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Browsing by Author "Ronayne, Conor"

Now showing 1 - 3 of 3
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    Biosynthetic and Energetic Lethality of Targeting Metabolic Plasticity for Cancer Treatment
    (2020-08) Ronayne, Conor
    Solid tumors are composed of numerous heterogeneous tissue types with a diverse molecular pathology. Uncontrolled replication and division, along with nutrient and oxygen gradients across the tumor, dictate dynamic intratumoral phenotypes that are reinforced by molecular hallmarks of cancer; largely shaping modern clinical treatment regimens. Importantly, deregulated energetics and reprogrammed tumor metabolism enable constitutive growth in challenging microenvironments. The ability of malignant cells to switch between numerous metabolic phenotypes (metabolic plasticity) allows for the generation of energy, appropriation of biosynthetic building blocks, and control of redox equilibrium. Hence, therapeutic targeting of metabolic plasticity with small molecules holds promise as a novel and enduring therapeutic strategy. In this regard, the current thesis work describes efforts toward developing novel small molecule mitochondrial pyruvate carrier inhibitors to induce bioenergetic and synthetic lethality in cancer cells.
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    Development of 2-(alkoxycarbonyl)-allyl esters as anticancer agents
    (2018-01) Ronayne, Conor
    Cancer is the second leading cause of human mortality in the United States, with the standard treatment options being surgery, cytotoxic chemotherapy, and radiation therapy. Recently, there has been strong emphasis in developing targeted small molecule therapies which has led to the development of numerous anticancer drugs. However, many of the current cancer chemotherapeutic options are burdened with toxicity and treatment resistance and hence novel therapies with reduced side effects are urgently needed. In the current work, a structurally diverse library of Baylis-Hillman reaction derived 2-(alkoxycarbonyl)-allyl esters have been synthesized, evaluated for their in vitro cell proliferation inhibition properties, in vitro cellular and molecular mechanisms of action, in vivo systemic toxicity study in CD-1 mice, and in vivo anticancer efficacy study in a triple negative breast cancer MDA-MB-231 xenograft model in NOD SCID mice. Several of the synthesized compounds exhibit promising in vitro anticancer properties. Further, the lead candidate compound is well tolerated in healthy mice as indicated by normal body weight changes, and exhibits similar if not slightly better tumor growth inhibition properties than clinically available cancer drug doxorubicin.
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