Medicinal-Pharmaceutical Chemistry Commons^™

Development Of An Lcms Method To Detect And Quantify Curcumin In A Novel Oral Formulation Of Turmeric, Brandon Renninger

Annual Research Symposium

No abstract provided.

Synthesis And Analysis Of Novel Troponoid-Based Chemical Probes, Alex Berkowitz

Dissertations, Theses, and Capstone Projects

Troponoids are a class of non-benzenoid aromatic species featuring a cycloheptatrienone ring and varying degrees of oxygenation. These scaffolds have proven ubiquitous amongst natural products, and have displayed promise as therapeutic agents against a variety of diseases. Herein, we will describe our efforts towards furthering troponoids as potential pharmaceuticals. In Chapter 1, we outline a kojic acid-derived oxidopyrylium cycloaddition/ring-opening method developed in our lab to generate ahydroxytropolones (aHTs). This route was successfully adapted to synthesize a small library of lipophilic aHTs that were proven to be effective against herpes simplex virus-1 (HSV-1) replication, while providing further insight into the mechanism …

The Discovery And Characterization Of Novel Potent 5-Substituted 3, 3’, 4’, 7-Tetramethoxyflavonoid Dna Triplex Specific Binding Ligands, Vanessa Marie Rangel

University of the Pacific Theses and Dissertations

Chemotherapy works by killing fast dividing cells. Unfortunately, these drugs are not specific to cancer tissue and can damage normal cells. Chemotherapy is like taking poison and hoping it kills the cancer cells before it kills you. As an alternative, many researchers have investigated the use of antigene therapy to selectively target cancer causing genes to avoid off target effects. Although promising, the theory is limited by the stability of the triplex structure. Here, we report the discovery of potent triplex binding ligands derived from the natural product quercetin. Chemical derivatives of 5-substituted 3, 3’, 4’, 7-tetramethoxyquercetin derivatives were characterized …

Gold (I) Tetrathiomolybdate Clusters: Synthesis, Characterization, Computational Studies, And Reactivity With Thiophenol And Selenophenol, Dhirgam Humaidy

Electronic Theses and Dissertations

This thesis describes the synthesis and reactivity of heterometallic complexes containing medicinally active Au(I) and tetrathiomolybdate, [MoS₄]^2-. The research is motivated by the idea of multifunctional drugs, which are designed to treat diseases through two or more mechanisms of action. Five clusters of the general form, [MoS₄(AuL)₂] were prepared: C-1 (L=IPr), C-2 (L=IBzMe), C-3 (L=IMes), C-4 (L=PPh₃), and C-5 (L=PEt₃). The clusters with NHC ligands, C-1, C-2, and C-3 were prepared for the first time and thoroughly characterized by ¹H NMR,¹³C{¹H} …

Designing And Synthesizing A Warhead-Fragment Inhibitory Ligand For Ivyp1 Through Fragment-Based Drug Discovery, Samuel Moore

Symposium of Student Scholars

Fragment-based drug discovery (FBDD) is a powerful tool for developing anticancer and antimicrobial agents. Within this, magnetic resonance spectroscopy (NMR) provides a comprehensive qualitative and quantitative approach to screening and validating weak and robust binders with targeted proteins, making NMR among the most attractive strategies in FBDD. Inhibitor of vertebrate lysozyme (Ivyp1) of P. aeruginosa serves as an excellent target because of its active cellular location and implications in clinical prognosis for cystic fibrosis and immunocompromised patients. This study uses current NMR and biophysical techniques to develop a covalent, fragment-linked warhead inhibitor for Ivyp1 through synthetic methods, warhead linking, and …

Investigating The Effects Of Ionic Liquids On Dna Gquadruplex And Protein Structure Using Molecular Dynamics Simulations, Nicholas J. Paradis

Theses and Dissertations

Nucleic acids and proteins have huge implications in biomedicine and bioengineering, however their storage instability limits their applicability and current storage protocols are expensive and globally-inaccessible. Finding an alternative biocompatible media to store nucleic acids and proteins would reduce costs and increase their applicability. Ionic liquids (ILs) are molten salt compounds that have been shown to modulate the stability and activity of nucleic acids and proteins. In this thesis, molecular modeling studies of DNA/RNA and protein structure in ILs will be discussed (Chapter 1) and this method will be used to study the IL effects on the structure on the …

Intracellular Delivery Of Therapeutic Biomolecules Through Versatile Polymer Nanotechnology, David C. Luther

Doctoral Dissertations

Advancing pharmaceutical technology has made it possible to treat diseases once considered ‘undruggable.’ Access to these new pharmaceutical targets is possible thanks to the advent of protein and nucleic acid therapeutics. Responses to the COVID-19 pandemic, as well as cutting-edge treatments for cancer and multiple sclerosis have centered on these biologic therapies, promising even greater value in the future. However, their utility is limited at a cellular level by inability to cross the plasma membrane. Nanocarrier technologies encapsulate therapeutics and facilitate uptake into the cell but are often trapped and degraded in endosomes. Arginine-functionalized gold nanoparticles (Arg-NPs) provide efficient, direct …

Effects Of Cannabinoids On Ligand-Gated Ion Channels, Murat Oz, Keun-Hang Susan Yang, Mohamed Omer Mahgoub

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Phytocannabinoids such as Δ⁹-tetrahydrocannabinol and cannabidiol, endocannabinoids such as N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, and synthetic cannabinoids such as CP47,497 and JWH-018 constitute major groups of structurally diverse cannabinoids. Along with these cannabinoids, CB1 and CB2 cannabinoid receptors and enzymes involved in synthesis and degradation of endocannabinoids comprise the major components of the cannabinoid system. Although, cannabinoid receptors are known to be involved in anti-convulsant, anti-nociceptive, anti-psychotic, anti-emetic, and anti-oxidant effects of cannabinoids, in recent years, an increasing number of studies suggest that, at pharmacologically relevant concentrations, these compounds interact with several molecular targets including G-protein coupled receptors, ion …

Probing Mechanisms Of Binding And Allostery In The Sars-Cov-2 Spike Omicron Variant Complexes With The Host Receptor: Revealing Functional Roles Of The Binding Hotspots In Mediating Epistatic Effects And Communication With Allosteric Pockets, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan

Mathematics, Physics, and Computer Science Faculty Articles and Research

In this study, we performed all-atom MD simulations of RBD–ACE2 complexes for BA.1, BA.1.1, BA.2, and BA.3 Omicron subvariants, conducted a systematic mutational scanning of the RBD–ACE2 binding interfaces and analysis of electrostatic effects. The binding free energy computations of the Omicron RBD–ACE2 complexes and comprehensive examination of the electrostatic interactions quantify the driving forces of binding and provide new insights into energetic mechanisms underlying evolutionary differences between Omicron variants. A systematic mutational scanning of the RBD residues determines the protein stability centers and binding energy hotpots in the Omicron RBD–ACE2 complexes. By employing the ensemble-based global network analysis, we …

Interpretable Machine Learning Models For Molecular Design Of Tyrosine Kinase Inhibitors Using Variational Autoencoders And Perturbation-Based Approach Of Chemical Space Exploration, Keerthi Krishnan, Ryan Kassab, Steve Agajanian, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

In the current study, we introduce an integrative machine learning strategy for the autonomous molecular design of protein kinase inhibitors using variational autoencoders and a novel cluster-based perturbation approach for exploration of the chemical latent space. The proposed strategy combines autoencoder-based embedding of small molecules with a cluster-based perturbation approach for efficient navigation of the latent space and a feature-based kinase inhibition likelihood classifier that guides optimization of the molecular properties and targeted molecular design. In the proposed generative approach, molecules sharing similar structures tend to cluster in the latent space, and interpolating between two molecules in the latent space …

Tetrahydrocurcumin Improves Lipopolysaccharide-Induced Myocardial Dysfunction By Inhibiting Oxidative Stress And Inflammation Via Jnk/Erk Signaling Pathway Regulation, Hanzhao Zhu, Liyun Zhang, Hao Jia, Lu Xu, Yu Cao, Mengen Zhai, Kaifeng Li, Lin Xia, Liqing Jiang, Xiang Li, Yenong Zhou, Jincheng Liu, Shiqiang Yu, Weixun Duan

Chemistry Student Publications

Background

Acute myocardial dysfunction in patients with sepsis is attributed to oxidative stress, inflammation, and cardiomyocyte loss; however, specific drugs for its prevention are still lacking. Tetrahydrocurcumin (THC) has been proven to contribute to the prevention of various cardiovascular diseases by decreasing oxidative stress and inflammation. This study was performed to investigate the functions and mechanism of action of THC in septic cardiomyopathy.

Methods

After the oral administration of THC (120 mg/kg) for 5 consecutive days, a mouse model of sepsis was established via intraperitoneal lipopolysaccharide (LPS, 10 mg/kg) injection. Following this, cardiac function was assessed, pathological section staining was …

Meta-Analysis Reveals Both The Promises And The Challenges Of Clinical Metabolomics, Heidi E. Roth, Robert Powers

Faculty Publications -- Chemistry Department

Clinical metabolomics is a rapidly expanding field focused on identifying molecular biomarkers to aid in the efficient diagnosis and treatment of human diseases. Variations in study design, metabolomics methodologies, and investigator protocols raise serious concerns about the accuracy and reproducibility of these potential biomarkers. The explosive growth of the field has led to the recent availability of numerous replicate clinical studies, which permits an evaluation of the consistency of biomarkers identified across multiple metabolomics projects. Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related death and has the lowest five-year survival rate primarily due to the lack of an …

Lc-Ms/Tof Characterization And Stability Study Of Artesunate In Different Solvent Systems, Kogila Oke, Amos Mugweru

Faculty Scholarship for the College of Science & Mathematics

Artemisinin (ART) is a sesquiterpene lactone and a popular malaria drug used in many parts of the world. Artesunate (ARTS) is a semi-synthetic derivative of ART with improved pharmacokinetic properties. However, the half-life of ARTS is less than an hour in vivo. The analysis of this drug in vitro in different solvent systems using LC-MS/TOF showed a solvent-driven breakdown. ARTS breakdown formed several derivatives, including dihydroartemisinin (DHA), artemether (ARTM) and DHA-dimer among others, at different rates in different solvent composition systems. The change in temperature from room temperature to physiological temperature (37 °C) was found to enhance the rate of …

Subtype-Selective Positive Modulation Of KCa2.3 Channels Increases Cilia Length, Young-Woo Nam, Rajasekharreddy Pala, Naglaa Salem El-Sayed, Denisse Laren-Henriquez, Farideh Amirrad, Grace Yang, Mohammad Asikur Rahman, Razan Orfali, Myles Downey, Keykavous Parang, Surya M. Nauli, Miao Zhang

Pharmacy Faculty Articles and Research

Small-conductance Ca²⁺-activated potassium (K_Ca2.x) channels are gated exclusively by intracellular Ca²⁺. The activation of K_Ca2.3 channels induces hyperpolarization, which augments Ca²⁺ signaling in endothelial cells. Cilia are specialized Ca²⁺ signaling compartments. Here, we identified compound 4 that potentiates human K_Ca2.3 channels selectively. The subtype selectivity of compound 4 for human K_Ca2.3 over rat K_Ca2.2a channels relies on an isoleucine residue in the HA/HB helices. Positive modulation of K_Ca2.3 channels by compound 4 increased flow-induced Ca²⁺ signaling and cilia length, while negative …

Editorial: Expansion Of The Genetic Code: Unnatural Amino Acids And Their Applications, Subhendu Sekhar Bag, Ishu Saraogi, Jiantao Guo

Faculty Publications -- Chemistry Department

No abstract provided.

Nmr And Metabolomics—A Roadmap For The Future, David S. Wishart, Leo L. Cheng, Valérie Copié, Arthur S. Edison, Hamid R. Eghbalnia, Jeffrey C. Hoch, Goncalo J. Gouveia, Wimal Pathmasiri, Robert Powers, Tracey B. Schock, Lloyd W. Sumner, Mario Uchimiya

Faculty Publications -- Chemistry Department

Metabolomics investigates global metabolic alterations associated with chemical, biological, physiological, or pathological processes. These metabolic changes are measured with various analytical platforms including liquid chromatography-mass spectrometry (LC-MS), gas chromatographymass spectrometry (GC-MS) and nuclear magnetic resonance spectroscopy (NMR). While LC-MS methods are becoming increasingly popular in the field of metabolomics (accounting for more than 70% of published metabolomics studies to date), there are considerable benefits and advantages to NMR-based methods for metabolomic studies. In fact, according to PubMed, more than 926 papers on NMR-based metabolomics were published in 2021—the most ever published in a given year. This suggests that NMR-based metabolomics …

Negative Photoresponse In Ti3C2TX Mxene Monolayers, Nataliia S. Vorobeva, Saman Bagheri, Angel Torres, Alexander Sinitskii

Faculty Publications -- Chemistry Department

Two-dimensional transition metal carbides, nitrides, and carbonitrides, collectively known as MXenes, are finding numerous applications in many different areas, including optoelectronics and photonics, but there is limited information about their intrinsic photoresponse. In this study, we investigated the visible and near-infrared range photoresponse of Ti₃C₂T_x, the most popular MXene material to date. The electrical measurements were performed on devices based on individual monolayer Ti₃C₂T_x MXene flakes, which were characterized by a variety of microscopic and spectroscopic methods. For MXene devices with different electrode layouts, the current reproducibly decreased under …

Characterization Of Three-Dimensional Fractional Viscoelastic Models Through Complex Modulus Analysis And Polar Decomposition, Avradip Ghosh, Avinash Kumar Both, Chin Li Cheung

Faculty Publications -- Chemistry Department

Soft materials such as gels, elastomers, and biological tissues have diverse applications in nature and technology due to their viscoelastic nature. These soft materials often exhibit complex rheology and display elastic and viscous characteristics when undergoing deformation. In recent years, fractional calculus has emerged as a promising tool to explain the viscoelastic behavior of soft materials. Scalar constants are primarily used to quantify viscoelastic elements such as springs and dashpots. However, in three-dimensional (3D) space, not all materials show the same elastic or viscoelastic properties in all directions, especially under elastic/viscoelastic wave propagation (or anisotropy). Though previously reported studies on …

Integrating Conformational Dynamics And Perturbation-Based Network Modeling For Mutational Profiling Of Binding And Allostery In The Sars-Cov-2 Spike Variant Complexes With Antibodies: Balancing Local And Global Determinants Of Mutational Escape Mechanisms, Gennady M. Verkhivker, Steve Agajanian, Ryan Kassab, Keerthi Krishnan

Mathematics, Physics, and Computer Science Faculty Articles and Research

n this study, we combined all-atom MD simulations, the ensemble-based mutational scanning of protein stability and binding, and perturbation-based network profiling of allosteric interactions in the SARS-CoV-2 spike complexes with a panel of cross-reactive and ultra-potent single antibodies (B1-182.1 and A23-58.1) as well as antibody combinations (A19-61.1/B1-182.1 and A19-46.1/B1-182.1). Using this approach, we quantify the local and global effects of mutations in the complexes, identify protein stability centers, characterize binding energy hotspots, and predict the allosteric control points of long-range interactions and communications. Conformational dynamics and distance fluctuation analysis revealed the antibody-specific signatures of protein stability and flexibility of the …

Multiplexed Monitoring Of Neurochemicals Via Electrografting- Enabled Site-Selective Functionalization Of Aptamers On Field-Effect Transistors, Zan Gao, Guangfu Wu, Yang Song, Huijie Li, Yuxuan Zhang, Michael J. Schneider, Yingqi Qiang, Jackson Kaszas, Zhengyan Weng, He Sun, Bryan D. Huey, Rebecca Lai, Yi Zhang

Faculty Publications -- Chemistry Department

Neurochemical corelease has received much attention in understanding brain activity and cognition. Despite many attempts, the multiplexed monitoring of coreleased neurochemicals with spatiotemporal precision and minimal crosstalk using existing methods remains challenging. Here, we report a soft neural probe for multiplexed neurochemical monitoring via the electrografting-assisted site-selective functionalization of aptamers on graphene field-effect transistors (G-FETs). The neural probes possess excellent flexibility, ultralight mass (28 mg), and a nearly cellular-scale dimension of 50 μm × 50 μm for each G-FET. As a demonstration, we show that G-FETs with electrochemically grafted molecular linkers (−COOH or −NH2) and specific aptamers can be used …