Fig 1.
General procedure for the synthesis of O-prenylated-3-carboxycoumarins.
Table 1.
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.
The data are shown as ± SD (n = 3).
Fig 2.
Michaelis-Menten (left) and Lineweaver-Burk (right) plots of human 15-LOX-1 inhibition by 4d.
The Y-intercept average (1/Vmax) of the Lineweaver-Burk plot is 376 ± 45 min.Abs-1 and KM = 8.73 ± 0.43 μM. The error bars are stated as ± SD (n = 4).
Table 2.
Data of the docking analyses results: Ki of the most populated cluster (KiMPC), average of all the lowest Ki from each cluster (KiLEC), average Ki of all the conformers (KiAC) and average Ki of a cluster in which lactone portion of coumarin directed towards Fe-OH core (KiLFC).
N = number of conformers. The data are shown as ± SEM.
Fig 3.
The four diagrams show the variations of -Log of KiLFC (A), KiAC (B), KiMPC and KiLFC versus -Log Kiexp.
The data are presented as ± SEM.
Fig 4.
(A) Stick view of bonding conformer with the lowest Ki which relates to the compounds 4d, 8d, 12d and 18d from the LFC cluster (consensus structures). (B) Stick view of consensus structure of compound 4d and its hydrogen bonding (dash line) with Fe-OH core. (C) Stick and solvent surface view of the rabbit 15-LOX-1 active site residues interactions with the consensus structure of 4d.
Fig 5.
Comparison between the chemical structure of compounds RS75091 and 4c.
Fig 6.
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).
In both figures, Ile663 is not shown.
Fig 7.
General structure of compounds 4d', 8d', 12d' and 18d' which relates to farnesyloxy substitution at position 5, 6, 7 and 8 respectively.