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) and 3,3’-iminodipropionitrile (IDPN) are notably effective but not cancer selective. Preliminary work has successfully produced effective β-APN prodrugs and developed a one-pot, modifiable, and greener method of synthesizing isoxazolines and isoxazoles using a recyclable surfactant as aqueous reaction media. In aim of increasing the aqueous solubility and potency of the first generation inhibitors, both of these methodologies were recently combined to synthesize heterocyclic β-APN prodrugs more greenly. In light of successfully producing a β-APN-coupled isoxazole derivation, this work presents the continued synthesis of heterocyclic LOX inhibitors using combinations of β-APN, IDPN, isoxazoline and isoxazole moieties in hopes of creating more potent inhibitors. These derivations will lead the expansion of a library of LOX inhibitors. 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 in situ 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 isoxazole or isoxazoline ring. Following reduction and subsequent oxidation, the aldehyde undergoes reductive amination with either β-APN or IDPN to yield inhibitors for submission to collaborators screening against breast cell cancer line MDA-MB-231.

Continued synthesis of isoxazolines and isoxazoles as inhibitors of lysyl oxidase

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