Medicinal and Pharmaceutical Chemistry | Open Access Articles

Loss-Of-Function KCa2.2 Mutations Abolish Channel Activity, Young-Woo Nam, Mohammad Asikur Rahman, Grace Yang, Razan Orfali, Meng Cui, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca²⁺-activated potassium channels subtype 2 (K_Ca2.2, also called SK2) are operated exclusively by a Ca²⁺-calmodulin gating mechanism. Heterozygous genetic mutations of K_Ca2.2 channels have been associated with autosomal dominant neurodevelopmental disorders including cerebellar ataxia and tremor in humans and rodents. Taking advantage of these pathogenic mutations, we performed structure-function studies of the rat K_Ca2.2 channel. No measurable current was detected from HEK293 cells heterologously expressing these pathogenic K_Ca2.2 mutants. When co-expressed with the K_Ca2.2_WT channel, mutations of the pore-lining amino acid residues (I360M, Y362C, G363S …

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Design And Synthesis Of Substituted N,3,3-Triphenylpropanamide And 1-Benzhydryl-N-Phenylazetidine-3-Carboxamide Analogs And Their Biological Evaluation, Michael Dorogan

Theses and Dissertations

As D₁R agonism has significant implications in the treatment of cognitive deficits, we sought to develop novel D₁R PAMs, through the derigidification of BMS D₁R PAM hit compound. While we were able to synthesize derigidified analogs of the BMS hit compound, derigidification did not produce active D₁R ligands.

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Effects Of Disulfiram On The Metabolome Of Mrsa, Surya Teja Naidu

Theses, Dissertations and Capstones

Disulfiram, known as Antabuse®, is an oral drug for the treatment of alcohol dependence. Previous studies have indicated that disulfiram (DSF) exhibits antibacterial effects, particularly against Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Our study delves into the antibacterial mechanism of DSF in MRSA through High-Pressure Liquid Chromatography (HPLC) metabolomics, investigating the underlying mechanism of DSF effects on thiamine and amino acid metabolism. Thiamine pyrophosphate (TPP) plays a crucial role as a cofactor for critical enzymes such as transketolase, pyruvate dehydrogenase, and 2-oxoglutarate dehydrogenase. These enzymes are integral to the carbohydrate metabolism process within bacterial cells. TPP also contributes …

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Soft X-Ray And Susceptibility Based Magnetic Resonance Imaging To Map Iron Distribution In Apples: Initial Results To Model Iron Storage In Water-Deficient Or Dehydrated Biological Tissue, Subhendra N. Sarkar, Eric Lobel, Evans Lespinasse, Zoya Vinokur, Analia Basilicata, Sonia Orellana, Maria Orellana, Aaliyah Salmon, Joanna Syska, Aravis Mcbroom, Jian Wang, Anam Riaz, Jodi-Ann Douglas

Publications and Research

Radiology departments have contributed significantly to greenhouse gases including release of toxic imaging contrast media to environment. We feel Radiology also has several spectroscopy and imaging tools that may apply to monitor and support cleaner environmental goals. The current manuscript is one of the firsts to prompt Radiology to move in that direction by non invasive imaging of bio metals that are less abundant in biological tissues but play key roles as co-factors in tissue structure and function. Conventional analytical tools are mostly invasive and cannot characterize the native oxidation states of bio metals. We chose carbohydrate matrix of metal-rich …

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Assessing Drug Development Proporties Of Antithrombotic And Anti - Cancer Agents, Elsamani I. Abdelfadiel

Theses and Dissertations

The current GAG anticoagulants such as heparin, heparin derivatives, and vitamin K antagonists, such as warfarin continue to be the backbone of anticoagulant therapy. These drugs act through an indirect mechanism to convey inhibition of several coagulation enzymes. However, xv their use leads to several serious adverse effects, such as excessive bleeding risk and unpredictability of patient response. Regardless of their clinical achievement, every individual agent is accompanied by several side effects, particularly major/minor bleeding, thrombocytopenia, drug-food or drug-drug interactions, or absence of antidote. Of all these side effects, bleeding, and a lack of an effective antidote to reverse excessive …

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An Updated Examination Of The Perception Of Barriers For Pharmacogenomics Implementation And The Usefulness Of Drug/Gene Pairs In Latin America And The Caribbean, Aimeé Salas-Hernández, Macarena Galleguillos, Matías Carrasco, Andrés López-Cortés, María Ana Redal, Dora Fonseca-Mendoza, Patricia Esperón, Farith González-Martínez, Ismael Lares-Asseff, Alberto Lazarowski, Verónica Loera-Castañeda, Diadelis Remírez, Matías F Martínez, Rodrigo Vargas, Fabricio Rios-Santos, Antonio Macho, Juan P Cayún, Germán R Perez, Carolina Gutierrez, Leslie C Cerpa, Tamara Leiva, Susan Calfunao, Lesly Xajil, Christopher Sandoval, Marcelo Suárez, Ariana Gonzalez, Gabriela Echeverría-Garcés, Luis Sullón-Dextre, Eugenia Cordero-García, Alexis R Morales, Andrea Avendaño, Enrique Sánchez, Laura C Bastone, Cesar Lara, Patricia Zuluaga-Arias, Ana María Soler, Julio Da Luz, Gabriela Burgueño-Rodríguez, Marcelo Vital, Elizabeth Reyes-Reyes, Alexander Huaccha, Yeimy V Ariza, Naomi Tzul, Ana L Rendón, Roberto Serrano, Larissa Acosta, Angelo Motta-Pardo, Leonardo Beltrán-Angarita, Erika Brand, Miguel A Jiménez, Gladys Maribel Hidalgo-Lozada, Marina M J Romero-Prado, Karla Escobar-Castro, Mariel Umaña-Rivas, Juan D Vivas, Paola Lagos, Yineth Ballén Martínez, Sharleth Quesada, Camila Calfio, Maria L Arias, María A Lavanderos, Dante D Cáceres, Alberto Salazar-Granara, Nelson M Varela, Luis A Quiñones

Faculty, Staff and Student Publications

Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers …

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Investigating The Use Of Mpges-1 Inhibitors For The Treatment Of Abdominal Aortic Aneurysms, Lauren M. Weaver

Theses and Dissertations--Pharmacy

The cardiovascular field is still searching for a treatment for abdominal aortic aneurysms (AAA). This inflammatory disease is a deadly, permanent ballooning of the aortic artery. It often goes undiagnosed until a late stage where associated rupture has a high mortality rate. Surgery is the only option available to patients, but it is risky. There are currently no FDA-approved pharmacological treatments for AAA available. Historically, drugs that have been examined in interventional clinical trials for treatment of AAA were repurposed therapeutics. Novel treatments have been unable to reach the clinic, stalling out in pre-clinical studies. Exceedingly few murine studies have …

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Optimization Of Orally Bioavailable Inhibitors Of Defective In Cullin Neddylation 1 (Dcn-1), Leah Kovalic

Theses and Dissertations--Pharmacy

Ubiquitin (UB) and ubiquitin-like protein (UBL) pathways have emerged as important targets for oncology drug discovery based on the success of proteasome inhibitors (bortezomib or carfilzomib), E3 inhibitors, and the NEDD8 E1 inhibitor pevonedistat (MLN42924). Chemical inhibitors have also proven to be useful probes for identifying and dissecting multifactor UB and UBL regulatory networks. Toward this end, we have pursued approaches to target NEDD8 ligation to Cullins, through developing small molecule inhibitors of DCN1 (defective in Cullin Neddylation 1). DCN1 was discovered as a potentiating RBX1-dependent NEDD8-ligation, through recognizing the acetylated N-terminal methionine of the NEDD8 E2s UBE2M and UBE2F. …

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Design And Synthesis Of Small Molecular Inhibitors Of Dcn1-Ube2m Interaction, Tucker J. Moseley

Theses and Dissertations--Pharmacy

Over the last century, advancements in medicine have been made to improve cancer patients' outcomes. The discovery of new druggable targets is essential to achieving this goal. Defective in Cullin Neddylation 1 is a proven oncogenetic driver that may lead to better clinical outcomes when targeted. In efforts to further improve a series of novel small molecular inhibitors of the DCN1 and UBE2M protein-protein interaction, the Guy lab has designed and synthesized 26 new compounds. These compounds were designed to specifically target the UBE2M N-Acetyl sub-pocket on DCN1 that was not occupied by compounds previously described in the literature.

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New Tools For Biocatalysis: Studies On The Carminomycin 4-O-Methyltransferase Dnrk, Elnaz Jalali

Theses and Dissertations--Pharmacy

Methyltransferases (MTs) are ubiquitous enzymes commonly involved in biosynthesis and regulation. The fundamental goal of this thesis was to explore the permissive nature of methyltransferases and leverage this unique biocatalytic feature to develop a new platform for chemoselective intramolecular cyclization reactions. To realize this ambitious goal, this thesis project set out to probe the substrate specificity of multiple natural product tailoring enzymes (MTs and glycosyltransferases), identify model substrates common to multiple such tailoring enzymes and subsequently establish multi-enzyme tandem reactions that would set the stage for a subsequent chemoselective intramolecular cyclization reaction. Chapter One highlights current state of the art …

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Lysosomes, Curcumin, And Anti-Tumor Effects: How Are They Linked?, Qian Shen, Xue Pan, Yi Li, Junchen Li, Chuanlong Zhang, Xiaochen Jiang, Fudong Liu, Bo Pang

Faculty, Staff and Student Publications

Curcumin is a natural active ingredient from traditional Chinese medicine (TCM) that has multi-target characteristics to exert extensive pharmacological activities and thus has been applied in the treatment of various diseases such as cancer, cardiovascular diseases, nervous system, and autoimmune disorders. As an important class of membranous organelles in the intracellular membrane system, lysosomes are involved in biological processes such as programmed cell death, cell metabolism, and immune regulation, thus affecting tumor initiation and progression. It has been shown that curcumin can modulate lysosomal function through the aforementioned pathways, thereby affecting tumor proliferation, invasion, metastasis, drug resistance, and immune function. …

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Development Of A Chemical Biology Approach To Uncover The Influence Of Sequence Variations On Ces1 Activity In Live Cells, Samuel James Knebel

Masters Theses

Drug metabolism is the biochemical process of modifying drugs to detoxify and remove them through enzymatic transformations. These biotransformation’s occur primarily in the liver and are critical to understanding how pharmaceutical compounds are chemically altered inside the human body. Human carboxylesterases (CESs) catalyze the hydrolysis of esters, amides, thioesters, and carbamates. CES-mediated hydrolysis plays an important role in the metabolism of many drugs including the first FDA approved antiviral treatment for COVID-19, remdesivir (Veklury), the seizure control medication rufinamide (Banzel), and the flu antiviral drug oseltamivir (Tamiflu). CES activity is known to be influenced by a variety of factors including …

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Full-Text Articles in Medicinal and Pharmaceutical Chemistry

Loss-Of-Function KCa2.2 Mutations Abolish Channel Activity, Young-Woo Nam, Mohammad Asikur Rahman, Grace Yang, Razan Orfali, Meng Cui, Miao Zhang

Pharmacy Faculty Articles and Research

Design And Synthesis Of Substituted N,3,3-Triphenylpropanamide And 1-Benzhydryl-N-Phenylazetidine-3-Carboxamide Analogs And Their Biological Evaluation, Michael Dorogan

Theses and Dissertations

Effects Of Disulfiram On The Metabolome Of Mrsa, Surya Teja Naidu

Theses, Dissertations and Capstones

Publications and Research

Assessing Drug Development Proporties Of Antithrombotic And Anti - Cancer Agents, Elsamani I. Abdelfadiel

Theses and Dissertations

Faculty, Staff and Student Publications

Investigating The Use Of Mpges-1 Inhibitors For The Treatment Of Abdominal Aortic Aneurysms, Lauren M. Weaver

Theses and Dissertations--Pharmacy

Optimization Of Orally Bioavailable Inhibitors Of Defective In Cullin Neddylation 1 (Dcn-1), Leah Kovalic

Theses and Dissertations--Pharmacy

Design And Synthesis Of Small Molecular Inhibitors Of Dcn1-Ube2m Interaction, Tucker J. Moseley

Theses and Dissertations--Pharmacy

New Tools For Biocatalysis: Studies On The Carminomycin 4-O-Methyltransferase Dnrk, Elnaz Jalali

Theses and Dissertations--Pharmacy

Lysosomes, Curcumin, And Anti-Tumor Effects: How Are They Linked?, Qian Shen, Xue Pan, Yi Li, Junchen Li, Chuanlong Zhang, Xiaochen Jiang, Fudong Liu, Bo Pang

Faculty, Staff and Student Publications

Development Of A Chemical Biology Approach To Uncover The Influence Of Sequence Variations On Ces1 Activity In Live Cells, Samuel James Knebel

Masters Theses