Several 1,2-dioxolanes were synthesized, submitted for testing at the National Cancer Institute, and a lead compound was identified. This compound was named FINO2 and displayed similar concentrations necessary to induce lethality in cancer cells as FDA-approved anti-cancer agents. Experiments were performed to demonstrate FINO2 is stable to at least 150 °C and is selective for cancer cells. One of the enantiomers was found to be more active than the other. No mechanism-of-action studies in cancer had previously been performed with compounds resembling FINO2. The data reported in this thesis indicate the mechanism of cell death induced by FINO2 is distinct from most chemotherapy agents and other peroxide-containing compounds. FINO2 does not induce apoptosis, but instead initiates ferroptosis, an iron-dependent, oxidative cell death pathway. These results indicate that FINO2 could lead to a safe treatment alternative to traditional chemotherapy that overcomes common resistance mechanisms such as mutation of p53 or expression levels of BCL-2 proteins.
|Advisor:||Woerpel, Keith A., Carroll, William L.|
|Commitee:||Arora, Paramjit, Kirshenbaum, Kent, Mahal, Lara|
|School:||New York University|
|School Location:||United States -- New York|
|Source:||DAI-B 77/08(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Organic chemistry, Oncology|
|Keywords:||Chemotherapy, Dioxolane, Ferroptosis, Lipoxygenase, Organic peroxide, Regulated cell death|
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