Lipoxygenase-1 Inhibition with a Series of Half-Product Analogs

A new series of sulfur-containing competitive inhibitors for lipoxygenase-1 from soybeans has been synthesized and characterized. The compounds resemble the ω-half of the product of catalysis, and can, therefore, be thought of as half-product analogs. A series of inhibitors differing in the length of the ω-terminal aliphatic substituent was assembled. Lipoxygenase-1 inhibition at pH 9 was greatest for (E)-4-thia-2-undecenal, the compound bearing then-C7H15substituent. Longer or shorter aliphatic substituents provided less effective inhibitors. This optimal fit of the inhibitory compounds reflecting the known substrate specificity of the enzyme along with the competitive inhibition kinetics displayed by these substances implicated an active site interaction. The relatively uncomplicated features of the compounds made it possible to explore synthetically for other aspects of the structure favorable for an inhibitory effect. Compounds containing functional groups other than the aldehyde at the 1-position were all less effective inhibitors. In addition to the optimal hydrophobic substituent, an electron-rich region in the molecule was also critical to the inhibitory effect. α,β-Unsaturated aldehydes were about 10 times more effective inhibitors than the saturated analogs. The 4-thia substituent was not absolutely required for inhibition, but electron density at this position was important. γ,δ-Unsaturation replaced the sulfur in this capacity with little effect on the inhibition constant. The electron-rich aldehydes showed no tendency to form hydrates in aqueous solution or Schiff base adducts with the enzyme. Physical evidence for a protein–ligand interaction was sought in a series of1H NMR spectroscopy experiments. There was clear evidence for a specific interaction between the compounds and the enzyme in these measurements.