<i>O</i>-prenylated 3-carboxycoumarins as a novel class of 15-LOX-1 inhibitors

<div><p>Allyloxy, Isopentenyloxy, geranyloxy and farnesyloxy derivatives of 3-carboxycoumarin, at position 5, 6, 7, and 8, were synthesized and their inhibitory potency against human 15-lipoxygenase-1 (human 15-LOX-1) were determined. Among the synthetic coumarins, <i>O</i>-allyl and <i>O</i>-isopentenyl derivatives demonstrated no considerable lipoxygenase inhibition while <i>O</i>-geranyl and <i>O</i>-farnesyl derivatives demonstrated potent inhibitory activity. 5-farnesyloxy-3-carboxycoumarin demonstrated the most potent inhibitory activity by IC₅₀ = 0.74 μM while 6-farnesyloxy-3-carboxycoumarin was the weakest inhibitor among farnesyl analogs (IC₅₀ = 10.4 μM). Bonding affinity of the designed molecular structures toward 15-LOX-1 3D structure complexed with RS75091, as potent 15-LOX-1 inhibitor, was studied by utilizing docking analysis. There was a direct relationship between lipoxygenase inhibitory potency and prenyl length chain. The ability of the prenyl portion to fill the lipophilic pocket which is formed by Ile663, Ala404, Arg403, Ile400, Ile173 and Phe167 side chains can explain the observed relationship. Similarity rate between the docked models and complexed form of RS75091, from point of view of configuration and conformation, could explain inhibitory potency variation between each prenyloxy substitution of 3-carboxycoumarins.</p></div

Michaelis-Menten (left) and Lineweaver-Burk (right) plots of human 15-LOX-1 inhibition by 4d.

<p>The Y-intercept average (1/V_max) of the Lineweaver-Burk plot is 376 ± 45 min.Abs^-1 and K_M = 8.73 ± 0.43 μM. The error bars are stated as ± SD (n = 4).</p

Superimposition of consensus structures of compounds 4c (pink stick) and 4d (green stick) from LFC on RS75091 (yellow stick) in rabbit 15-LOX-1 active site (left). Superimposition of consensus structure of 4d (green stick) from LFC on consensus structure of 4d' (brown stick) from similar cluster (right).

<p>In both figures, Ile663 is not shown.</p

Data of the docking analyses results: Ki of the most populated cluster (Ki_MPC), average of all the lowest Ki from each cluster (Ki_LEC), average Ki of all the conformers (Ki_AC) and average Ki of a cluster in which lactone portion of coumarin directed towards Fe-OH core (Ki_LFC).

<p>N = number of conformers. The data are shown as ± SEM.</p

Inhibitory assessment data of the synthetic compounds in comparison with 4-methyl-2-(4-methylpiperazinyl)pyrimido[4, 5-b]benzothiazine (4-MMPB) against human 15-LOX-1.

<p>The data are shown as ± SD (n = 3).</p

General procedure for the synthesis of <i>O</i>-prenylated-3-carboxycoumarins.

<p>General procedure for the synthesis of <i>O</i>-prenylated-3-carboxycoumarins.</p

General structure of compounds 4d', 8d', 12d' and 18d' which relates to farnesyloxy substitution at position 5, 6, 7 and 8 respectively.

<p>General structure of compounds 4d', 8d', 12d' and 18d' which relates to farnesyloxy substitution at position 5, 6, 7 and 8 respectively.</p