Session: Undergraduate Research Posters: Organic Chemistry:

Lysyl oxidase (LOX) is a copper-dependent amine oxidase best characterized by its function to crosslink elastin and collagen. It is known that the overexpression of LOX in hypoxic tumors is known to cause metastasis of many cancers, most notably breast. Inhibitors such as β-aminopropionitrile (β-APN) are notably effective but add the challenge of toxicity to healthy cells. Thus, prodrugs that release β-APN directly to cancerous tumors, such as those tethered to isoxazoles that may decrease drug toxicity while increasing aqueous solubility are of high priority. However useful, one of the main issues with isoxazoles and β-APN inhibitors is their traditional synthesis involving toxic and environmentally irresponsible solvents.
In order to challenge these dynamic problems, previous work has successfully led to produce inhibitory β-APN derivatizations and the development of a high yielding, one-pot, greener method of synthesizing isoxazolines using a recyclable surfactant solution as the reaction solvent. While the current inhibitors are produced in good yield, many of them have limited water solubility. Therefore, in hopes of increased potency, water solubility, yield and a greener workup, we herein propose a novel synthesis of β-APN-coupled isoxazoles, whereby β-APN is already integral to the starting material that would normally be used to synthesize an isoxazoline. The surfactant DL-α-tocopherol methoxypolyethylene glycol succinate (TPGS-750-M) has been chosen for its promise of recyclability and formation of optimally-sized micelles that serve as aqueous reaction microenvironments. Oximes in a micellular environment generated in situ via an aldehyde are oxidized to their corresponding nitrile oxide. This subsequent intermediate then reacts with the prepared alkyne dipolarophile in 1,3-dipolar cycloaddition fashion to produce an isoxazole. An alkyne with suggested β-APN chain is not commercially available, however, literature precedence has allowed us to successfully create a stock for further research.
The workup has successfully increased water solubility and yield of the inhibitors. Multiple variables including temperature and the electronic nature of substituents have contributed to affecting isoxazoline yields. This work presents these changes made in isoxazoles also.

Matthew Goulart

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