2-Arylbenzo[b]furan derivatives as potent human lipoxygenase inhibitors

Figures & data

Table 1. IC₅₀ values (μM) of inhibitors against human 5, 12, 15-LOXs.

Compounds	Structure	5-LOX^a^,^b	12-LOX^a^,^b	15-LOX^a^,^b	Cell lysates^a^,^c
1		2.35 ± 0.04^e	0.21 ± 0.01	1.21 ± 0.24	0.77 ± 0.19
2		1.67 ± 0.37^e	1.30 ± 0.08	0.84 ± 0.08	0.79 ± 022
3		3.50 ± 0.23^e	1.06 ± 0.52	3.30 ± 0.09	NA^d
4		4.95 ± 1.27^e	4.46 ± 0.76	4.65 ± 0.24	1.38 ± 0.06
5		1.50 ± 0.07	3.84 ± 0.57	1.59 ± 0.15	1.69 ± 0.18
6		5.40 ± 0.35	3.02 ± 1.14	4.23 ± 0.96	1.84 ± 0.77
7		9.92 ± 0.56	3.96 ± 0.62	2.98 ± 0.14	5.37 ± 0.38
8		14.34 ± 1.36	25.34 ± 9.64	7.05 ± 1.18	7.19 ± 1.74
9		10.12 ± 1.66	7.37 ± 0.94	3.62 ± 0.61	7.60 ± 1.78
10		17.90 ± 2.91	36.71 ± 0.25	9.20 ± 0.35	3.26 ± 1.36
NDGA		0.52 ± 0.04	1.65 ± 0.05	0.12 ± 0.04	0.12 ± 0.03

^aIC₅₀ values were determined from the results of at least three independent tests, and attempts to determine IC₅₀ values were made if the inhibition rate at 20 μM was larger than 40%.

^b The purified 5-LOX, 12-LOX and 15-LOX were the enzyme expressed in E. coli.

^c The cell lysates of SF21 cells containing active human wide-type 5-LOX.

^d NA, not available.

^e From work by Weinstein et al.²⁹.

Figure 1. Inhibitory activities of 1 and 2 against 5-, 12-, 15-LOXs. Lineweaver–Burk plots of LOXs inhibition by 1 and 2. The panel shows the representative double reciprocal plots of 1/v vs 1/S at various compound concentrations. 1: (A) (5-LOX); (B) (12-LOX); (C) (15-LOX). 2: (D) (5-LOX); (E) (12-LOX); (F) (15-LOX).

Figure 2. Compound 1 is a redox-active inhibitor of LOXs. This figure shows the radical scavenging activity of compound 1. Various amounts of 1 were incubated with 10 nmoles DPPH in 100 μl EtOH for 30 min in the dark and the absorbance at 520 nm was recorded. All data are represent as mean ± SD.

Figure 3. Effect of 1 on LTB4 generation in neutrophils. Isolated mouse neutrophils were pretreated with various concentrations of 1 for 30 min, then simulated with A23187 (10 μM) for another 30 min. LTB4 levels in the supernatant were determined by a commercial ELISA kit. NDGA (10 μM) was used as a positive control. All data are represent as mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001. p Values were obtained by the one-way ANOVA test.

Figure 4. Effect of 1 on fMLP-induced neutrophils migration. Neutrophils isolated from the bone marrow of mouse were pretreated with various concentrations of 1 for 30 min and then simulated with fMLP (5 μM) for 37 °C for 1 h using a 96-well chemotaxis plate with 3 μm pore diameter. Migrated cells were collected and counted. NDGA (10 μM) was used as a positive control. All data are represented as mean ± SD. **p < 0.01, ***p < 0.001. p Values were obtained by the one-way ANOVA test.

Figure 5. Effect of 1 (20 mg/kg and 50 mg/kg, i.p.) on acetic-acid-induced vascular permeability test in ICR mice. NDGA serves as a positive control (20 mg/kg, i.p.). All data are represented as mean ± SD (n = 6). *p < 0.05, **p < 0.01. p Values obtained performed by the one-way ANOVA test.

Wu D, Mei H, Tan P, et al. Total synthesis of the 2-arylbenzo[b]furan-containing natural products from Artocarpus. Tetrahedron Lett 2015;56:4383–7

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