear sites are commonly found in metalloenzymes that perform elegant transformation in biological systems, underlying their significance. Inorganic chemists take inspiration from nature and design model bimetallic complexes to further study this cooperativity effect. A bimetallic platform offers many structural and functional differences such as the identity of the metal …

Preclinical Evaluation Of Ag10 For Therapeutic Use Against Familial Amyloid Cardiomyopathy And Its Application In Various Other Technologies, Mark Russell Miller

University of the Pacific Theses and Dissertations

Transthyretin (TTR) amyloidosis is a progressive, fatal disease in which deposition of amyloid derived from either mutant or wild-type TTR causes severe organ damage and dysfunction. TTR cardiomyopathy is an infiltrative, restrictive cardiomyopathy characterized by progressive left and right heart failure. Familial amyloid cardiomyopathy (FAC) is driven by pathogenic point mutations in the TTR gene that destabilize the TTR tetramer, prompting its dissociation into dimers and monomers, with subsequent misfolding, aggregation and deposition of toxic TTR amyloid aggregates in the myocardium. The most prevalent mutation that causes FAC is the V122I variant, carried by 3.4% of African Americans, that increases …

The Synthesis Of Various Substituted 3-Amino-7-Hydroxy-2,2-Dimethyltetralins And Their Opioid-Related Activities, David Alan Lippman

University of the Pacific Theses and Dissertations

A series of aminotetralones and aminotetralins were synthesized from the common intermediate F, 3-amino-2,2-dimethyl-7-methoxy- 1-tetralone. The final compounds derived from F were simple substituted and/or reduced analogues. The products would allow a progressive structure activity relationship to be drawn based on pharmacological testing.

The common intermediate F was synthesized utilizing a six step procedure starting with p-methoxyphenylacetic acid. The overall yield from the precursor to the F:HC1 was 25%. Compound F was either O-demethylated to form 3-amino-2,2-dimethyl-7-hydroxy-l-tetralone (I) or was dimethylated on the amine and subsequently O-demethylated to yield the 3-dimethylamino-7-hydroxy-2,2-dimethyl-l-tetralone (J). The last major modification was the reduction of …

Toxicology And Pharmacology Of N¹-Acetylspermidine And N⁸-Acetylspermidine, Othman A. Alshabanah

University of the Pacific Theses and Dissertations

The polyamines are a group of natural compounds which have been found in almost all living tissues. N¹- and N⁸- acetylspermidine have been known for a considerable time as normal constituents in human urine, but their physiological role is unknown. Recent studies have indicated the presence of enzymes in the tissues capable of converting spermidine into N¹-acetylspermidine and N⁸-acetylspermidine and other enzyme activities which catalyze deacetylation and interconversion reactions.

One approach for determining physiologic activity of an endogenous compound is to observe their pharmacologic and toxicologic effects. In the present study, the …