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Medicinal-Pharmaceutical Chemistry Commons

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Synthesis And In-Vitro Cell Viability/Cytotoxicity Studies Of Novel Pyrrolobenzodiazepine Derivatives, John M. Jarrett 2017 East Tennessee State University

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 ...


Discovery Of Thienoquinolone Derivatives As Selective And Atp Non-Competitive Cdk5/P25 Inhibitors By Structure-Based Virtual Screening, Arindam Chatterjee, Stephen J. Cutler, Robert J. Doerksen, Ikhlas A. Khan, John S. Williamson 2017 University of Mississippi

Discovery Of Thienoquinolone Derivatives As Selective And Atp Non-Competitive Cdk5/P25 Inhibitors By Structure-Based Virtual Screening, Arindam Chatterjee, Stephen J. Cutler, Robert J. Doerksen, Ikhlas A. Khan, John S. Williamson

John Williamson

Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer’s disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP ...


Cytotoxic And Antimicrobial Effects Of Silver-Containing Surfaces, Sarah Goderecci 2017 Rowan University

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 ...


Docking Studies Of Isoform-Selectivity Of Phosphatidylinositol 3-Kinase (Pi3k) Inhibitors, Kaitlin Goettsch 2017 University of Nebraska at Omaha

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

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: 2RD0 ...


Improving Binding Affinity Through Cyclization, Kaylee M. Newcomb, Nicolas Abrigo 2017 Virginia Commonwealth University

Improving Binding Affinity Through Cyclization, Kaylee M. Newcomb, Nicolas Abrigo

Undergraduate Research Posters

Cancer chemotherapy results in systematic damage as the drugs used are also toxic to benign tissue. Sensitizing a cancer cell to therapy by interfering with the DNA repair mechanisms would decrease overall toxicity, as the necessary dosage of chemotherapy drugs would be lowered. The Hartman lab developed a peptide (8.6) that binds with a KD of 1 μM to the C-terminal domain of breast cancer associated protein (BRCA1), blocking homologous recombination. The crystal structure of the peptide shows the tyrosine and threonine residues are close together, suggesting that by cyclizing these positions, the peptide may already be constrained into ...


Phage Display To Identify Functional Resistance Mutations To Rigosertib, Nedim Filipovic 2017 Claremont McKenna College

Phage Display To Identify Functional Resistance Mutations To Rigosertib, Nedim Filipovic

CMC Senior Theses

In vitro protein selection has had major impacts in the field of protein engineering. Traditional screens assay individual proteins for specific function. Selection, however, analyzes a pool of mutants and yields the best variants. Phage display, a successful selection technique, also provides a reliable link between variant phenotype and genotype. It can also be coupled with high throughput sequencing to map protein mutations; potentially highlighting vital mutations in variants. We propose to apply this technique to cancer therapy. RAF, a serine/threonine kinase, is critical for cell regulation in mammals. RAF can be activated by oncogenic RAS, found in over ...


Amino Acid Catabolism In Staphylococcus Aureus And The Function Of Carbon Catabolite Repression, Cortney R. Halsey, Shulei Lei, Jacqueline K. Wax, Mckenzie K. Lehman, Austin S. Nuxoll, Laurey Steinke, Marat Sadykov, Robert Powers, Paul D. Fey 2017 University of Nebraska Medical Center

Amino Acid Catabolism In Staphylococcus Aureus And The Function Of Carbon Catabolite Repression, Cortney R. Halsey, Shulei Lei, Jacqueline K. Wax, Mckenzie K. Lehman, Austin S. Nuxoll, Laurey Steinke, Marat Sadykov, Robert Powers, Paul D. Fey

Faculty Publications -- Chemistry Department

Staphylococcus aureus must rapidly adapt to a variety of carbon and nitrogen sources during invasion of a host. Within a staphylococcal abscess, preferred carbon sources such as glucose are limiting, suggesting that S. aureus survives through the catabolism of secondary carbon sources. S. aureus encodes pathways to catabolize multiple amino acids, including those that generate pyruvate, 2-oxoglutarate, and oxaloacetate. To assess amino acid catabolism, S. aureus JE2 and mutants were grown in complete defined medium containing 18 amino acids but lacking glucose (CDM). A mutation in the gudB gene, coding for glutamate dehydrogenase, which generates 2-oxoglutarate from glutamate, significantly reduced ...


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 2017 University of Nebraska-Lincoln

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

Faculty Publications -- Chemistry Department

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 ...


Fidelity Of Implementation: An Overlooked Yet Critical Construct To Establish Effectiveness Of Evidence-Based Instructional Practices, Marilyne Stains, Trisha Vickrey 2017 University of Nebraska-Lincoln

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

Faculty Publications -- Chemistry Department

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 ...


Peptidylarginine Deiminase 1-Catalyzed Histone Citrullination Is Essential For Early Embryo Development, Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang 2016 Nanjing Medical University

Peptidylarginine Deiminase 1-Catalyzed Histone Citrullination Is Essential For Early Embryo Development, Xiaoqian Zhang, Xiaoqiu Liu, Mei Zhang, Tingting Li, Aaron Muth, Paul R. Thompson, Scott A. Coonrod, Xuesen Zhang

Thompson Lab Publications

Peptidylarginine deiminase (PADI) enzymes are increasingly being associated with the regulation of chromatin structure and gene activity via histone citrullination. As one of the PADI family members, PADI1 has been mainly reported to be expressed in the epidermis and uterus, where the protein in keratinocytes is thought to promote differentiation by citrullinating filament proteins. However, the roles of PADI1 in preimplantation development have not been addressed. Using a PADI1-specific inhibitor and Padi1-morpholino knockdown, we found that citrullination of histone tails at H4R3 and H3R2/8/17 were markedly reduced in the 2- and 4-cell embryos. Consistent with this observation, early ...


Synthesis Of Orthogonally Protected Thioamide Dipeptides For Use In Solid-Phase Peptide Synthesis, Fintan Kelleher, Kim Manzor 2016 Institute of Technology, Tallaght

Synthesis Of Orthogonally Protected Thioamide Dipeptides For Use In Solid-Phase Peptide Synthesis, Fintan Kelleher, Kim Manzor

Articles

Orthogonally protected thioamide-containing dipeptides were efficiently and cleanly prepared from the precursor dipeptides using Curphey’s method (P4S10, hexamethyldisiloxane (HMDO), reflux, DCM) in 67-96% isolated yield. This was in contrast to the use of Lawesson’s or Berzelius’ reagents where significant issues with reaction non-completion, decomposition and purification were observed. Subsequent clean removal of the dipeptides’ t-butyl ester protecting groups gave thioamide dipeptide acids which were suitable for use in solid-phase peptide synthesis (SPPS).


Synthesis Of Polymeric Bismuth Chlorido Hydroxamato Complexes; X-Ray Crystal Structure And Antibacterial Activity Of A Novel Bi(Lll) Salicylhydroxamato Complex, Donal M. Keoghan, Lauren E. Fagan, Thayse Marques Passos, Helge Müller-Bunz, Bríd Quilty, Darren M. Griffith 2016 Royal College of Surgeons in Ireland

Synthesis Of Polymeric Bismuth Chlorido Hydroxamato Complexes; X-Ray Crystal Structure And Antibacterial Activity Of A Novel Bi(Lll) Salicylhydroxamato Complex, Donal M. Keoghan, Lauren E. Fagan, Thayse Marques Passos, Helge Müller-Bunz, Bríd Quilty, Darren M. Griffith

Pharmaceutical and Medicinal Chemistry Articles

Reaction of salicylhydroxamic acid (Sha) and 2-aminophenyl hydroxamic acid (2-NH2-pha) with BiCl3 affords the corresponding novel polymeric bismuth chlorido hydroxamato complexes; [BiCl2(-Sha-1H)]∞ and [BiCl3(--Pha-1H)]∞ respectively. The X-ray crystal structure of the THF-solvated polymeric bismuth chlorido salicylhydroxamato complex, [BiCl2(-Sha-1H)(THF)]∞ was solved, confirming the polymeric structure of this class of compounds and the (O,μ-O’)-bidentate bridging coordination mode of the hydroxamato ligand. The antibacterial activity of the THF-free polymeric bismuth chlorido salicylhydroxamato complex, [BiCl2(-Sha-1H)]∞, was investigated against a broad panel of bacteria, further highlighting the antibacterial properties of Bi-based compounds against Gram-positive and Gram-negative pathogenic and ...


Novel Improved Synthesis Of Hsp70 Inhibitor, Pifithrin-Μ. In Vitro Synergy Quantification Of Pifithrin-Μ Combined With Pt Drugs In Prostate And Colorectal Cancer Cells., Aoife M. McKeon, Alan Egan, Jay Chandanshive, Helena McMahon, Darren M. Griffith 2016 Royal College of Surgeons in Ireland

Novel Improved Synthesis Of Hsp70 Inhibitor, Pifithrin-Μ. In Vitro Synergy Quantification Of Pifithrin-Μ Combined With Pt Drugs In Prostate And Colorectal Cancer Cells., Aoife M. Mckeon, Alan Egan, Jay Chandanshive, Helena Mcmahon, Darren M. Griffith

Pharmaceutical and Medicinal Chemistry Articles

We describe a novel improved approach to the synthesis of the important and well-known heat shock protein 70 inhibitor (HSP70), pifithrin-μ, with corresponding and previously unreported characterisation. The first example of a combination study comprising HSP70 inhibitor pifithrin-μ and cisplatin or oxaliplatin is reported. We have determined, using the Chou-Talalay method, (i) moderate synergistic and synergistic effects in co-treating PC-3 prostate cancer cells with pifithrin-μ and cisplatin and (ii) significant synergistic effects including strong synergism in cotreating HT29 colorectal cancer cells with oxaliplatin and pifithrin-μ.


Gas Chromatography-Mass Spectrometry Based Isotopic Abundance Ratio Analysis Of Biofield Energy Treated Methyl-2-Napthylether (Nerolin), Mahendra Trivedi 2016 Trivedi Global Inc.

Gas Chromatography-Mass Spectrometry Based Isotopic Abundance Ratio Analysis Of Biofield Energy Treated Methyl-2-Napthylether (Nerolin), Mahendra Trivedi

Mahendra Kumar Trivedi

Methyl-2-napthylether (nerolin) is an organic compound and has the applications in pharmaceutical, and perfume industry. The stable isotope ratio analysis is increasing importance in various field of scientific research. The objective of the current study was to evaluate the effect of the biofield energy treatment on the isotopic abundance ratios of PM+1/PM+ (2H/1/sup>H or 13C/12C or 17O/16O) and PM+2/PM (18O/16O) in nerolin using the gas chromatography-mass spectrometry (GC-MS). The compound nerolin was divided into two parts - one part was control sample (untreated), and another part was considered as biofield energy ...


Synthesis Of A Small Molecule Nitrosocysteine Inhibitor To Reduce The Activity Of Caspase-1, Catherine A. Shamblen, Caitlin E. Karver 2016 DePaul University

Synthesis Of A Small Molecule Nitrosocysteine Inhibitor To Reduce The Activity Of Caspase-1, Catherine A. Shamblen, Caitlin E. Karver

DePaul Discoveries

Caspase-1 is an enzyme that is overactive in autoimmune and autoinflammatory diseases cleaving pro-interleukin-1β to the cytokine interleukin-1β (IL-1β), which leads to inflammatory symptoms. The inhibition of caspase-1 will cause a decrease in the concentration of interleukin-1β (IL-1β), resulting in the reduction of inflammatory symptoms. Recent research has revealed that the appending of a nitric oxide (NO) or nitroxyl (HNO) donating group to non-steroidal anti-inflammatory drugs (NSAIDs) reduced, or avoided, the side effects caused by currently available treatments. A small molecule based on a known caspase-1 inhibitor with a nitrosocysteine appended on was synthesized to look at the effect of ...


Conformational Dynamics And Stability Associated With Magnesium Or Calcium Binding To Dream In The Regulation Of Interactions Between Dream And Dna Or Presenilins, Khoa Ngoc Pham 2016 Florida International University

Conformational Dynamics And Stability Associated With Magnesium Or Calcium Binding To Dream In The Regulation Of Interactions Between Dream And Dna Or Presenilins, Khoa Ngoc Pham

FIU Electronic Theses and Dissertations

Downstream regulatory element antagonist modulator (DREAM) is involved in various interactions with targets both inside and outside of the nucleus. In the cytoplasm, DREAM interacts with the C-terminal fragments of presenilins to facilitate the production of β-amyloid plaques in Alzheimer’s disease. In the nucleus, Ca2+ free DREAM directly binds to specific downstream regulatory elements of prodynorphin/c-fos gene to repress the gene transcription in pain modulation. These interactions are regulated by Ca2+ and/or Mg2+ association at the EF-hands in DREAM. Therefore, understanding the conformational dynamics and stability associated with Ca2+ and/or Mg ...


Enzyme-Mediated And Mechanistic Investigations Of Tetrahydroisoquinoline Synthesis Through The Pictet-Spengler Reaction, Jordan Elise Fauser 2016 DePaul University

Enzyme-Mediated And Mechanistic Investigations Of Tetrahydroisoquinoline Synthesis Through The Pictet-Spengler Reaction, Jordan Elise Fauser

College of Science and Health Theses and Dissertations

Tetrahydroisoquinolines (THI) are biologically active natural products with applications to a variety of diseases. These compounds also act as precursors for other pharmacologically active natural products. In this investigation, a new synthetic approach for generation of halogenated THIs was proposed. Using cross-linked tyrosinase aggregate, halogenated tyrosine and tyramine were oxidized to form halogenated catechols such as halogenated L-DOPA and dopamine. In a one-pot synthetic approach, the enzyme oxidation reaction was coupled to the Pictet-Spengler reaction, through the addition of an aldehyde, to generate halogenated THIs. The Pictet-Spengler reaction was catalyzed by the phosphate buffer in the reaction solution. The role ...


Optimizing Sequence Coverage For A Moderate Mass Protein In Nano-Electrospray Ionization Quadrupole Time-Of-Flight Mass Spectrometry, Ryan E. Matsuda, Venkata Kolli, Megan Woods, Eric D. Dodds, David S. Hage 2016 University of Nebraska-Lincoln

Optimizing Sequence Coverage For A Moderate Mass Protein In Nano-Electrospray Ionization Quadrupole Time-Of-Flight Mass Spectrometry, Ryan E. Matsuda, Venkata Kolli, Megan Woods, Eric D. Dodds, David S. Hage

David Hage Publications

Sample pretreatment was optimized to obtain high sequence coverage for human serum albumin (HSA, 66.5 kDa) when using nano-electrospray ionization quadrupole time-of-flight mass spectrometry (nESI-Q-TOF-MS). Use of the final method with trypsin, Lys-C and Glu-C digests gave a combined coverage of 98.8%. The addition of peptide fractionation resulted in 99.7% coverage. These results were comparable to those obtained previously with matrixassisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The sample pretreatment/nESI-Q-TOF-MS method was also used with collision-induced dissociation to analyze HSA digests and to identify peptides that could be employed as internal mass calibrants in future ...


Abrogation Of Collagen-Induced Arthritis By A Peptidyl Arginine Deiminase Inhibitor Is Associated With Modulation Of T Cell-Mediated Immune Responses, Joanna Kawalkowska, Anne-Marie Quirke, Fatemeh Ghari, Simon Davis, Venkataraman Subramanian, Paul R. Thompson, Richard O. Williams, Roman Fischer, Nicholas B. La Thangue, Patrick J. Venables 2016 University of Oxford

Abrogation Of Collagen-Induced Arthritis By A Peptidyl Arginine Deiminase Inhibitor Is Associated With Modulation Of T Cell-Mediated Immune Responses, Joanna Kawalkowska, Anne-Marie Quirke, Fatemeh Ghari, Simon Davis, Venkataraman Subramanian, Paul R. Thompson, Richard O. Williams, Roman Fischer, Nicholas B. La Thangue, Patrick J. Venables

Open Access Articles

Proteins containing citrulline, a post-translational modification of arginine, are generated by peptidyl arginine deiminases (PAD). Citrullinated proteins have pro-inflammatory effects in both innate and adaptive immune responses. Here, we examine the therapeutic effects in collagen-induced arthritis of the second generation PAD inhibitor, BB-Cl-amidine. Treatment after disease onset resulted in the reversal of clinical and histological changes of arthritis, associated with a marked reduction in citrullinated proteins in lymph nodes. There was little overall change in antibodies to collagen or antibodies to citrullinated peptides, but a shift from pro-inflammatory Th1 and Th17-type responses to pro-resolution Th2-type responses was demonstrated by serum ...


Crystal Protein Cry5b As A Novel And Powerful Anthelmintic, David Koch, Zeynep Mirza, Yan Hu, Thanh-thanh Nguyen, Gary R. Ostroff, Raffi V. Aroian 2016 University of Massachusetts Medical School

Crystal Protein Cry5b As A Novel And Powerful Anthelmintic, David Koch, Zeynep Mirza, Yan Hu, Thanh-Thanh Nguyen, Gary R. Ostroff, Raffi V. Aroian

UMass Center for Clinical and Translational Science Research Retreat

Soil-transmitted helminths (STHs), most notably, hookworms, whipworms, and Ascaris, are nematodes that infect more than 1.5 billion of the poorest people and are amongst the leading causes of morbidity worldwide. Only two classes of de-worming drugs (anthelmintics) are available for treatment, and only one is commonly used in mass drug administrations. New anthelmintics are urgently needed to overcome emerging resistance and to produce higher cure rates. Crystal (Cry) proteins, in particular Cry5B, made by Bacillus thuringiensis (Bt) are promising new candidates. Cry5B has excellent anthelmintic properties against many free-living and parasitic nematodes, including in vivo efficacy against multiple STH ...


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