Browsing by Subject "Department of Medicinal Chemistry"

Now showing 1 - 6 of 6
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    Characterization of Death Receptor 5 Targeting Nanoring Cancer Drugs
    (2012-04-18) Palmatier, Katelyn
    To maximize the effectiveness and minimize the adverse effects of chemotherapeutic agents, it is strategic to create drugs that specifically target cancer cells via ligand-receptor interactions. Several variations of a drug containing a ligand that binds to Death Receptor 5 were created and in vitro properties were characterized.
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    COMPUTATIONAL AND EXPERIMENTAL SCREENING STRATEGIES TOWARD NOVEL ANTHRAX TOXIN LETHAL FACTOR INHIBITORS
    (2010-11-29) Patel, Ajay
    Here, 9 lead compounds, with at least micromolar-level inhibition of LF as determined by experimental High Throughput Screening (HTS), were tested against virtual databases using programs such as Volsurf (Tripos SYBYL) and QikProp (Schrodinger Maestro) to predict various pharmacokinetic properties such as Blood Brain Barrier (BBB) permeability, percent Human Intestinal Absorption (%HIA) and HERG K+ channel blockage (HERG).
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    Design of Bacillus anthracis Lethal Factor Protein Inhibitor Through Structure-Based Design
    (2019) Westberg, Austin; McDermott, Connor; Ambrose, Elizabeth A.
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    Development of APOBEC3 Cytosine Deaminase Inhibitors
    (2011-09-27) Grover, Torie; Perkins, Angela; Li, Ming; Harris, Reuben; Harki, Daniel
    The APOBEC3 (A3) family of proteins degrade non-native or ‘foreign’ DNA in cells. We have hypothesized that blocking the enzymatic activity of A3 proteins could enhance the efficiency of foreign DNA introduction (transfection) into cells that are otherwise refractory to the process. APOBEC3 proteins degrade ‘foreign’ DNA by converting cytosines into uracils, which then triggers the cell to degrade the DNA due to the presence of a non-native DNA base (uracil). To identify small molecules that could inhibit A3 proteins, High Throughput Screening (HTS) was performed at the University of Minnesota and the Sanford-Burnham Medical Research Institute and over 350,000 compounds were tested for inhibition of A3A and A3G proteins. Follow-up studies by the Harris laboratory (University of Minnesota) have identifed hundreds of potential candidate molecules that can inhibit A3 activity in vitro. Three lead molecules from this study include MN152, MN184 and MN132. The Harki laboratory (University of Minnesota) is collaborating with the Harris laboratory to conduct detailed medicinal chemistry campaigns to optimize lead molecules for strong potency and minimal toxicity. Preliminary results from our synthesis studies of these chemotypes are presented here.
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    Inhibition of Fatty Acid Synthase for Prostate Cancer
    (2009-04-08) Belden, Jenna
    Prostate cancer is the number one diagnosed cancer in men, with treatments that have low survival rates and are unable to cure the cancer. The purpose of the research that I conducted was to discover compounds that could potentially be used as a new treatment for prostate cancer. Fatty acid synthase (FAS) is an enzyme that helps cancer cells grow, leading researchers to theorize that if FAS can be repressed then the cancer cells will stop growing. Orlistat, an over-the-counter weight loss drug, is the only known compound that inhibits the thioesterase domain of FAS (FAS TE). When orlistat has been injected into mice, it has shown anti-cancer efficacy in a model of prostate cancer. However, orlistat cannot be absorbed by the body when taken orally, so new compounds that can inhibit FAS TE need to be discovered. The research that I conducted dealt with the synthesis of fatty acid derivatives in order to find a compound that would be able to inhibit FAS TE when taken orally and effectively treat prostate cancer, without causing too much harm to the body. Over the course of these studies I was able to synthesize several potential FAS TE inhibitors that are currently being tested for inhibition of FAS TE and cytotoxicity against prostate cancer cells.
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    Synthesis and Applications of Site- Specific Analogue of Farnesyltransferase in Reversible Immobilization
    (2011-04-13) Song, James
    Protein farnesylation is a post translational modification of proteins catalyzed by protein farnesyltransferases (pFTase), and involves attachment of a farnesyl (15 carbons) isoprenoid moiety to a C-terminal residue of protein containing a CAAX-box motif, where C is cysteine, A is an aliphatic amino acid, and X is a specific amino acid that controls the isoprenoid moiety addition1. The high site specificity of pFTase and its moderate tolerance of subtle changes in farnesyl moiety make farnesylation a valuable method of protein immobilization, and a novel tool for analyzing proteinprotein interactions in chemical biology3. During spring of 2011, I worked on synthesis of a novel farnesyl analogue containing a formylbenzoate moiety and characterized its effectiveness with pFTase to be used in further experimentation in protein immobilization by a Ph. D. candidate, Mohammad Rashidian. The novel farnesyl analogue, Geranyl FormylBenzoate Pyrophosphate (GFBPP), was optimized from original multistep synthesis of seven reactions to five reactions with dramatic increase in final product yield from 5.6% to 14%. Enzymatic evaluation of GFBPP with pFTase showed higher affinity of enzyme to GFBPP at the cost of slower reaction rate. GFBPP was later evaluated as an analogue for rapid reversible protein immobilization using pFTase by Mr. Rashidian.