Medicinal and Pharmaceutical Chemistry Commons^™

Investigating The Effect Of Khat (Catha Edulis) On Selected Obesity Markers And Pathways In C57bl/6j Male Mice, Mustafa Ahmed Al-Shagga

Student Works (2020-2029)

In East African and South Western Arabian populations, Catha edulis (khat) is believed to suppress appetite and reduce body weight. First, this study conducted a systematic review of the literature on the effects of khat and its active alkaloid cathinone on body weight and appetite regulation. Second, this study investigated the effect of khat and cathinone on selected metabolic and histopathologic parameters and their influence on the expression of obesity-related genes in high-fat diet-induced obese mice. Forty-two male C57BL/6J mice were divided into seven groups (n= 6); normal diet control treated with vehicle (NDC), normal diet treated with 200 mg/kg …

Rethinking Fda Regulation Of Complex Products, Philip E. Alford

Minnesota Journal of Law, Science & Technology

No abstract provided.

Studies Of Salvinorin-Based Antagonists To Elucidate Pertinent Interactions For Kappa Opioid Receptor Antagonism, Madeline Keane

Honors Theses

Opioid abuse, leading to addiction and related deaths, has created a chronic epidemic in the United States for the past 30 years. This crisis has sprung from reliance on the prescription of opioid analgesics as the primary method for the management of pain in the 1990s. At that time, these drugs, specifically Purdue Pharma’s OxyContin, were marketed as non-addictive. Due to this systemic minimization of the addictive properties of opioid analgesics, as prescription rates increased, opioid-related mortality rates climbed. This epidemic continues to be pervasive, as opioid-related overdose resulted in 47,600 deaths in 2017. In addition to the opioid epidemic, …

Toward An Enzyme-Coupled, Bioorthogonal Platform For Methyltransferases: Probing The Specificity Of Methionine Adenosyltransferases, Tyler D. Huber

Theses and Dissertations--Pharmacy

Methyl group transfer from S-adenosyl-l-methionine (AdoMet) to various substrates including DNA, proteins, and natural products (NPs), is accomplished by methyltransferases (MTs). Analogs of AdoMet, bearing an alternative S-alkyl group can be exploited, in the context of an array of wild-type MT-catalyzed reactions, to differentially alkylate DNA, proteins, and NPs. This technology provides a means to elucidate MT targets by the MT-mediated installation of chemoselective handles from AdoMet analogs to biologically relevant molecules and affords researchers a fresh route to diversify NP scaffolds by permitting the differential alkylation of chemical sites vulnerable to NP MTs that are unreactive to …

Investigating The Effect Of Rutaecarpine On The Benzo[A]Pyrene-Induced Dna Damage In Vitro, You Li

University of the Pacific Theses and Dissertations

Benzo[a]pyrene (BaP), is one of the most potent mutagens and carcinogens known. It requires metabolic activation through cytochrome P450 (CYP)1A1 to yield the ultimate carcinogenic metabolite, benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE can bind to DNA and form predominantly covalent (+) trans adducts at the N2 position of guanine causing DNA damage. Rutaecarpine (RTC) is an herbal medicine that has been used to treat several diseases such as headache, hypertension, gastrointestinal disorders, amenorrhea, and anti-inflammation. It has also been reported as a potent inducer of CYP enzymes, including CYP1A1, and CYP1A2. The mechanisms underlying up-regulation of CYP1A1 by RTC is dependent on aryl …

Harmonizing Lipidomics: Nist Interlaboratory Comparison Exercise For Lipidomics Using Srm 1950-Metabolites In Frozen Human Plasma, J Bowden, C Ulmer, C Jones, J Koelmel, L Abdullah, Houli Jiang, Michal Schwartzman, Amaury Cazenave-Gassiot, Antonio Checa, Michelle Cinel, Romain Colas, Serge Cremers, Edward Dennis, James Evans, Alexander Fauland, Jun Han, Houli Jiang, Michal Schwartzman

NYMC Faculty Publications

As the lipidomics field continues to advance, self-evaluation within the community is critical. Here, we performed an interlaboratory comparison exercise for lipidomics using Standard Reference Material (SRM) 1950-Metabolites in Frozen Human Plasma, a commercially available reference material. The interlaboratory study comprised 31 diverse laboratories, with each laboratory using a different lipidomics workflow. A total of 1,527 unique lipids were measured across all laboratories and consensus location estimates and associated uncertainties were determined for 339 of these lipids measured at the sum composition level by five or more participating laboratories. These evaluated lipids detected in SRM 1950 serve as community-wide benchmarks …

B7h6: A Cancer Biomarker For The Development Of Novel Immunotherapy Approaches, Mariana Phillips

Seton Hall University Dissertations and Theses (ETDs)

Cancer-based immunotherapy has led the evolution of biologics that can stimulate immune responses towards tumor eradication. The synthesis of small to intermediate size molecules with the targeting and effector functions of mAb may represent a novel class of immunotherapeutics that may overcome the limitations of their biological counterparts.Towards this objective, B7H6 has been identified as a protein ligand localized on the cell surface of transformed tumor cells. B7H6 binds specifically to the activating receptor NKp30, constitutively expressed on all resting and active NK cells. Upon ligand:receptor binding, B7H6 triggers NK cell activation and release of chemokines and pro-inflammatory cytokines such …

Study Of Molecular Interactions Of Glycosaminoglycans And Glycosaminoglycan Mimetics With Their Protein Targets, Daniel K. Afosah

Theses and Dissertations

Glycosaminoglycans (GAGs) are complex linear chain carbohydrate molecules found on virtually all animal cell surfaces. Owing to their negatively charged nature, GAGs interact with a number of different proteins. Thus, although they have great potential as therapeutic agents, their apparent promiscuous interactions increase their side effect risk. GAG mimetics, including GAG oligosaccharides and non-saccharide GAG mimetics (NSGMs) are viable approaches to address this. This work discusses sulfated benzofuran thrombin inhibitors with submaximal protease inhibition, sulfated diflavonoid inhibitors of plasmin and GAG oligosaccharides with selectivity for human neutrophil elastase (HNE).

Anticoagulants are very important for the treatment of thrombotic diseases. The …

Synthesis Of Huacat® Analogues As Novel Organocatalysts For The Formation Of Asymmetric C-C Bonds, Kenneth Laboy

Loma Linda University Electronic Theses, Dissertations & Projects

The synthesis of organic compounds with preferential stereochemistry is ubiquitous in the scientific community. A chemical reaction that asymmetrically induces one stereoisomer over another is achieved through the use of catalysts and various coupling reagents.1 Inorganic catalysts, such as TiCl4 and ZnCl2, have been documented for many decades as effective agents in the synthesis of asymmetric bonds, however, there are environmental limitations to their use. First, the asymmetric reactions involving these metal catalysts require solvents that are not environmentally-friendly, especially when used on an industrial scale and second, the metal catalysts are recycled when possible, however, there is always metal …

Piperlongumine (Piplartine) And Analogues: Antiproliferative Microtubule-Destabilising Agents, Mary J. Meegan, Seema M. Nathwani, Brendan Twamley, Daniela M. Zisterer, Niamh O'Boyle

Articles

Piperlongumine (piplartine, 1) is a small molecule alkaloid that is receiving intense interest due to its antiproliferative and anticancer activities. We investigated the effects of 1 on tubulin and microtubules. Using both an isolated tubulin assay, and a combination of sedimentation and Western blotting, we demonstrated that 1 is a tubulin-destabilising agent. This result was confirmed by immunofluorescence and confocal microscopy, which showed that microtubules in MCF-7 breast cancer cells were depolymerised when treated with 1. We synthesised a number of analogues of 1 to explore structure-activity relationships. Compound 13 had the best cytotoxic profile of this series, …

Probing Allosteric, Partial Inhibition Of Thrombin Using Novel Anticoagulants, Stephen S. Verespy Iii

Theses and Dissertations

Thrombin is the key protease that regulates hemostasis; the delicate balance between procoagulation and anticoagulation of blood. In clotting disorders, like deep vein thrombosis or pulmonary embolism, procoagulation is up-regulated, but propagation of clotting can be inhibited with drugs targeting the proteases involved, like thrombin. Such drugs however, have serious side effects (e.g., excessive bleeding) and some require monitoring during the course of treatment. The reason for these side effects is the mechanism by which the drugs’ act. The two major mechanisms are direct orthosteric and indirect allosteric inhibition, which will completely abolish the protease’s activity. Herein we sought an …

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most …

Investigating Propargyl-Linked Antifolates In Inhibiting Bacterial And Fungal Dihydrofolate Reductase, Joshua Andrade

Honors Scholar Theses

Antimicrobial agents have been invaluable in reducing illness and death associated with bacterial infection. However, over time, bacteria have evolved resistance to all major drug classes as a result of selective pressure. The advancement of new drug compounds is therefore vital. The Anderson-Wright Lab has focused on developing potent and selective inhibitors of dihydrofolate reductase (DHFR), an enzyme key in cell proliferation and survival, in several pathogenic species. The lab has found that a set of compounds, known as propargyl-linked antifolates, are DHFR inhibitors that are both biologically effective and have strong pharmacokinetic properties.

The efficacy of novel propargyl-linked antifolates …

Design, Development, And Characterization Of Novel Antimicrobial Peptides For Pharmaceutical Applications, Yazan H. Akkam

Graduate Theses and Dissertations

Candida species are the fourth leading cause of nosocomial infection. The increased incidence of drug-resistant Candida species has emphasized the need for new antifungal drugs. Histatin 5 is a naturally occurring human salivary antifungal peptide and the first line of defense against infections of the oral cavity. This research has focused on understanding the activity of histatin 5, and subsequently designing novel peptides that may serve as models for the further development of therapeutics to treat fungal infection.

This objective has been achieved in three steps: studying the structural requirement of histatin 5 involved in antifungal activity, the identification of …

Plant Lectin Can Target Receptors Containing Sialic Acid, Exemplified By Podoplanin, To Inhibit Transformed Cell Growth And Migration, Jhon Ochoa-Alvarez, Harini Krishnan, Yongquan Shen, Nimish Acharya, Min Han, Dean Mcnulty, Hitoki Hasegawa

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Cancer is a leading cause of death of men and women worldwide. Tumor cell motility contributes to metastatic invasion that causes the vast majority of cancer deaths. Extracellular receptors modified by α2,3-sialic acids that promote this motility can serve as ideal chemotherapeutic targets. For example, the extracellular domain of the mucin receptor podoplanin (PDPN) is highly O-glycosylated with α2,3-sialic acid linked to galactose. PDPN is activated by endogenous ligands to induce tumor cell motility and metastasis. Dietary lectins that target proteins containing α2,3-sialic acid inhibit tumor cell growth. However, anti-cancer lectins that have been examined thus far target receptors …

The Synthesis Of Various Substituted 3-Amino-7-Hydroxy-2,2-Dimethyltetralins And Their Opioid-Related Activities, David Alan Lippman

University of the Pacific Theses and Dissertations

A series of aminotetralones and aminotetralins were synthesized from the common intermediate F, 3-amino-2,2-dimethyl-7-methoxy- 1-tetralone. The final compounds derived from F were simple substituted and/or reduced analogues. The products would allow a progressive structure activity relationship to be drawn based on pharmacological testing.

The common intermediate F was synthesized utilizing a six step procedure starting with p-methoxyphenylacetic acid. The overall yield from the precursor to the F:HC1 was 25%. Compound F was either O-demethylated to form 3-amino-2,2-dimethyl-7-hydroxy-l-tetralone (I) or was dimethylated on the amine and subsequently O-demethylated to yield the 3-dimethylamino-7-hydroxy-2,2-dimethyl-l-tetralone (J). The last major modification was the reduction of …