Medicinal and Pharmaceutical Chemistry Commons^™

Genomic Context And Tp53 Allele Frequency Define Clinical Outcomes In Tp53-Mutated Myelodysplastic Syndromes, Guillermo Montalban-Bravo, Rashmi Kanagal-Shamanna, Christopher B. Benton, Caleb A. Class, Kelly S. Chien, Koji Sasaki ,, Kiran Naqvi, Yesid Alvarado, Tapan M. Kadia, Farhad Ravandi, Naval Daver, Koichi Takahashi, Elias Jabbour, Gautham Borthakur, Naveen Pemmaraju, Marina Konopleva, Kelly A. Soltysiak, Sherry R. Pierce, Carlos E. Bueso-Ramos, Keyur P. Patel, Hagop Kantarjian, Guillermo Garcia-Manero

Scholarship and Professional Work – COPHS

TP53 mutations are associated with adverse outcomes and shorter response to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS). Limited data have evaluated the impact of the type, number, and patterns of TP53 mutations in response outcomes and prognosis of MDS. We evaluated the clinicopathologic characteristics, outcomes, and response to therapy of 261 patients with MDS and TP53 mutations. Median age was 68 years (range, 18-80 years). A total of 217 patients (83%) had a complex karyotype. TP53 mutations were detected at a median variant allele frequency (VAF) of 0.39 (range, 0.01-0.94). TP53 deletion was associated with lower overall response rate …

Antiproliferative And Apoptotic Effects Of Proteins From Black Seeds (Nigella Sativa) On Human Breast Mcf-7 Cancer Cell Line, Yamna Khursid, Basir Syed, Shabana U. Simjee, Obaid Beg, Aftab Ahmed

Pharmacy Faculty Articles and Research

Background

Nigella sativa (NS), a member of family Ranunculaceae is commonly known as black seed or kalonji. It has been well studied for its therapeutic role in various diseases, particularly cancer. Literature is full of bioactive compounds from NS seed. However, fewer studies have been reported on the pharmacological activity of proteins. The current study was designed to evaluate the anticancer property of NS seed proteins on the MCF-7 cell line.

Methods

NS seed extract was prepared in phosphate-buffered saline (PBS), and proteins were precipitated using 80% ammonium sulfate. The crude seed proteins were partially purified using gel filtration …

Measuring The Effects Of Lobinaline-N-Bioxide (419) On Alcohol Consumption, Nicotine Locomotor Sensitization, And Conditioned Place Preference In Mice And Rats, Cocanut M. Suhail

Theses and Dissertations--Medical Sciences

Objective: Novel drug 419 was examined to see the effect it has in vivo mice and rats on alcohol consumption, nicotine locomotor sensitization, and conditioned place preference (CPP) models regarding behavioral tests on dopamine transporter activity.

Methods: Mice and rats were used to see how they react to the drug 419 and control vehicle, in each of the models. The animals were assessed to pre- and post- drug administration of novel drug 419. We examined each model to see the association between how drug 419 will help with treating drug abuse.

Results: We found that in alcohol consumption model the …

Correlating The Physicochemical Properties Of Magnesium Stearate With Tablet Dissolution And Lubrication, Julie L. Calahan

Theses and Dissertations--Pharmacy

Magnesium stearate (MgSt) is the most commonly used pharmaceutical excipient and is present in over half the tablet formulations on the market. In spite of its popularity as an effective lubricant, it has been repeatedly recognized that there is significant variability between MgSt samples, which can cause inconsistent lubrication between batches of MgSt. The hypothesis of this research is that the batch-to-batch variability in tablet lubrication and dissolution observed in tablet formulations containing different MgSt samples can be correlated with differences in MgSt physicochemical properties (fatty acid salt composition, crystal hydrate form, particle size and surface area). Developing correlations between …

Novel Small Molecule Antifungals For Invasive Fungal Infections, Emily Dennis

Theses and Dissertations--Pharmacy

Human fungal pathogens cause a range of diseases from benign skin conditions (i.e., ringworm) to thrush, mucosal membrane infections, and life-threatening systemic infections including bloodstream infections (i.e., aspergillosis and candidiasis) and Cryptococcal meningitis. These systemic infections occur most often in immunocompromised individuals and have high mortality rates. Current antifungal agents used in the clinic belong to three main classes: the polyenes (e.g., amphotericin B (AmB)), the echinocandins (e.g., caspofungin (CFG)), and the azoles (e.g., fluconazole (FLC)). In addition, the antimetabolite pyrimidine analogue flucytosine is used in combination with AmB. The …

Design, Synthesis, And Biological Evaluation Of Aryl Piperazines With Potential As Antidiabetic Agents Via The Stimulation Of Glucose Uptake And Inhibition Of Nadh:Ubiquinone Oxidoreductase, R. Devine, M. Kelada, S. Leonard, D.S.D. Martin, J.M.D. Walsh, C.J. Breen, R.B. Driver, Gemma K. Kinsella, J.B.C Findlay, J.C. Stephens

Articles

The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose …

Oral Contraceptives As Possible Acl Injury Prevention Method, Haley Schweizer

Capstone Showcase

ABSTRACT

Introduction: Anterior Cruciate Ligament (ACL) injuries are an upsetting setback for many athletes that require a long and costly recovery process. The injury rates are four times greater in women than men. Preventative measures that help to prevent ACL injuries are limited to stretching and strengthening. Therefore, this review aims to investigate if oral contraceptive [I] usage provides a possible new avenue for prevention of ACL injury [O] in young female athletes (ages 18-30) [P] compared to those that do not take oral contraceptives [C].

Methods: A literature review was performed though PubMed, Google Scholar, SCOPUS Database, and ClinicalKey …

Clinical Risk Assessment In Early Pregnancy For Preeclampsia In Nulliparous Women: A Population Based Cohort Study, Anna Sandstrom, Jonathan Snowden, Jonas Höijer, Matteo Bottai, Anna-Karin Wikström

OHSU-PSU School of Public Health Faculty Publications and Presentations

Objective

To evaluate the capacity of multivariable prediction of preeclampsia during pregnancy, based on detailed routinely collected early pregnancy data in nulliparous women.

Design and setting

A population-based cohort study of 62 562 pregnancies of nulliparous women with deliveries 2008–13 in the Stockholm-Gotland Counties in Sweden.

Methods

Maternal social, reproductive and medical history and medical examinations (including mean arterial pressure, proteinuria, hemoglobin and capillary glucose levels) routinely collected at the first visit in antenatal care, constitute the predictive variables. Predictive models for preeclampsia were created by three methods; logistic regression models using 1) pre-specified variables (similar to the Fetal Medicine …

Elephant And Anchors ‒ Photoelectron Photoion Coincidence Spectroscopy Of Small Oxygenated Molecules, Apeter Weidner

University of the Pacific Theses and Dissertations

The dissociative photoionization reactions of two small, oxygenated organics, namely 1,3-dioxolane and methyl vinyl ketone, were studied by photoelectron photoion coincidence (PEPICO) spectroscopy. Experiments involving 1,3-dioxolane were carried out in the photon energy range of 9.5‒13.5 eV. The statistical thermodynamics model shows that a total of six dissociation channels are involved in the formation of three fragment ions, namely C3H5O2+ (m/z 73), C2H5O+ (m/z 45) and C2H4O+ (m/z 44), with two channels contributing to the formation of each. By comparing the results of ab initio quantum chemical calculations to the experimentally derived appearance energies of the fragment ions, the most …

Studies On The Size And Non-Planarity Of Aromatic Stacking Moiety On Conformation Selectivity And Thermal Stabilization Of G-Quadruplexes, Mandeep Singh

University of the Pacific Theses and Dissertations

Targeting DNA has the advantage over proteins for cancer remediation because of the fewer copies of the ligands required for the desired therapeutic effect. Traditionally, covalent DNA binders like alkylating agents have been used to induce genetic instability through the formation of DNA lesions and strand breaks, leading to cellular apoptosis. The primary drawback of this treatment is the non-specific binding that affects both cancerous and non-cancerous cells. G-quadruplexes are the DNA secondary structures that are present in abundance near the promoter regions of the oncogenes and are involved in the regulation of their activities. A ligand-mediated stabilization of G-quadruplexes …

Development Of A Screening Assay For Type Iii Secretion System Inhibitors And High Throughput Screening Campaign Of Inhibitors Of Prp Of Staphylococcus Aureus, Heather A. Pendergrass

Theses and Dissertations

Antibiotics inhibit the growth or survival of bacteria by targeting their essential functions.¹ Due to weaknesses in traditional antibiotics and the increasing prevalence of antibiotic resistance genes, virulence factors are being targeted for therapeutic treatment of bacterial infection.² We have developed an assay to quantify and observe type III secretion system (T3SS) activity. The type III secretion system (T3SS) is a virulence factor present in some Gram-negative pathogens including enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC, respectively),³ and others.^4–9 The T3SS between EPEC and EHEC are highly conserved and share over 90% sequence identity with …

Chemical Composition And Behavioural Responses Of Male And Female Bactrocera Dorsalis To Their Volatile Emissions, Fikira Kimbokota

Journal of Humanities and Social Sciences

Bactrocera dorsalis, (Tephritidae) presented a grave threat to a broad range of fruit and vegetables in the tropics, including Tanzania. Bactrocera dorsalis is among the most destructive tephritid fruit fly, causing devastating loss of fruits especially mango. Insects use olfactory cues to locate hosts, oviposition sites and mating, in which pheromones are believed to be a strong cue used by insect to locate their mates. However, due to their high ability to adapt and occupy different ecological niches into various agroecological zones, there is a need to evaluate pheromonal composition from time to time to improve their control strategies. Therefore, …

Glucocorticoids Rapidly Activate Camp Production Via GΑs To Initiate Non-Genomic Signaling That Contributes To One-Third Of Their Canonical Genomic Effects, Francisco J. Nuñez, Timothy B. Johnstone, Maia L. Corpuz, Austin G. Kazarian, Nicole N. Mohajer, Omar Tliba, Reynold A. Pannettieri Jr., Cynthia J. Koziol-White, Moom Roosan, Rennolds S. Ostrom

Pharmacy Faculty Articles and Research

Glucocorticoids are widely used for the suppression of inflammation, but evidence is growing that they can have rapid, non-genomic actions that have been unappreciated. Diverse cell signaling effects have been reported for glucocorticoids, leading us to hypothesize that glucocorticoids alone can swiftly increase the 3′,5′-cyclic adenosine monophosphate (cAMP) production. We found that prednisone, fluticasone, budesonide, and progesterone each increased cAMP levels within 3 minutes without phosphodiesterase inhibitors by measuring real-time cAMP dynamics using the cAMP difference detector in situ assay in a variety of immortalized cell lines and primary human airway smooth muscle (HASM) cells. A membrane- impermeable glucocorticoid showed …

Design And Biological Evaluation Of Colchicine-Cd44-Targeted Peptide Conjugate In An In Vitro Model Of Crystal Induced Inflammation, Khalid A. Zoghebi, Emira Bousoik, Keykavous Parang, Khaled A. Elsaid

Pharmacy Faculty Articles and Research

Gout is an inflammatory arthritis due to the joint deposition of monosodium urate (MSU) crystals. Phagocytosis of MSU crystals by tissue macrophages results in the generation of reactive oxygen species (ROS) and production of inflammatory cytokines and chemokines. Colchicine use in gout is limited by severe toxicity. CD44 is a transmembrane glycoprotein that is highly expressed in tissue macrophages and may be involved in gout pathogenesis. The P6 peptide is a 20-amino acid residue peptide that binds to CD44. We hypothesized that the conjugation of colchicine to the P6 peptide would reduce its off-target cytotoxicity while preserving its anti-inflammatory effect. …

Design, Synthesis, & Biological Evaluation Of Novel Het-Aromatic/Aromatic Analogs For The Treatment Of Hiv, Cancer, & Cognitive Dysfunctions, Mohit Gupta

Electronic Theses and Dissertations

Cyclophilin A are a class of peptidyl-prolyl isomerases that catalyzes isomerization of the proline residue within a protein. Cyclophilin A plays an instrumental role in the pathogenesis of HIV and HCV virus. Using structure-based drug we designed and synthesized small molecule inhibitors of cyclophilin A. These inhibitors were biologically evaluated for their ability to inhibit WT HIV-1 inhibition.

Mitogen-Activated Protein Kinase signaling cascades plays a critical role in cancer cell survival, metastasis, and chemo-resistance. The MEK5/ERK5 pathway, which is a member of MAPK signaling cascade, is involved in cell survival, anti-apoptotic signaling, angiogenesis, and cell motility. It is found to …

Synthesis And Characterization Of Long Acting Darunavir Prodrugs, Mary Banoub

Theses & Dissertations

Patient adherence is critical for ART success to ensure adequate viral suppression, therefore, long-acting antiretrovirals are soon replacing current daily regimens. In recent years, two drugs were successfully transformed into long-acting injectables; CAB LA and RPV LA. These long-acting nanoformulations made it possible to abandon the daily pill burden, instead approximately a bimonthly injection of both drugs is enough to suppress and maintain viral load suppression. Our laboratory has been instrumental in transforming FDA-approved and experimental-HIV medications into long-acting slow effective release drugs, also known as LASER ART. LASER ART consists of slow drug metabolism and high permeability and retention …

Identification Of More Potent And Efficacious Analogs Of The Novel Host-Derived Immunostimulant Ep67, Abdul Alshammari

Theses & Dissertations

EP67 is a human C5a-derived decapeptide agonist of C5a Receptor 1 (C5aR1/CD88) that selectively activates mononuclear phagocytes over neutrophils to stimulate protective innate and adaptive immune responses while potentially minimizing neutrophil-mediated toxicity. Two N-alkyl amino acids Pro⁷ and N-methyl-Leu⁸ (nme-Leu⁸) within EP67 induce structural changes that increase potency and selective activation of mononuclear phagocytes over neutrophils. Cis/trans isomerization at these positions, however, likely limits the activity of EP67 and low coupling efficiency between Pro⁷ and nme-Leu⁸ increases scale-up costs for clinical use. Thus, the goals of this study were to …

Computational Studies And Design Of Pparγ And Glut1 Inhibitors, Suliman Almahmoud

Theses & Dissertations

The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. PPARγ is a target for insulin-sensitizing drugs, and it plays a significant function in prostate cancer. PPARγ antagonists have anti-proliferative effects in a broad range of hematopoietic and epithelial cell lines. The ligand binding domain (LBD) of PPARγ is large and has orthosteric and allosteric binding sites. Several PPARγ-ligand co-crystal structures show two bound molecules, one to the orthosteric pocket and a second to the allosteric …

Amphiphilic Cell-Penetrating Hybrid Cyclic-Linear Peptides As A Drug Delivery System, Saghar Mozaffari

Pharmaceutical Sciences (PhD) Dissertations

A number of cyclic peptides containing a positively charged ring composed of arginine residues attached to hydrophobic tail made of tryptophan residues through a lysine linker namely [R₅K]W₅, [R₆K]W₅, [R₅K]W₆, [R₇K]W₅, [R₅K]W₇, [R₆K]W₆, and [R₇K]W₇ were synthesized and evaluated as molecular transporters. The peptides were evaluated for their ability to deliver, fluorescence-labeled cell-impermeable negatively charged phosphopeptide (F′-GpYEEI), and fluorescent labeled anti-HIV drugs (F′-FTC and F′-d4T). The results indicated that the presence of positively …

Synthesis Of Gadolinium-Doxorubicin Prodrug Carrying Functional Nanoceria For The Targeted Drug Delivery And Cancer Treatment, Arth Patel

Electronic Theses & Dissertations

The main focus of this research was the development of a polymer-coated nanoceria (PNC) platform to be used as a drug delivery system. Water-dispersible PNC is synthesized using a water-based alkaline precipitation method. Cerium nitrate hexahydrate and poly (acrylic acid) are used for the preparation of PNC. The synthesized PNC was characterized using ZETA, and UV- Vis characterization techniques. Polyacrylic acid (PAA)-coated cerium oxide nanoparticles fabricated for the targeted combination therapy of TNBC (MDA-MB-231) and MCF-7. Using EDC/NHS chemistry, the surface carboxylic acid groups of nanoceria was designed and synthesized with ICAM-1 antibody to target ICAM-1 overexpressing TNBC. Next, doxorubicin …