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Medicinal-Pharmaceutical Chemistry Commons

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‘Cassette’-Ises (In Situ Enzymatic Screening) Identifies Complementary Chiral Scaffolds For Hydrolytic Kinetic Resolution Across A Range Of Epoxides, Sangeeta Dey, Douglas R. Powell, Chunhua Hu, David B. Berkowitz 2018 University of Nebraska - Lincoln

‘Cassette’-Ises (In Situ Enzymatic Screening) Identifies Complementary Chiral Scaffolds For Hydrolytic Kinetic Resolution Across A Range Of Epoxides, Sangeeta Dey, Douglas R. Powell, Chunhua Hu, David B. Berkowitz

Faculty Publications -- Chemistry Department

‘Cassette’-ISES (In Situ Enzymatic Screening) Identifies Complementary Chiral Scaffolds for Hydrolytic Kinetic Resolution Across a Range of Epoxides

A new ‘Cassette’-In Situ Enzymatic Screen (ISES) for combinatorial catalysis is introduced. This allows the experimentalist to obtain an information-rich readout, in real time, providing an estimate of the sense and magnitude of enantioselectivity across more than one substrate. In its first iteration, the screen identified CoIII-salen catalysts with β-pinene- and α-naphthylalanine-derived chiral scaffolds with broad, yet complementary, substrate specificities.


Development Of Betulinic Acid Triazole Conjugates As Potential Anti-Cancer Agents, Gayathri Jampana 2018 Rowan University

Development Of Betulinic Acid Triazole Conjugates As Potential Anti-Cancer Agents, Gayathri Jampana

Theses and Dissertations

Betulin and betulinic acid are pentacyclic triterpenoid natural product isolated from the bark of birch trees. While betulin is abundantly available in the bark, betulinic acid is present in scarce quantities in nature. However, betulinic acid can be conveniently synthesized from betulin via simple redox manipulations. Betulinic acid shows selective cytotoxicity profile against cancer cells in vitro while being relatively safe for normal cells. One of the challenges for the clinical development of betulinic acid is its lack of aqueous solubility. The three key structural features of betulin/betulinic acid that have been routinely exploited for structural modifications to enhance ...


Nanoparticle Microarray For High-Throughput Microbiome Metabolomics Using Matrix-Assisted Laser Desorption Ionization Mass Spectrometry, Rebecca L. Hansen, Maria Emilia Duenas, Torey Looft, Young Jin Lee 2018 Iowa State University

Nanoparticle Microarray For High-Throughput Microbiome Metabolomics Using Matrix-Assisted Laser Desorption Ionization Mass Spectrometry, Rebecca L. Hansen, Maria Emilia Duenas, Torey Looft, Young Jin Lee

Chemistry Publications

A high-throughput matrix-assisted laser desorption/ionization mass spectrometry (MALDI)-MS-based metabolomics platform was developed using a pre-fabricated microarray of nanoparticles and organic matrices. Selected organic matrices, inorganic nanoparticle (NP) suspensions, and sputter coated metal NPs, as well as various additives, were tested for metabolomics analysis of the turkey gut microbiome. Four NPs and one organic matrix were selected as the optimal matrix set: α-cyano-4-hydroycinnamic acid, Fe3O4 and Au NPs in positive ion mode with 10 mM sodium acetate, and Cu and Ag NPs in negative ion mode with no additive. Using this set of five matrices, over two thousand unique ...


Drug Resistance Mutation L76v Alters Nonpolar Interactions At The Flap-Core Interface Of Hiv-1 Protease, Andres Wong-Sam, Yuan-Fang Wang, Ying Zhang, Arun K. Ghosh, Robert W. Harrison, Irene T. Weber 2018 Georgia State University

Drug Resistance Mutation L76v Alters Nonpolar Interactions At The Flap-Core Interface Of Hiv-1 Protease, Andres Wong-Sam, Yuan-Fang Wang, Ying Zhang, Arun K. Ghosh, Robert W. Harrison, Irene T. Weber

RNA Therapeutics Institute Publications

Four HIV-1 protease (PR) inhibitors, clinical inhibitors lopinavir and tipranavir, and two investigational compounds 4 and 5, were studied for their effect on the structure and activity of PR with drug-resistant mutation L76V (PRL76V). Compound 5 exhibited the best K i value of 1.9 nM for PRL76V, whereas the other three inhibitors had K i values of 4.5-7.6 nM, 2-3 orders of magnitude worse than for wild-type enzymes. Crystal structures showed only minor differences in interactions of inhibitors with PRL76V compared to wild-type complexes. The shorter side chain of Val76 in the mutant lost hydrophobic interactions with ...


Efforts Towards The Discovery Of Novel Methods For The Synthesis Of Pharmacologically Relevant Molecular Scaffolds, Graham Joseph Haun 2018 Rowan University

Efforts Towards The Discovery Of Novel Methods For The Synthesis Of Pharmacologically Relevant Molecular Scaffolds, Graham Joseph Haun

Theses and Dissertations

With the introductions of pharmaceuticals into modern day society many people have been using them to improve their lives. Due to this high increase in demand along with the ever-growing concern of environmental impact pharmaceutical companies have been pressed to synthesis new and existing drugs at a higher rate. This increased rate can cause low yield drugs or have a heavy environmental impact. As the use of pharmaceuticals becomes more widespread the need for greener and simpler organic synthesis methods to make these pharmaceuticals becomes more needed.

Herein is reported the methodological development of different pharmacologically relevant scaffolds. This work ...


T Cell Epitope Engineering: An Avian H7n9 Influenza Vaccine Strategy For Pandemic Preparedness And Response, Leonard Moise, Bethany M. Biron, Christine M. Boyle, Nese Kurt Yilmaz, Hyesun Jang, Celia A. Schiffer, Ted M. Ross, William D. Martin, Anne S. De Groot 2018 University of Rhode Island

T Cell Epitope Engineering: An Avian H7n9 Influenza Vaccine Strategy For Pandemic Preparedness And Response, Leonard Moise, Bethany M. Biron, Christine M. Boyle, Nese Kurt Yilmaz, Hyesun Jang, Celia A. Schiffer, Ted M. Ross, William D. Martin, Anne S. De Groot

Schiffer Lab Publications

The delayed availability of vaccine during the 2009 H1N1 influenza pandemic created a sense of urgency to better prepare for the next influenza pandemic. Advancements in manufacturing technology, speed and capacity have been achieved but vaccine effectiveness remains a significant challenge. Here, we describe a novel vaccine design strategy called immune engineering in the context of H7N9 influenza vaccine development. The approach combines immunoinformatic and structure modeling methods to promote protective antibody responses against H7N9 hemagglutinin (HA) by engineering whole antigens to carry seasonal influenza HA memory CD4(+) T cell epitopes - without perturbing native antigen structure - by galvanizing HA-specific memory ...


Modulating Viscoelasticity, Stiffness, And Degradation Of Synthetic Cellular Niches Via Stoichiometric Tuning Of Covalent Versus Dynamic Noncovalent Cross-Linking, Yu Tan, Henry Huang, David C. Ayers, Jie Song 2018 University of Massachusetts Medical School

Modulating Viscoelasticity, Stiffness, And Degradation Of Synthetic Cellular Niches Via Stoichiometric Tuning Of Covalent Versus Dynamic Noncovalent Cross-Linking, Yu Tan, Henry Huang, David C. Ayers, Jie Song

Open Access Articles

Viscoelasticity, stiffness, and degradation of tissue matrices regulate cell behavior, yet predictive synergistic tuning of these properties in synthetic cellular niches remains elusive. We hypothesize that reversible physical cross-linking can be quantitatively introduced to synthetic hydrogels to accelerate stress relaxation and enhance network stiffness, while strategic placement of isolated labile linkages near cross-linking sites can predict hydrogel degradation, both of which are essential for creating adaptive cellular niches. To test these hypotheses, chondrocytes were encapsulated in hydrogels formed by biorthogonal covalent and noncovalent physical cross-linking of a pair of hydrophilic building blocks. The stiffer and more viscoelastic hydrogels with DBCO-DBCO ...


Synthetic Approaches Towards Novel Isoform Selective Pi3k Inhibitors And Their Biological Activities Against Prostate Cancer Cells, Idris Wazeerud-Din 2018 Atlanta University Center

Synthetic Approaches Towards Novel Isoform Selective Pi3k Inhibitors And Their Biological Activities Against Prostate Cancer Cells, Idris Wazeerud-Din

Electronic Theses & Dissertations Collection for Atlanta University & Clark Atlanta University

The development of novel imidazopyridines, which includes both tetrahydroimidazo[1,5-a]pyridine (rIMP) and imidazo[1,5-a]pyridine (IMP) was investigated using conventional and microwave induced procedures that afforded compounds at high yield of 88-96%. rIMP was synthesized using a two-step procedure that involved the microwave synthesis of IMP, then the reduction of the pyridine moiety of the fused imidazopyridine rings using 10% Pd/C and hydrazine monohydrate. The microwave synthesis of imidazopyridines involved the one pot reaction of 2-benzoylpyridine, substituted benzaldehyde and ammonium formate in acetic acid under open vessel microwave conditions, which resulted in products within 40 minutes ...


Conformationally-Controlled Late-Stage Modifications For Sar Studies Of The C-3-Glcp Moiety Of Ipomoeassin F, Lucas Whisenhunt 2018 University of Arkansas, Fayetteville

Conformationally-Controlled Late-Stage Modifications For Sar Studies Of The C-3-Glcp Moiety Of Ipomoeassin F, Lucas Whisenhunt

Theses and Dissertations

The resin glycoside, ipomoeassin F has been shown to be extremely potent against multiple cancer lines (IC50 = 4.2-36 nM). However, the mechanism of action of this potent and complex natural product is still not fully understood. The α,β-unsaturated esters of the glucosyl moiety have been shown to be vital for the overall cytotoxicity of ipomoeassin F. Nevertheless, the importance of the tigloyl ester of the glucosyl moiety is still largely unknown. This work aimed to study the pharmacophore importance of the tigloyl ester by creating, an efficient, scalable, and flexible synthesis route for various analogs. The 18-linear step ...


The Effects Of Cold Plasma Treatment On Sweet Basil (Ocimum Basilicum), Sauvelson Auguste 2018 Seton Hall University

The Effects Of Cold Plasma Treatment On Sweet Basil (Ocimum Basilicum), Sauvelson Auguste

Seton Hall University Dissertations and Theses (ETDs)

The study discussed herein looks both to continue and to expand upon previous work conducted here at Seton Hall University, which investigated the effect of cold plasma processing on sweet basil and their essential oils. It was found that the application of cold plasma treatment increases plant growth and eugenol concentration, which is an essential oil component and one of the potential natural antioxidants used in food preservation. In this study, we considered methods for increasing the production and harvesting of plants that produce essential oils such as sweet basil (Ocimum basilicum). The study also incorporated more controls than the ...


Hiv-1 Integrase-Targeted Short Peptides Derived From A Viral Protein R Sequence, Xue Zhi Zhao, Mathieu Métifiot, Evgeny Kiselev, Jacques Kessl, Kasthuraiah Maddali, Christophe Marchand, Mamuka Kvaratskhelia, Yves Pommier, Terrence R. Burke Jr. 2018 Center of Cancer Research

Hiv-1 Integrase-Targeted Short Peptides Derived From A Viral Protein R Sequence, Xue Zhi Zhao, Mathieu Métifiot, Evgeny Kiselev, Jacques Kessl, Kasthuraiah Maddali, Christophe Marchand, Mamuka Kvaratskhelia, Yves Pommier, Terrence R. Burke Jr.

Faculty Publications

HIV-1 integrase (IN) inhibitors represent a new class of highly effective anti-AIDS therapeutics. Current FDA-approved IN strand transfer inhibitors (INSTIs) share a common mechanism of action that involves chelation of catalytic divalent metal ions. However, the emergence of IN mutants having reduced sensitivity to these inhibitors underlies efforts to derive agents that antagonize IN function by alternate mechanisms. Integrase along with the 96-residue multifunctional accessory protein, viral protein R (Vpr), are both components of the HIV-1 pre-integration complex (PIC). Coordinated interactions within the PIC are important for viral replication. Herein, we report a 7-mer peptide based on the shortened Vpr ...


Visible Light Generation Of High-Valent Corrole-Manganese(V)-Oxo Intermediates And Biomimetic Studies Of The Oxidation Of Organic Sulfides Catalyzed By Manganese Corroles With Iodobenzene Diacetate, Davis Ray Ranburger 2018 Western Kentucky University

Visible Light Generation Of High-Valent Corrole-Manganese(V)-Oxo Intermediates And Biomimetic Studies Of The Oxidation Of Organic Sulfides Catalyzed By Manganese Corroles With Iodobenzene Diacetate, Davis Ray Ranburger

Masters Theses & Specialist Projects

High-valent transition metal-oxo intermediates play essential roles as active oxidizing species in enzymatic and biomimetic catalytic systems. Extensive research has been conducted on a variety of transition metal catalysts being studied as models for the ubiquitous cytochrome P450 enzymes. In doing so, the production of enzyme-like oxidation catalysts and probing studies on the sophisticated oxygen atom transfer mechanism are taking place.

In this work, visible-light irradiation of highly-photo-labile corrole-manganese(IV) bromates and chlorates was studied in two corrole systems with differing electronic environments, i.e. 5,10,15-trisphenylcorrole (H3TPC) and 5,10,15- tris(pentafluorophenyl)corrole (H3TPFC). In ...


Photochemical Investigation Of High-Valent Metal-Oxo Intermediates Containing Corrole And Light-Harvesting Porphyrin Ligands, Jonathan Malone 2018 Western Kentucky University

Photochemical Investigation Of High-Valent Metal-Oxo Intermediates Containing Corrole And Light-Harvesting Porphyrin Ligands, Jonathan Malone

Masters Theses & Specialist Projects

In enzymatic and synthetic catalytic oxidations, high-valent iron-oxo intermediates play a vital role as the active oxidant. In this regard, many synthetic metal catalysts are designed as biomimetic models to resemble the active site of Cytochrome P450 enzymes (P450) which are the predominant oxidation catalysts in nature. Vitamin B12 cofactors, with a corrole-like structure corrin, are also utilized in some of the more difficult reactions in nature such as rearrangement and reductase reactions.

In this work, application of the promising photochemical method to corrolecontaining ligands systems showed much success in the generation of manganese(V)-oxo corrole intermediates using two ...


The Development Of Metallohydroxamates As Novel Anti-Bacterial And Anti-Leishmanial Agents, Donal Keogan 2018 Royal College of Surgeons in Ireland

The Development Of Metallohydroxamates As Novel Anti-Bacterial And Anti-Leishmanial Agents, Donal Keogan

PhD theses

Since the initial development and clinical use of antibiotics, there has been a steady and alarming increase in the levels of antibiotic resistant bacterial infections arising worldwide. The reduced efficacy of antibiotics coupled to the lack of new classes of antibiotics being developed, may result in antibiotic resistance infections rising to epidemic levels.

The decrease in new antibiotic discovery has resulted in increased interest in repurposing and repositioning of previously developed drugs as effective anti-bacterial treatments. The use of metals in medicine is not a new phenomenon as they have been used in medicine for thousands of years. Nonetheless the ...


Glucosamine From Hydrolysis Of 3d Printing Chitosan For Osteoarthritis Treatment, Ruj Dansriboon, Laphon Premcharoen 2018 Kamnoetvidya Science Academy

Glucosamine From Hydrolysis Of 3d Printing Chitosan For Osteoarthritis Treatment, Ruj Dansriboon, Laphon Premcharoen

The International Student Science Fair 2018

This project aims to introduce a new way for osteoarthritis treatment which is expected to increase in the future. Glucosamine is the main subject for a treatment, which can be derived by hydrolyzing chitosan. This project also includes extraction of chitosan from shrimp waste to make a worthy use of food waste from industry. In this project, 3D printer is applied to print chitosan gel since 3D printing is adjustable to form various shapes of the gel.

The research process begins with the extraction of chitosan from shrimp shells. For the next step, the percent of deacetylation of chitosan was ...


Preparation Of Supramolecular Amphiphilic Cyclodextrin Bilayer Vesicles For Pharmaceutical Applications, Kate E. Frischkorn 2018 California Polytechnic State University, San Luis Obispo

Preparation Of Supramolecular Amphiphilic Cyclodextrin Bilayer Vesicles For Pharmaceutical Applications, Kate E. Frischkorn

Master's Theses and Project Reports

Recent pharmaceutical developments have investigated using supramolecular nanoparticles in order to increase the bioavailability and solubility of drugs delivered in various methods. Modification of the carbohydrate cyclodextrin increases the ability to encapsulate hydrophobic pharmaceutical molecules by forming a carrier with a hydrophobic core and hydrophilic exterior. Guest molecules are commonly added to these inclusion complexes in order to add stability and further increase targeting abilities of the carriers. One such guest molecule is adamantine combined with a poly(ethylene glycol) chain. Vesicles are formed by hydrating a thin film of amphiphilic cyclodextrin and guest molecules in buffer solution that mimics ...


Tumor-Targeting Fluorinated Phthalocyanines For Theranostic Applications, Erik Nathaniel Carrión 2018 Seton Hall University

Tumor-Targeting Fluorinated Phthalocyanines For Theranostic Applications, Erik Nathaniel Carrión

Seton Hall University Dissertations and Theses (ETDs)

Hydrocarbon-based therapeutics and imaging agents are prone to chemical oxidation and degradation resulting in loss of activity and limited functional utility. Thus, more material is required to achieve long-lasting therapeutic effects. Phthalocyanines (Pcs) and their metal complexes (PcMs) can be utilized as prodrugs requiring only renewable energy resources namely, air and light, for cancer therapy and diagnostic (theranostic) applications related to photodynamic therapy (PDT). Replacement of labile C-H bonds in the Pc scaffold with a combination of fluoro and perfluoroisopropyl groups has resulted in a stable yet reactive oxidation catalyst of biological significance and importance. For example, F64PcZn ...


Dissecting Structure-Encoded Determinants Of Allosteric Cross-Talk Between Post-Translational Modification Sites In The Hsp90 Chaperones, Gabrielle Stetz, Amanda Tse, Gennady M. Verkhivker 2018 Chapman University

Dissecting Structure-Encoded Determinants Of Allosteric Cross-Talk Between Post-Translational Modification Sites In The Hsp90 Chaperones, Gabrielle Stetz, Amanda Tse, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Post-translational modifications (PTMs) represent an important regulatory instrument that modulates structure, dynamics and function of proteins. The large number of PTM sites in the Hsp90 proteins that are scattered throughout different domains indicated that synchronization of multiple PTMs through a combinatorial code can be invoked as an important mechanism to orchestrate diverse chaperone functions and recognize multiple client proteins. In this study, we have combined structural and coevolutionary analysis with molecular simulations and perturbation response scanning analysis of the Hsp90 structures to characterize functional role of PTM sites in allosteric regulation. The results reveal a small group of conserved PTMs ...


Donated Chemical Probes For Open Science, Susanne Muller, Paul R. Thompson, Anke Mueller-Fahrnow 2018 Goethe University

Donated Chemical Probes For Open Science, Susanne Muller, Paul R. Thompson, Anke Mueller-Fahrnow

Open Access Articles

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of ...


Organocatalyzed Synthesis Of Epoxides From Chalcones Utilizing Amino Acids, Sabrina N. Kegeler 2018 Western Michigan University

Organocatalyzed Synthesis Of Epoxides From Chalcones Utilizing Amino Acids, Sabrina N. Kegeler

Master's Theses

The epoxide functional group is important throughout the chemical and pharmaceutical industries, as well as in nature. In the chemical industry, epoxides are present in resins and fragrances. In the pharmaceutical industry, epoxide-containing compounds are used as intermediates in the manufacturing of drugs. In nature, many natural products contain epoxide groups and are used for medicinal purposes, and for models to create synthetic molecules.

One approach to epoxide synthesis involves the use of an alkene precursor, a base, and an oxidizing agent. This is where my investigations began. The first step was to optimize the epoxidation reaction, examining substrate scope ...


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