Chemistry Commons^™

Inhibiting Translesion Dna Synthesis As An Approach To Combat Drug Resistance To Dna Damaging Agents, Jung-Suk Choi, Seol Kim, Edward Motea, Anthony J. Berdis

Chemistry Faculty Publications

Anti-cancer agents exert therapeutic effects by damaging DNA. Unfortunately, DNA polymerases can effectively replicate the formed DNA lesions to cause drug resistance and create more aggressive cancers. To understand this process at the cellular level, we developed an artificial nucleoside that visualizes the replication of damaged DNA to identify cells that acquire drug resistance through this mechanism. Visualization is achieved using "click" chemistry to covalently attach azide-containing fluorophores to the ethynyl group present on the nucleoside analog after its incorporation opposite damaged DNA. Flow cytometry and microscopy techniques demonstrate that the extent of nucleotide incorporation into genomic DNA is enhanced …

Solid-Phase Peptide Synthesis Of Analogues Of The N-Terminus A-Ring Fragment Of The Lantibiotic Nisin: Replacements For The Dehydroalanine (Dha) Residue At Position 5 And The First Incorporation Of A Thioamide Residue, Kim Manzor, Keith Ó Proinsias, Fintan Kelleher

Articles

A number of A-ring analogues of the lantibiotic nisin, containing replacements for the Dha at position 5, have been successfully prepared by solid-phase peptide synthesis. The Dha replacements include glycine, alanine, phenylalanine, serine and 1-aminocyclopropyl carboxylic acid (ACCa). The incorporation of a thioamide-isoleucine residue at position 4 is also described and is the first report of the preparation of a lantibiotic ring fragment containing a thioamide link.

Synthesis And Identification Of An Investigational Essential Precursor Compound For The Purpose Of The Development Of A Vaccine Treatment Against The Peanut Allergy, Thomas F. Anguella

Theses and Dissertations

Presented in this master's thesis are several studies carried out to determine the viability of several allergoid candidates utilizing the major peanut allergen Ara h 2. The Ara h 2 allergen protein appears naturally as a doublet when observed by gel electrophoresis, SDS-PAGE. Optimization of allergen purification methods successfully led to Ara h 2 purity, and the ability to standardize procedures to yield consistently pure samples. The purified allergen was chemically crosslinked with diketone derivatives selected for their abilities to react with specific amino acids accessible on the Ara h 2 protein. Chemically modified allergen samples were also evaluated using …

Development Of Novel Therapeutic Approaches: (I) Targeting Allergic Responses To Peanuts And (Ii) Inhibition Of Dpp-Iv Enzyme Involved In Diabetes, Savan V. Patel

Theses and Dissertations

There is an increase in prevalence of peanut allergy, especially in the western world. The only current treatment for peanut allergy is avoidance of peanut from diet and contact. Additionally, there is currently no specific vaccine that can be taken to decrease peanut allergies. The method of desensitizing a person allergic to peanut allergy is deemed unsafe as the smallest amount of peanut can trigger an anaphylaxis reaction. Thus, various allergoids were created by modifying major peanut protein allergen Ara h2 using various cross-linkers and modification agents in order to disrupt the binding surface epitopes of the antigen to antibody. …

From The Making To The Tuning To The Use Of Chlorins For Biomedical Applications, Junior Gonzales

Dissertations, Theses, and Capstone Projects

Chlorins are porphyrins missing a double bond. These pigments are optimal platforms for the development of novel dyes that display drug-like attributes such as photodynamic therapy (PDT) agents. More recently, it was demonstrated that chlorins can serve both as a PDT agent and as a modality for fluorescence or PET imaging. Thus, multifunctional chlorins eliminate the differences that may occur in specificity, uptake, and distribution between separate compounds or constructs for imaging and therapy. The overall goal of this dissertation is to take advantage of the reputed intrinsic attributes of chlorins as a viable tool in biomedical applications. In this …

Copalic Acid Analogs Down-Regulate Androgen Receptor And Inhibit Small Chaperone Protein, Nethrie D. Idippily, Qiaoyun Zheng, Chunfang Gan, Aicha Quamine, Morgan M. Ashcraft, Bo Zhong, Bin Su Ph.D.

Chemistry Faculty Publications

Copalic acid, one of the diterpenoid acids in copaiba oil, inhibited the chaperone function of α-crystallin and heat shock protein 27 kD (HSP27). It also showed potent activity in decreasing an HSP27 client protein, androgen receptor (AR), which makes it useful in prostate cancer treatment or prevention. To develop potent drug candidates to decrease the AR level in prostate cancer cells, more copalic acid analogs were synthesized. Using the level of AR as the readout, 15 of the copalic acid analogs were screened and two compounds were much more potent than copalic acid. The compounds also dose-dependently inhibited AR positive …

Conformational Studies Of Gram-Negative Bacterial Quorum Sensing 3-Oxo N-Acyl Homoserine Lactone Molecules, Darren Crowe, Alan Nicholson, Adrienne Fleming, Ed Carey, Goar Sanchez-Sanz, Fintan Kelleher

Articles

In their ¹H NMR spectra in CDCl₃ 3-oxo-N-acyl homoserine lactones (OHLs) show significant downfield chemical shifts of the amide N-H proton when compared to the parent N-acyl homoserine lactones (AHLs). NMR spectroscopic and DFT calculation studies have shown that this is most likely due to the presence of a stabilising intramolecular H-bond from the N-H to the 3-oxo group. The ¹H NMR spectra also show evidence for the enol tautomers and that the amount of enol present for a range of OHLs is 4.1-4.5% in CDCl₃ and 6.5-7.2% in CD₃CN. In …

Detection Of Cathinone And Mephedrone In Plasma By Lc-Ms/Ms Using Standard Addition Quantification Technique, Theron W. Ng-A-Qui

Student Theses

Designer drugs are structural analogs of Drug Enforcement Agency (DEA) Schedule I and II substances. They are synthesized to mimic the effects of illegal drugs of abuse and to bypass the provisions of drug regulations. Despite the increased availability of designer drugs, few studies have focused on specific analytical extraction techniques for their detection and quantification in biological samples. Solid phase extraction (SPE) is the most commonly used technique for sample preparation. The purpose of this study is to evaluate the extraction efficiency of the various SPE columns with different sorbent materials for two designer drugs, cathinone and mephedrone in …

Design, Synthesis And Glioblastoma Activity Of 1,3-Diazinane Based Aryl Amides And Benzo Fused Heterocycles, Rebecca Hron

LSU New Orleans Theses and Dissertations

The development of novel targeted therapeutics for the treatment of cancer remains difficult due to the complex nature of the disease itself as well as the challenges associated with the synthesis of these therapeutics. Impediments to the discovery of novel drug candidates include lack of available starting materials and access to well-developed syntheses which are both convenient and economically feasible. Semicarbazides, for instance, are a critical synthon for the manufacture of numerous biologically important molecules. Historically, convenient methods for the synthesis of semicarbazides and their derivatives did not exist. Recently, a facile and efficient method for the preparation of semicarbazides …

Studies Directed Towards The Iridium Catalyzed Synthesis Of New Carbon-Nitrogen Bonds., Maria Lindsay

LSU New Orleans Theses and Dissertations

Amines are ubiquitous in nature and serve a variety of functions in living organisms. Because of this fact amines are of great biological and pharmaceutical interest. The iridium catalyst (pentamethylcyclopentadienyl) iridium dichloride dimer ([Cp*IrCl₂]₂) has been used in a number of ways to synthesize new carbon-nitrogen bonds. These studies were directed toward the development of a method for the iridium catalyzed N-alkylation of alpha-amino acid esters as well as the development of a strategy for synthesis of the natural product 275A.

We have optimized a method for the N-alkylation for alpha-amino acid esters. Using this …

Understanding The Dynamic Process Of Dissolution Using In-Situ Ft-Ir Spectroscopy, Vrushali M. Bhawtankar

Seton Hall University Dissertations and Theses (ETDs)

Dissolution studies provide valuable and critical drug release information (in vitro) that are important for quality control drug development. Using in-situ FT-IR spectroscopy methods has been developed for analyzing and monitoring dissolutions of pharmaceutical APIs. The accuracy of this technique was found to be ± 3% relative to HPLC and UV/Vis Spectroscopy. A dynamic analysis of the dissolution and subsequent hydrolysis of aspirin has been determined by in-situ FT-IR. This technique allows real-time analysis of the behavior of aspirin under simulated physiological conditions (pH 1.2, 4.5, 6.8) as aspirin (1205 cm^-1) and salicylic acid (1388 cm^-1) …

Development Of Neurotensin-Based Radiopharmaceuticals For Neurotensin-Receptor-1-Positive Tumors Targeting, Yinnong Jia

Theses & Dissertations

The neurotensin receptor 1 (NTR1) is overexpressed in many cancers, due to its role as a growth pathway. These NTR1-positive cancers include pancreatic, colon, prostate and breast cancers. In the radiopharmaceutical field, the overexpression of NTR1 in cancer has prompted the development of NTR1-targeted diagnostics and therapeutics. The neurotensin (NT) peptide exhibits low nanomolar affinity for NTR1 and has been the paradigm for NTR1-targeted agents. Since the 1980’s, radiolabeled NT analogs have been developed and evaluated for targeting NTR1-positive cancers. Since native NT is rapidly degraded in vivo by a variety of peptidases, a tremendous amount of effort has been …

Synthesis And In-Vitro Cell Viability/Cytotoxicity Studies Of Novel Pyrrolobenzodiazepine Derivatives, John M. Jarrett

Undergraduate Honors Theses

Pyrrolobenzodiazepines (PBDs) are a group of naturally occurring compounds that were discovered in the cultures of Streptomyces in the 1960s. Some natural PBDs discovered in these cultures, such as anthramycin and sibiromycin, were shown to possess a broad spectrum of anti-tumor activity. Since cancer is still a leading cause of death globally, the development of novel anti-proliferative derivatives of PBDs is essential for human welfare worldwide. Further synthesis and structure-activity relationship (SAR) studies of the parent natural products and their tetracyclic analogs will lead to the discovery of drug candidates. In this work, thirteen PBD analogues were synthesized using no …

Molecular Basis Of Substrate Recognition In Bjai, An Ahl Synthase From Bradyrhizobium Japonicum, Nicole Cornell

Boise State University Theses and Dissertations

Resistance to antibiotics has become a major challenge in today’s society for treating bacterial infections. Inhibition of quorum sensing has a potential to be a non-antibiotic based therapeutic that could be used to fight these bacterial infections. Quorum sensing is a cell density dependent, intercellular communication mechanism that bacteria use to synchronize behavior such as virulence and resistance to antibiotics. If this switch from planktonic to communal behavior can be inhibited, the bacteria will be less virulent. One possible way to accomplish this is by inhibiting the enzymes that are responsible for making the quorum sensing signaling molecules in Gram-negative …

Cytotoxic And Antimicrobial Effects Of Silver-Containing Surfaces, Sarah Goderecci

Theses and Dissertations

This study examines applications of sputtered silver coatings as alternatives to traditional antibiotic treatments. Given the increase in reports of antibiotic-resistant bacteria, new treatments and coatings for in-dwelling medical devices such as catheters and orthopedic implants are necessary. Silver oxide films were deposited onto Ti surfaces to examine the efficacy of such coatings against a variety of bacterial species both in vitro and in vivo. Bacterial growth studies showed that coatings exhibited antimicrobial activity against a range of bacterial species acting either in a bacteriostatic or bactericidal mechanism, depending on the target. Limited toxicity to in vitro mammalian cells was …

Poly(Ethyl Glyoxylate)-Poly(Ethylene Oxide) Nanoparticles: Stimuli- Responsive Drug Release Via End-To-End Polyglyoxylate Depolymerization, Bo Fan, Elizabeth Gillies

Chemistry Publications

The ability to disrupt polymer assemblies in response to specifi c stimuli provides the potential to release drugs selectively at certain sites or conditions in vivo. However, most stimuli-responsive delivery systems require many stimuli initiated events to release drugs. “ Self-immolative polymers” offer the potential to provide amplifi ed responses to stimuli as they undergo complete end-to-end depolymerization following the cleavage of a single end-cap. Herein, linker end-caps were developed to conjugate self-immolative poly(ethyl glyoxylate) (PEtG) with poly(ethylene oxide) (PEO) to form amphiphilic block copolymers. These copolymers were self-assembled to form nanoparticles in aqueous solution. Cleavage of the linker …

Docking Studies Of Isoform-Selectivity Of Phosphatidylinositol 3-Kinase (Pi3k) Inhibitors, Kaitlin Goettsch

UNO Student Research and Creative Activity Fair

Phosphatidylinositol 3-kinases (PI3Ks) and their related pathways are reputed targets for drug-based anticancer therapies. Mutations in PI3K genes, expression, and pathways are frequent among multiple cancer types. Four isoforms of PI3Ks exist: α, β, γ, & δ and studies have identified several ligands for each isoform which are capable of serving as inhibitory therapeutic compounds. However, the biochemical efficacy of these molecules varies and the isoform selectivity is not well understood. In this study, we applied in silico docking methods and free energy calculation methods to estimate the binding of reported PI3K ligands against 5 PI3K structures: PI3Kα (PBD ID: …

Hmba Is A Putative Hsp70 Activator Stimulating Hexim1 Expression That Is Down-Regulated By Estrogen, Rati Lama, Chunfang Gan, Nethrie Idippily, Viharika Bobba, David Danielpour, Monica Montano, Bin Su Ph.D.

Chemistry Faculty Publications

Hexamethylene bis-acetamide inducible protein 1 (HEXIM1) is identified as a novel inhibitor of estrogen stimulated breast cell growth, and it suppresses estrogen receptor-a transcriptional activity. HEXIM1 protein level has been found to be downregulated by estrogens. Recently, HEXIM1 has been found to inhibit androgen receptor transcriptional activity as well. Researchers have used Hexamethylene bisacetamide (HMBA) for decades to stimulate HEXIM1 expression, which also inhibit estrogen stimulated breast cancer cell gene activation and androgen stimulated prostate cancer gene activation. However, the direct molecular targets of HMBA that modulate the induction of HEXIM1 expression in mammalian cells have not been identified. Based …

Iterative Non-Proteinogenic Residue Incorporation Yields Α/Β-Peptides With A Helix-Loop-Helix Tertiary Structure And High Affinity For Vegf, James W. Checco, Samuel H. Gellman

Department of Chemistry: Faculty Publications

Inhibition of specific protein-protein interactions is attractive for a range of therapeutic applications, but the large and irregularly shaped contact surfaces involved in many such interactions make it challenging to design synthetic antagonists. Here, we describe the development of backbone-modified peptides containing both α- and β-amino acid residues (“α/β-peptides”) that target the receptor-binding surface of vascular endothelial growth factor (VEGF). Our approach is based on the Z-domain, which adopts a three-helix bundle tertiary structure. We show how a two-helix “mini-Z-domain” can be modified to contain β and other non-proteinogenic residues while retaining the target-binding epitope using iterative non-natural residue incorporation. …

A Dilute-And-Shoot Flow-Injection Tandem Mass Spectrometry Method For Quantification Of Phenobarbital In Urine, Ravali Alagandula, Xiang Zhou, Baochuan Guo

Chemistry Faculty Publications

RATIONALE: Liquid chromatography/tandem mass spectrometry (LC/MS/MS) is the gold standard of urine drug testing. However, current LC-based methods are time consuming, limiting the throughput of MS-based testing and increasing the cost. This is particularly problematic for quantification of drugs such as phenobarbital, which is often analyzed in a separate run because they must be negatively ionized.

METHODS: This study examined the feasibility of using a dilute-and-shoot flow-injection method without LC separation to quantify drugs with phenobarbital as a model system. Briefly, a urine sample containing phenobarbital was first diluted by 10 times, followed by flow injection of the diluted sample …

Fluorogenic Protein Labeling Using A Genetically Encoded Unstrained Alkene, Xin Shang, X. Song, C. Faller, R. Lai, H. Li, R. Cerny, Wei Niu, Jiantao Guo

Department of Chemistry: Faculty Publications

We developed a new fluorogenic bioorthogonal reaction that is based on the inverse electron-demand Diels–Alder reaction between styrene (an unstrained alkene) and a simple tetrazine. The reaction forms a new fluorophore with no literature precedent. We have identified an aminoacyl-tRNA synthetase/tRNA pair for the efficient and site-specific incorporation of a styrene-containing amino acid into proteins in response to amber nonsense codon. Fluorogenic labeling of purified proteins and intact proteins in live cells were demonstrated. The fluorogenicity of the styrene–tetrazine reaction can be potentially applied to the study of protein folding and function under physiological conditions with low background fluorescence interference.

Validation Of A Membrane Touch Biosensor For The Qualitative Detection Of Igg Class Antibodies To Herpes Simplex Virus Type 2, Tony Loughman, Baljit Singh, Brian Seddon, Philip Noone, Padmanabhan Santhosh

Articles

A novel type of biosensor was assessed for application to the qualitative determination of circulating antibodies to herpes simplex virus type 2 (HSV-2). The device utilises a high activity HSV-2 type specific gG2 antigen for antibody capture and commercially available ELISA reagents. The study compares the diagnostic performance of a prototype HSV-2 biochip to well-established in vitro tests routinely applied in clinical procedures. A panel of human serum samples (n = 60) previously characterised for HSV-2 serological status using the DiaSorin LIAISON® HSV-2 chemiluminescent immunoassay were assayed on the HSV-2 biochip and the Focus Diagnostics HerpeSelect® 2 ELISA IgG kit …

Soft Robotic Actuators, Filip Ilievski, Xin Chen, Aaron D. Mazzeo, George M. Whitesides, Robert F. Shepherd, Ramses V. Martinez, Won Jae Choi, Sen Wai Kwok, Stephen A. Morin, Adam Stokes, Zhihong Nie

Department of Chemistry: Faculty Publications

A soft robotic device includes a flexible body having a width, a length and a thickness, wherein the thickness is at least 1 mm, the flexible body having at least one channel disposed within the flexible body, the channel defined by upper, lower and side walls, wherein at least one wall is strain limiting; and a pressurizing inlet in fluid communication with the at least one channel, the at least one channel positioned and arranged such that the wall opposite the strain limiting wall preferentially expands when the soft robotic device is pressurized through the inlet.

Fidelity Of Implementation: An Overlooked Yet Critical Construct To Establish Effectiveness Of Evidence-Based Instructional Practices, Marilyne Stains, Trisha Vickrey

Department of Chemistry: Faculty Publications

The discipline-based education research (DBER) community has been invested in the research and development of evidence-based instructional practices (EBIPs) for decades. Unfortunately, investigations of the impact of EBIPs on student outcomes typically do not characterize instructors’ adherence to an EBIP, often assuming that implementation was as intended by developers. The validity of such findings is compromised, since positive or negative outcomes can be incorrectly attributed to an EBIP when other factors impacting implementation are often present. This methodological flaw can be overcome by developing measures to determine the fidelity of implementation (FOI) of an intervention, a construct extensively studied in …

Fluorogenic Protein Labeling Using A Genetically Encoded Unstrained Alkene, X. Shang, X. Song, C. Faller, R. Lai, H. Li, Ronald Cerny, Wei Niu, Jiantao Guo

Department of Chemistry: Faculty Publications

We developed a new fluorogenic bioorthogonal reaction that is based on the inverse electron-demand Diels–Alder reaction between styrene (an unstrained alkene) and a simple tetrazine. The reaction forms a new fluorophore with no literature precedent. We have identified an aminoacyl-tRNA synthetase/tRNA pair for the efficient and site-specific incorporation of a styrene-containing amino acid into proteins in response to amber nonsense codon. Fluorogenic labeling of purified proteins and intact proteins in live cells were demonstrated. The fluorogenicity of the styrene–tetrazine reaction can be potentially applied to the study of protein folding and function under physiological conditions with low background fluorescence interference.

Bis(N-Amidinohydrazones) And N-(Amidino)-N'-Aryl-Bishydrazones: New Classes Of Antibacterial/Antifungal Agents, Sanjib K. Shrestha, Liliia M. Kril, Keith D. Green, Stefan Kwiatkowski, Vitaliy M. Sviripa, Justin Robert Nickell, Linda Phyliss Dwoskin, David S. Watt, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

The emergence of multidrug-resistant bacterial and fungal strains poses a threat to human health that requires the design and synthesis of new classes of antimicr obial agents. We evaluated bis(N-amidinohydrazones) and N-(amidino)-N'-aryl-bishydrazones for their antibacterial and antifungal activities against panels of Gram-positive/Gram-negative bacteria as well as fungi. We investigated their potential to develop resistance against both bacteria and fungi by a multi-step, resistance-selection method, explored their potential to induce the production of reactive oxygen species, and assessed their toxicity. In summary, we found that these compounds exhibited broad-spectrum antibacterial and antifungal activities against most of …

Synthesis Of Vorinostat And Cholesterol Conjugate To Enhance The Cancer Cell Uptake Selectivity, Nethrie D. Idippily, Chunfang Gan, Paul Orefice, Jane Peterson, Bin Su Ph.D.

Chemistry Faculty Publications

Histone deacetylase (HDAC) inhibitors modulate various cellular functions including proliferation, differentiation, and apoptosis. Vorinostat (SuberAniloHydroxamic Acid, SAHA) is the first HDAC inhibitor approved by FDA for cancer treatment. However, SAHA distributes in cancer tissue and normal tissue in similar levels. It will be ideal to selectively deliver SAHA into cancer cells. Rapidly growing cancer cells have a great need of cholesterol. Low-density lipoprotein (LDL) is the major cholesterol carrier in plasma and its uptake is mediated by LDL-receptor (LDL-R), a glycoprotein overexpressed on the surface of cancer cells. Herein, we designed and synthesized a SAHA cholesterol conjugate, and further formed …

Synthesis And Biological Activity Of Novel Tu100 Derivatives, Oladotun J. Alao

College of Graduate Studies: Theses & Dissertations

In an attempt to create more effective chemotherapeutic compounds, the naphthoquinone adduct, 12,13-dihydro-N-methyl-6,11,13-trioxo-5H-benzo[4,5]cyclohepta [1,2 b]naphthalen-5,12-imine (hereafter called TU100) was synthesized. Inspired by its unique and novel mechanism of action, a series of structural derivatives were synthesized to explore structure-activity relationships. The analogues exhibited different cytotoxicity profiles, revealing the indicated regions are involved in cell death induction. Furthermore, the analogues had dramatically different effects on cellular ATP production, suggesting different molecular targets. Synthesis, biological activity, and SAR study of these analogues will be revealed.

Analysis Of Novel Cyanide Antidote Dimethyl Trisulfide For Pharmacokinetic Studies, And Sulfur Mustard Metabolites For Identification Of Biomarker Of Inhaled Dose, Erica Manandhar

Electronic Theses and Dissertations

Cyanide poisoning by accidental or intentional exposure poses a severe health risk. The current FDA approved antidotes for cyanide poisoning can be effective, but each suffers from specific major limitations. Dimethyl trisulfide (DMTS), a sulfur donor that detoxifies cyanide by converting it into thiocyanate, is a promising next generation cyanide antidote. Although a validated analytical method to analyze DMTS is not currently available from any matrix, one will be vital for the approval of DMTS as a therapeutic agent against cyanide poisoning. Hence, a stir bar sorptive extraction (SBSE) gas chromatography – mass spectrometry (GC-MS) method was developed and validated …

Structure And Characterization Of A Class 3b Proline Utilization A: Ligand-Induced Dimerization And Importance Of The C-Terminal Domain For Catalysis, David A. Korasick, Thameesha T. Gamage, Shelbi Christgen, Kyle M. Stiers, Lesa J. Beamer, Michael T. Henzl, Donald F. Becker, John J. Tanner

Department of Chemistry: Faculty Publications

The bifunctional flavoenzyme proline utilization A (PutA) catalyzes the two-step oxidation of proline to glutamate using separate proline dehydrogenase (PRODH) and L-glutamate-y-semialdehyde dehydrogenase active sites. Because PutAs catalyze sequential reactions, they are good systems for studying how metabolic enzymes communicate via substrate channeling. Although mechanistically similar, PutAs vary widely in domain architecture, oligomeric state, and quaternary structure, and these variations represent different structural solutions to the problem of sequestering a reactive metabolite. Here, we studied PutA from Corynebacterium freiburgense (CfPutA), which belongs to the uncharacterized 3B class of PutAs.A2.7A˚ resolution crystal structure showed the canonical arrangement of PRODH, L-glutamate-y-semialdehyde dehydrogenase, …