Thesis

Radical coupling reactions under neutral conditions and their biological relevance

Breast cancer is the second most prominent form of cancer among women in the United States. It is considered to be a multifactorial disorder where estrogens (estradiol and estrone) play a key role in the initiation and progression of the disease. Normally, estrogens are synthesized from testosterone and androstenedione by a Cytochrome P450 19Al enzyme aromatase (steroidogenesis). Its inhibition can effectively reduce the circulating estrogen levels and effectively starve breast cancer cells of the necessary signals. Although there are potent and effective drugs on the market, they cause serious side effects, such as arthralgia, bone pain, bone stiffness, hot flashes, night sweats, and genitourinary diseases. A new generation of aromatase inhibitors should be designed in such a way so that a low toxicity and side effects will become intrinsic properties of these future drugs. The chemistry part of my research is focused on synthesizing novel therapeutics for breast cancer treatment using cobalt-complexed propargyl cations as precursors. These transient species are usually synthesized under acidic conditions (HBF4, BF3, CF3COOH, H2S04), thus severely limiting the substrate base and its applicability to the synthesis of molecular assemblies bearing labile acid-sensitive functional groups (acetal, benzyloxy). In this project, we developed three new organometallic reactions: (1) a high temperature, spontaneous generation of cobalt-complexed propargyl cations (up to 147�C); (2) propargyl methyl ethers interaction with triflic anhydride that, for the first time, allows for generation of prop argyl cations under neutral conditions; and (3) a low temperature (- 50�C) variant of the parent reaction utilizing cobaltocene as an external reducing agent. These new methodologies allowed us to synthesize a variety of topologically diverse, polysubstituted 3,4-diaryl-1,5-alkadiynes m high yields and excellent d,ldiastereoselectivity (up to 99%). Decomplexation with eerie ammonium nitrate afforded metal free d,l-3,4-diaryl-1,5-alkadiynes, the potential aromatase inhibitors. Overall, the generation of cobalt-complexed propargyl cations under neutral conditions substantially expanded the scope of both ionic and radical reactions, allowing for involvement of substrates with acid-sensitive peripheral functionalities. Once these compounds were synthesized, they were tested as potential aromatase inhibitors on a MCF7 breast cancer cell line. These cells were incubated for two days with potential drug candidates, at various concentrations, then cell viability was measured using the MTT assay. Preliminary results indicated that d,l-3,4-di-(4'-methoxyphenyl)-1,5-hexadiyne inhibits cell proliferation with its efficiency being superior to that of aminogluthimide used as a reference.

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