Medicinal-Pharmaceutical Chemistry Commons^™

Brain Endothelial Permeability, Transport, And Flow Assessed Over 10 Orders Of Magnitude Using The In Situ Brain Perfusion Technique, Quentin R. Smith, Haritha Mandula, Jagan Mohan R. Parepally, Jun Oki, Fancy Thomas, Helen R. Thorsheim, Abraham J. Al‑Ahmad, Thomas J. Abbruscato, Per Ask, David S. Hage, Peter J. Robinson

David Hage Publications

Background Cerebral blood flow normally places a limit on the magnitude of brain vascular permeability (P) that can be measured in vivo. At normal cerebral blood flow, this limit falls at the lower end of lipophilicity for most FDAapproved CNS drugs. In this study, we report on two methods that can be used to overcome this limitation and measure brain vascular permeability values that are up to ~1000 times higher using the in situ brain perfusion technique.

Methods Rat brain was perfused with physiological saline at increased flow rate and in the presence of various concentrations of plasma protein, serum …

Design, Synthesis, And Nmr-Guided Characterization Of A Targeted Covalent Inhibitor-Like Molecule Against Ivyp1 From P. Aeruginosa, Samuel Taylor Moore

Master's Theses

Multi-drug resistance poses a serious threat to future generations and historical antibiotic pipelines; consequently, the medical and economic burdens associated with treating multidrug-resistant bacteria are substantiated. In this context, P. aeruginosa (PA) emerges as one of the most significant healthcare challenges, being a leading cause of resistance-associated mortality worldwide. Despite modern efforts to combat these poor outcomes, drug-resistant cases continue to rise, and the need for novel antibiotic treatment is apparent. To this end, we investigated relevant resistance mechanisms and past antibiotic targets within PA, and in doing so, we identified relationships between peptidoglycan biology and a periplasmic protein, Inhibitor …

Computational Logp Calculations And Determination Of Lipophilicity Values Of Fluorinated Morphine Derivatives, Mirabella Romano, Allison Vu, Emily Chen

Student Scholar Symposium Abstracts and Posters

The addictive effect of opioids impacted 60 million people globally in 2023. This opioid crisis necessitates the development of opioid derivatives that maintain analgesic efficacy while minimizing addictive effects from opioid use. The present work focuses on morphine, a commonly prescribed opioid with high affinity to the mu-opioid receptor (MOR). Morphine binds non-selectively within both healthy and inflamed tissue. By modifying morphine’s structure through fluorination to counteract its non-selective binding, the drug’s pharmacological ability to provide effective pain relief comes with a lower risk of addiction. Specifically, the addition of fluorine to differing beta positions of the main binding site …

Rings Of Power: Controlling Sod Mimic Activity By The Addition Of Pyridine Rings Within The Pyridinophane Scaffold, Katherine J. Smith, Timothy M. Schwartz, David M. Freire, Cameron Bowers, Sarah K. Dunn, Jackson F. Bonnell, Magy A. Mekhail, Giridhar Akkaraju, Kayla N. Green

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Superoxide dismutase enzymes are a major defense against superoxide, which is a potent reactive oxygen species. Misregulation of reactive oxygen species and subsequent neuronal damage are etiological hallmarks of neurodegenerative disease. Macrocyclic small molecules have offered inroads toward functional SOD1 mimics. Herein, we report a series of five tetra-aza macrocyclic ^RPy₂N₂ ligands, varied by 4-position substitution of the pyridine ring with both electron-donating (R = OMe) and withdrawing groups (R = Cl, I, and CF₃) to offer the first comparison to well-studied ^RPyN₃ congeners and other mimics in the literature. New ligands …

Alphafold2-Based Characterization Of Apo And Holo Protein Structures And Conformational Ensembles Using Randomized Alanine Sequence Scanning Adaptation: Capturing Shared Signature Dynamics And Ligand-Induced Conformational Changes, Nishank Raisinghani, Vedant Parikh, Brandon Foley, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Proteins often exist in multiple conformational states, influenced by the binding of ligands or substrates. The study of these states, particularly the apo (unbound) and holo (ligand-bound) forms, is crucial for understanding protein function, dynamics, and interactions. In the current study, we use AlphaFold2, which combines randomized alanine sequence masking with shallow multiple sequence alignment subsampling to expand the conformational diversity of the predicted structural ensembles and capture conformational changes between apo and holo protein forms. Using several well-established datasets of structurally diverse apo-holo protein pairs, the proposed approach enables robust predictions of apo and holo structures and conformational ensembles, …

Sufex-Enabled Stereospecific Deoxygenative Diversification Of Alcohols, Amaechi Odoh

All Dissertations

Alcohols represent an important class of functional group in organic synthesis and medicinal chemistry, given that they are structurally diverse and prevalent in many natural products, biomolecules and renewable feedstocks. As such, they are highly attractive precursors for building-block synthesis, late-stage functionalization, and numerous synthetic transformations. However, existing strategies for the deoxygenative diversification of alcohols operate under constrained conditions, often leading to competing pathways (such as elimination), poor stereospecificity, low efficiencies, and limited substrate compatibility. To address these challenges, we have developed a conceptually novel use of sulfonyl fluorides as bifunctional reagents for the one-step deoxygenative diversification of complex alcohol …

Influence Of Glycopolymer Structure On Amphiphilic, Hybrid, Linear Branched Block Copolymer Properties For Use In Biomedical Applications, Kevin Green

Dissertations

The focus of this dissertation is evaluating and adding fundamental knowledge regarding the structure-property relations of glycopolymers used in the design of hybrid block copolymers (HBC) that are cable of self-assembling into delivery vehicles for biomedical applications. A shift to the utilization of natural materials in the design and fabrication of drug-delivery vehicles has garnered significant attention. Understanding the effects of linear glycopolymers content and composition on the resulting HBCs properties can provide valuable insight into how these materials may be tailored for use in targeted biological applications.

The first chapter introduces current literature on the need for improvement in …

Synthesis Of Photocleavable Molecules For Neurological Applications, Nishal Madujith Egodawaththa Arachchilage Don

Theses and Dissertations

In recent biomedical research, the precise control of molecular dynamics through light activation has emerged as a powerful tool, particularly in the field of neurobiology. This approach involves the use of photocleavable cages or photoprotective groups (PPGs) that are chemically tethered to biologically active molecules such as neurotransmitters or calcium chelators. These cages remain inert until exposed to specific wavelengths of light, typically in the visible range, triggering the release of the active compound with high spatiotemporal precision.

For neurotransmitter systems, such as glutamate (Glu), which plays a critical role in synaptic transmission and memory formation, researchers have developed novel …

Synthesis And Characterization Of Water Soluble Thiosemicarbazone-Alkylthiocarbamate Ligands And Their Cu(Ii) Complexes, John J. Garvey Iv, Sanjit Karki, Haixun Guo, Levi J. Beverly, Craig A. Grapperhaus, Robert M. Buchanan

The Cardinal Edge

Thiosemicarbazone-alkylthiocarbamate N₂S₂ hybrid ligands are emerging as an important class of potential bioactive molecules that possess important pharmacokinetic properties. Resulting metal complexes have electronic properties that are composites of their homolog forms, bis-thiosemicarbazones and bis-alkylthiocarbamates, allowing for tuning redox potentials over a nearly 450 mV range. These versatile ligand frameworks possess remarkable antiproliferation activity against a broad range of solid tumors and low toxicity towards normal cells¹ indicating great promise for future drug development. Herein, we describe recent synthetic efforts to improve water solubility of thiosemicarbazone-alkylthiocarbamate hybrid ligand Cu(II) complexes. The parent 4-methyl-3-thiosemicarbazide half arm was …

Editorial: Leveraging Multi-Omics Approaches To Understand And Manage Gastrointestinal And Hepatic Diseases, Isis Trujillo-Gonzalez, Paul G. Thomes, Isin Tuna Sakallioglu, Kusum K. Kharbanda

Department of Chemistry: Faculty Publications

The Research Topic “Leveraging multi-omics approaches to understand and manage gastrointestinal and hepatic diseases” proposed by the Frontiers in Pharmacology has attracted a total of four articles on preclinical studies that were covered in three original research manuscripts and one review article. Two research articles were on metabolic dysfunction-associated steatotic liver disease (MASLD), previously named non-alcoholic fatty liver disease (NAFLD), which is now recognized as a predominant cause of chronic liver disease worldwide, affecting over 30% of the adult population (Teng et al., 2023; Miao et al., 2024). Current pharmacological treatments for MASLD are limited and, until a recent FDA-approved …

Ks18, A Mcl-1 Inhibitor, Improves The Effectiveness Of Bortezomib And Overcomes Resistance In Refractory Multiple Myeloma By Triggering Intrinsic Apoptosis., Omar S Al-Odat, Weam Othman Elbezanti, Krishne Gowda, Sandeep K Srivastava, Shantu G Amin, Subash C. Jonnalagadda, Tulin Budak-Alpdogan, Manoj K Pandey

Cooper Medical School of Rowan University Departmental Research

Despite a record number of clinical studies investigating various anti-myeloma treatments, the 5-year survival rate for multiple myeloma (MM) patients in the US is only 55%, and almost all patients relapse. Poor patient outcomes demonstrate that myeloma cells are "born to survive" which means they can adapt and evolve following treatment. Thus, new therapeutic approaches to combat survival mechanisms and target treatment resistance are required. Importantly, Mcl-1, anti-apoptotic protein, is required for the development of MM and treatment resistance. This study looks at the possibility of KS18, a selective Mcl-1 inhibitor, to treat MM and overcome resistance. Our investigation demonstrates …

Alphafold2 Modeling And Molecular Dynamics Simulations Of The Conformational Ensembles For The Sars-Cov-2 Spike Omicron Jn.1, Kp.2 And Kp.3 Variants: Mutational Profiling Of Binding Energetics Reveals Epistatic Drivers Of The Ace2 Affinity And Escape Hotspots Of Antibody Resistance, Nishank Raisinghani, Mohammed Alshahrani, Grace Gupta, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

AlphaFold2-based atomistic predictions of structures and conformational ensembles of the SARS-CoV-2 spike complexes with the host receptor ACE2 for the most dominant Omicron variants JN.1, KP.1, KP.2 and KP.3 to examine the mechanisms underlying the role of convergent evolution hotspots in balancing ACE2 binding and antibody evasion. Using the ensemble-based mutational scanning of the spike protein residues and computations of binding affinities, we identified binding energy hotspots and characterized the molecular basis underlying epistatic couplings between convergent mutational hotspots. The results suggested the existence of epistatic interactions between convergent mutational sites at L455, F456, Q493 positions that protect and restore …

Improving Ligand Pharmacokinetics Via Bioisosteric Substitution Of Amides With 1, 2, 3-Triazoles While Maintaining Dopamine D4 Receptor Selectivity And Potency, Mohammad Alkhatib

Theses and Dissertations

Several neurophysiological functions, such as attention, cognition, and emotional regulation, are regulated by the binding of dopamine on G-Protein coupled receptors. D4Rs are mainly located in the prefrontal cortex and the hippocampus and are known to have a key role in decision-making, memory formation, cognition, and attention. Administration of D4Rs- selective ligands during the preclinical studies enhance the outcomes and the results in animal models suffering from neuropsychiatric disorders, including ADHD, substance use disorders (SUD), and Alzheimer's disease. Recently, we reported a group of D4R-selective ligands with different efficacies depending on their phenylpiperazine ring scaffold to illustrate D4R function during …

Microfiltration Membrane Pore Functionalization With Primary And Quaternary Amines For Pfas Remediation: Capture, Regeneration, And Reuse, Sam Thompson, Angela Gutierrez, Jennifer Bukowski, Dibakar Bhattacharyya

UK CARES Faculty Publications

The widespread production and use of multi-fluorinated carbon-based substances for a variety of purposes has contributed to the contamination of the global water supply in recent decades. Conventional wastewater treatment can reduce contaminants to acceptable levels, but the concen- trated retentate stream is still a burden to the environment. A selective anion-exchange membrane capable of capture and controlled release could further concentrate necessary contaminants, mak- ing their eventual degradation or long-term storage easier. To this end, commercial microfiltration membranes were modified using pore functionalization to incorporate an anion-exchange moiety within the membrane matrix. This functionalization was performed with primary and …

Protein And Water Modeling In Computer-Aided Drug Discovery, Mossa Ghattas

Dissertations, Theses, and Capstone Projects

The field of Computer-Aided Drug Design (CADD) is continuously evolving to improve protein modeling, a crucial step in the drug discovery process. However, limitations exist in how CADD accounts for the various configurations a protein can adopt due to different rotamer and protonation states of its residues. This thesis explores advancements in CADD to address this challenge, focusing on protein modeling and water interactions.

In Chapter 1, I introduce the drug discovery process with a brief overview of its history, the purpose of FDA clinical trials, and the cost and time duration for bringing a drug to the market. I …

Fourier Transform Ion Cyclotron Resonance Mass Spectrometry Applications For Metabolomics, Darcy Cochran, Robert Powers

Robert Powers Publications

Metabolomics is an interdisciplinary field that aims to study all metabolites < 1500 Da that are ubiquitously found within all organisms. Metabolomics is experiencing exponential growth and commonly relies on high-resolution mass spectrometry (HRMS). Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) is a form of HRMS that is particularly well suited for metabolomics research due to its exceptionally high resolution (10⁵–10⁶) and sensitivity with a mass accuracy in parts per billion (ppb). In this regard, FT-ICR-MS can provide valuable insights into the metabolomics analysis of complex biological systems due to unique capabilities such as the easy separation of isobaric and isomeric species, isotopic fine structure analysis, spatial resolution of metabolites in cells and tissues, and a high confidence (error) in metabolite identification. Alternatively, the large and complex data sets, long acquisition times, high cost, and limited access mainly through national mass spectrometry facilities may impede the …

Investigation Of The Prevalence Of Fentanyl Analogs In A Drug Testing Population Using Liquid Chromatography Tandem Mass Spectrometry (Lc-Ms-Ms), Ivan Cordova

Student Theses

This study serves to determine the prevalence of novel fentanyl analogs that are present within a drug testing population in New York State. Samples were analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS) to qualitatively determine the presence of various possible fentanyl analogs. The sample preparation of this assay consisted of a simple dilute and shoot. This method of sample preparation can be quicker, eliminating sample preparation times as well as being less financially strenuous to clinical laboratories as it eliminates the need for various solvents and solid/liquid phase cartridges. The assay was aimed to see if analytes can be …

Discovering Potential In Non-Cancer Medications: A Promising Breakthrough For Multiple Myeloma Patients., Omar S Al-Odat, Emily Nelson, Tulin Budak-Alpdogan, Subash C. Jonnalagadda, Dhimant Desai, Manoj K Pandey

College of Science & Mathematics Departmental Research

Multiple myeloma (MM) is a common type of cancer that unfortunately leads to a significant number of deaths each year. The majority of the reported MM cases are detected in the advanced stages, posing significant challenges for treatment. Additionally, all MM patients eventually develop resistance or experience relapse; therefore, advances in treatment are needed. However, developing new anti-cancer drugs, especially for MM, requires significant financial investment and a lengthy development process. The study of drug repurposing involves exploring the potential of existing drugs for new therapeutic uses. This can significantly reduce both time and costs, which are typically a major …

Study Of Modified Salinomycin Analogs On Inhibition Of Triple Negative Breast Cancer Metastasis And Invasion, Farnaz Malekmarzban

Theses and Dissertations

Triple negative breast cancer (TNBC) is a more aggressive type of breast cancer which contains faster growth, higher metastasis rate and worse prognosis. The main challenge toward treatment of this type of cancer is being heterogeneous. Recently, Salinomycin (SAL) has been considered as a potential agent for triple negative breast cancer treatment. However, chemical modification of SAL is needed to improve SAL selectivity to cations and decrease its cytotoxicity. The purpose of this study was to evaluate the effect of chemically modified analogs of SAL on the viability, metastasis, Wnt pathway as well as angiogenesis of Triple negative breast cancer …

Microencapsulation Of Cosmos Caudatus Kunth Extract Using Sodium Alginate And In Vitro Antioxidant Activity Test, Safina Samara Nur Fadlila, Oktavia Eka Puspita, Zubaidah Ningsih, Anna Safitri

Makara Journal of Science

This study aims to encapsulate Cosmos caudatus K. leaf extract in sodium alginate crosslinked with calcium chloride (CaCl₂) as coating materials through freeze-drying. Antioxidant assays were performed to evaluate the applicability of the microcapsules as antidiabetic medicines. Their characteristics, antioxidant activity, and encapsulation efficiency (EE) were also examined. Results indicated that the concentration of sodium alginate and pH influenced the manufacturing process of the microcapsules. The highest EE was obtained at pH 6 and alginate concentration of 2% (w/v). The IC₅₀ for the antioxidant activity of the microcapsules was 139.96 ± 1.094 μg/mL. Scanning electron microscopy confirmed …