Browsing by Author "Schumacher, Tanner"

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    Development of Drug Candidates Targeting Mitochondrial Bioenergetics for Cancer Treatment
    (2024-05) Schumacher, Tanner
    Cancer tumors have been shown to be metabolically heterogeneous in their means for acquiring bioenergetics, biosynthetic components for generating biomass, and controlling redox equilibrium. Differences in oxygen and nutrient availability, along with rapid proliferation, drives spatial metabolic phenotypes within a tumor. Having an adaptable metabolism allows for sustained growth in differing microenvironments. Metabolic adaptability of malignant tissues has posed a challenge for current therapies, as treatment of one metabolic pathway has been overcome by a compensatory upregulation of another pathway. Hence, targeting the ability of tumors to adapt their metabolism shows promise as a novel effective therapeutic strategy. In this regard, we have taken up two projects to inhibit metabolic heterogeneity in cancers. One project involves the design and synthesis of a novel small molecule inhibitor of mitochondrial pyruvate carrier (MPC), called D7. We have shown that D7 is specifically potent in highly energetic oxidative cancer cells, inhibits mitochondrial pyruvate import at nanomolar concentrations, and causes a monocarboxylate transporter 1 (MCT1) dependent intracellular accumulation of lactate. In addition, D7 has been shown to be well tolerated when administered in vivo, providing up to ~71% tumor mass reduction in a 67NR syngraft model and ~41% tumor mass reduction in a highly aggressive isogenic 4T1 syngraft model. The second project involves the repurposing of FDA approved metabolically targeting agents as anticancer agents. An extensive literature search in identifying FDA approved drugs or drug candidates with either glycolysis or oxidative phosphorylation (OxPhos) inhibition properties resulted in the selections of ~30 drugs for further evaluation. After preliminary evaluation in our lab, we further narrowed down our original list of ~30 drugs to 4 drug candidates: BAY-876 (glycolysis inhibitor), niclosamide (OxPhos inhibitor), and pyrvinium pamoate (OxPhos inhibitor) and IMD-0354 (OxPhos inhibitor). As single agents these candidate compounds were shown to induce compensatory metabolic pathways that were found to be suppressed when administered as combination therapies, highlighting the capacity for these candidates to be repurposed as anticancer agents targeting cancers metabolic adaptability. In addition, these candidate compounds were shown to be well tolerated in vivo in our lab, with single agent administration showing 61-68% tumor reduction in a 67NR syngraft model.
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    Synthesis and Biological Evaluation of Novel 2- benzoylbenzofurans as Potential Anticancer Agents
    (2019-07) Schumacher, Tanner
    The heterocyclic benzofuran moiety is a privileged chemical entity that has been utilized in the development of novel pharmaceuticals. Benzofurans have been studied for therapeutic uses in cancer, cardiovascular diseases, antimicrobial, psychotic disorders, renal disorders and inflammation. Another privileged structure in drug development is the piperazine unit. The addition of this structure has been shown to greatly improve water solubility making this template well utilized in many clinically successful drugs. Our group’s interest in the development of anticancer agents has pushed us to discover the therapeutic potential of piperazine bearing benzofurans. A recent report involving the synthesis and evaluation of an piperazino N,N-diethyl benzofuran has peaked our interest due to the simplicity of synthesis and good cytotoxicity properties. In this regard, we sought to synthesis and evaluate a series of piperazine substituted 2-benzoylbenzofurans. Through a two-step Rap-Stoermer condensation between salicylaldehydes and phenacyl bromide prior to ipso substitution with piperazine, numerous candidate compounds have been synthesized. These compounds have been evaluated via MTT cell proliferation assay for their cytotoxic properties on six cancer cell lines: 4T1, 67NR, MIA PaCa-2, MCF7, MDAMB-231, and WiDr. Compounds 2.36 and 2.40 were found to be the most potent with IC50 values ranging from ~2-4 M and ~2-8 M across all cell lines. The synthesis and in vitro evaluation studies are presented in this thesis.
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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.