2-Chloro-1,4-naphthoquinone derivative of quercetin as an inhibitor of aldose reductase and anti-inflammatory agent

Figures & data

Figure 1. Chemical structures of 3,7-dihydroxy-2-[4-(2-chloro-1,4-naphthoquinone-3-yloxy)-3-hydroxyphenyl]-5-hydroxychromen-4-one (1), quercetin (2) and 2-chloro-3-hydroxy-[1,4]-naphthoquinone (3).

Figure 2. Inhibitory effect of compound 1 (2-chloro-1,4-naphthoquinone derivative of quercetin) on rat lens aldose reductase. Typical double reciprocal plot of the initial enzyme velocity versus the concentration of substrate (d,l-glyceraldehyde) in the presence or absence of inhibitor: (•) no inhibitor; (○) 2 μmol/l compound 1 (non-competitive type of inhibition).

Table 1. Inhibitory effect of compound 1 on rat ALR2 and ALR1 in comparison with quercetin (2).

	IC50 (µM)
Compound	Rat lens ALR2	Rat kidney ALR1
1	2.1 ± 0.6	11.1 ± 1.1
Quercetin (2)	13.6 ± 3.6	*61.5 ± 3.2%

*%I at 10 µM concentration; results are mean values ± SD from at least three measurements.

Figure 3. Geometry of the aldose reductase active site for compound 1.

Table 2. Effect of compound 1 on sorbitol accumulation in isolated rat lenses cultivated with high glucose* in comparison with quercetin (2).

Incubation	Sorbitol (nmol/g)	n
− Glucose	233.99 ± 7.80†	15
+ Glucose	755.27 ± 17.59	21
+ Glucose + 1 (2 μmol/l)	650.78 ± 81.21	4
+ Glucose + 1 (20 μmol/l)	560.12 ± 62.13†	6
+ Glucose + 2 (2 μmol/l)	720.15 ± 67.93	4
+ Glucose + 2 (20 μmol/l)	651.52 ± 17.28‡	5
+ Glucose + 2 (100 μmol/l)	479.14 ± 42.60†	3

Results are mean values ± SEM from n independent incubations.

*Glucose, 50 mmol/l; time of incubation, 3 h; 37 °C.

†p < 0.001 versus (+)Glucose (Student’s t test).

‡p < 0.05 versus (+)Glucose (Student’s t test).

Table 3. Effect of compound 1 and quercetin (2) on acute experimental colitis induced in rats by acetic acid*.

Experimental group	Colitis score	n
Untreated colitis	7.4 ± 1.2	8
DMSO treated	9.4 ± 1.0	8
DMSO + 1 (2 × 50 mg/kg)	3.4 ± 1.0†‡	8
DMSO + 2 (2 × 50 mg/kg)	9.5 ± 0.5	8

Results are mean values ± SD from n animals in the group.

*4% water solution of acetic acid, 1.5 ml.

†p < 0.001 versus DMSO treated; Mann–Whitney U test.

‡p < 0.05 versus untreated colitis; Mann–Whitney U test.

Figure 4. Effect of compounds 1 and 3 on osmotic fragility of rat erythrocytes. Erythrocyte suspensions (0.4% haematocrit) in 10 mmol/l phosphate buffer containing increasing concentrations of NaCl were incubated at 37 °C for 1 h in the absence (•) or presence of compound 1 (○, 25 μmol/l) or compound 3 (▴, 25 μmol/l). Experimental points represent mean values ± SD from at least three independent experiments.