Design, synthesis and sar study of isopropoxy allylbenzenes as 15-lipoxygenase inhibitors and study of their inhibitory mechanism

There is a correlation between 15-LOX-1 (one of the members of lipoxygenase family of enzymes) overexpression and degree of prostate cancer malignancy. Thus, inhibition of this enzyme might beuseful for prostate cancer treatment. New derivatives of Allyl benzenes (5a-e) were designed, synthesized and evaluated as soybean 15-lipoxygenase(SLO) inhibitors. Among the synthesized compounds, N-(3-allyl-4-isopropoxyphenyl)adamantane carboxamide (5e) showed the best inhibition activity(IC50= 1.35 ±0.08 μm). All compounds were docked into SLO that retrieved from RCBS Protein Data Bank(PDB entry:1IK3) and they showed that orientation of the amid and allyl moieties in 5c and 5e was different against which had been obser ved in the docked models of the other inhibitors respectively. But all of them were fixed in lipophilic pocket and the active site of the enzyme by H- bonds with Gln514, Gln716 and His513. Another study about inhibitory mechanism analyses was determined, the result showed that the 5e inhibit lipoxygenase activity by the competitive mechanism