Lysyl oxidase (LOX) is a copper-dependent amine oxidase best characterized by its function to crosslink elastin and collagen, however, its overexpression in hypoxic tumors is associated with the metastasis of many cancers. Inhibitors such as β-aminopropionitrile (β-APN) are notably effective but are toxic to healthy cells. Thus, it is hypothesized that β-APN containing small molecules with heterocyclic isoxazoline or isoxazole cores may offer similar potency while decreasing drug toxicity and increasing aqueous solubility. However useful, the traditional synthesis of these heterocycles and β-APN inhibitors heavily relies on toxic and environmentally irresponsible solvents. Previous work has successfully produced β-APN derivatizations and developed a one-pot, modifiable, and greener method of synthesizing isoxazolines and isoxazoles using a recyclable surfactant solution as the solvent. Current inhibitors are produced in good yield but with limited water solubility. Therefore, in aim of increased potency, water solubility, yield and a greener workup, this work presents a novel synthesis of β-APN-coupled isoxazoles and isoxazolines.<br/>The surfactant DL-α-tocopherol methoxypolyethylene glycol succinate (TPGS-750-M) was chosen for its promises of recyclability and formation of optimally sized micelles that serve as aqueous reaction microenvironments. Aromatic oximes are generated <i>in situ</i> via an aldehyde and oxidized to their corresponding nitrile oxides in a micellular environment. This reacts with an ester-bearing alkyne or alkene dipolarophile in 1,3-dipolar cycloaddition fashion to produce either ring. Following reduction and subsequent oxidation, the aldehyde undergoes reductive amination with β-APN to yield these inhibitors for submission to collaborators screening against breast cell cancer line MDA-MB-231.

Synthesis of isoxazoline and isoxazole heterocycles as potential inhibitors of lysyl oxidase

ACS Spring 2022

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