Browsing by Author "Gardner, Zachary"

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    Synthesis and Biological Evaluation of Simple Baylis-Hillman Carboxylic Acid Esters as Potential Anticancer Agents
    (2017) Zhang, Yishu; Gibbons, Jake; Hubbard, Skylar; Schumacher, Tanner; Gardner, Zachary
    Baylis Hillman (BH) reaction is important for C-C bond forming reactions in organic synthesis. Allyl alcohols can be synthesized readily by this reaction and these alcohols undergo nucleophilic rearrangement to provide wide range of useful synthons for organic and medicinal chemistry. We are interested in the development of new molecules based on BH reaction and we have initiated this project to explore novel functionalized allyl esters derived from BH reaction as potential anticancer agents. We synthesized several carboxylic acids derived analogs of bromomethyl phenyl acrylate obtained from BH reaction. The allyl ester was further dihydroxylated using OsO4. The synthesized molecules have been evaluated against several cancer cells including triple negative breast cancer cell line MDA-MB-231, and pancreatic cancer cell line MIAPaCa-2. These studies have indicated that several of the synthesized compounds show good cytotoxicity with EC50 values in the range of 3-73μM. Interestingly, the removal of electrophilic double bond in both compounds 2 and 4 reduced the biological activity.
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    Synthesis and Evaluation of Novel Tri-Aryl Phosphonium Derivatives as Potential Anti-Cancer Agents
    (2020-01) Gardner, Zachary
    The metabolic properties of cancer cells differ significantly from those of normal cells due to their high demand for energy for rapid proliferation and the need to produce anabolic building blocks for increasing cell mass. In fact, altered metabolism has been recognized as one of the critical hallmarks of cancer, and tumors characteristically exhibit aggressive glycolysis even in the presence of sufficient amounts of oxygen. Several recent studies have revealed additional levels of complexity and also recognized the importance of mitochondrial OxPhos to generate a large portion of ATP in cancer cells. OxPhos also plays an important role in cancer cell survival, drug resistance, relapse, and metastasis. OxPhos intermediates are utilized in the Kreb’s cycle and many of which are shuttled into numerous biosynthetic pathways including fatty acids, amino acids, and nucleotides. Selective inhibition of OxPhos will lead to severe ATP depletion and dysfunction of the TCA cycle, starving cancer cells of critical components for cell survival and proliferation. In this regard, we designed, synthesized and evaluated mitochondrial OxPhos inhibitors with therapeutically relevant features. We undertook a structure-activity study using triphenylphosphine as a structural template. For this purpose, several modified phosphonium salts conjugated to α-halomethylacrylate template with high potential for reactivity within the mitochondria were synthesized. In this thesis, the design, synthesis, in vitro cell proliferation inhibition, mitochondrial activity, systemic toxicity in mice and in vitro fluorescence microscopy studies will be presented.