Abstract
As rate-limited enzyme of polyol pathway, aldose reductase (ALR2) is one of the key inhibitory targets for alleviating diabetic complications. To reduce the toxic side effects of the inhibitors and to decrease the level of oxidative stress, the inhibitory selectivity towards ALR2 against detoxicating aldehyde reductase (ALR1) and antioxidant activity are included in the design of multifunctional ALR2 inhibitors. Hydroxypyridinone derivatives were designed, synthesized and evaluated their inhibitory behavior and antioxidant activity. Notably, {2-[2-(3,4-dihydroxy-phenyl)-vinyl]-5-hydroxy-4-oxo-4H-pyridin-1-yl}-acetic acid (7l) was the most potent, with IC50 values of 0.789 μM. Moreover, 7l showed excellent selectivity towards ALR2 with selectivity index 25.23, which was much higher than that of eparlestat (17.37), the positive control. More significantly, 7l performed powerful antioxidative action. At a concentration of 1 μM, phenolic compounds 7l scavenged DPPH radical with an inhibitory rate of 41.48%, which was much higher than that of the well-known antioxidant Trolox, at 11.89%. Besides, 7l remarkably suppressed lipid peroxidation with a rate of 88.76% at a concentration of 100 μM. The binding mode derived from molecular docking proved that the derivatives were tightly bound to the activate site, suggesting strongly inhibitory action of derivatives against ALR2. Therefore, these results provided an achievement of multifunctional ALR2 inhibitors capable with potency for both selective ALR2 inhibition and as antioxidants.
Highlights
Diabetes mellitus (DM) is a metabolic disorder resulting from defects in insulin secretion, insulin action, or both
As the first and rate-determining enzyme in the polyol pathway, aldose reductase (ALR2, EC 1.1.1.21) reduces glucose into sorbitol in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) [6,7,8,9]. (Figure 1) Subsequently, the NAD+ -dependent sorbitol dehydrogenase oxidizes the intermediate sorbitol to fructose
The results demonstrated that most of 5-hydroxy-2-styryl-1H-pyridin-4-ones derivatives showed good to excellent inhibitory activity against ALR2 with IC50 values varying from 0.789 to 17.11 μM
Summary
Diabetes mellitus (DM) is a metabolic disorder resulting from defects in insulin secretion, insulin action, or both. Large amounts of evidence proved that the overproduction of sorbitol and increased level of oxidative stress are the crucial reasons accelerating process of diabetic complications [3,4,5]. As the first and rate-determining enzyme in the polyol pathway, aldose reductase (ALR2, EC 1.1.1.21) reduces glucose into sorbitol in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) [6,7,8,9]. Most of the cellular glucose is converted into glucose 6-phosphate and metabolized by hexokinase in glycolytic pathway [10,11]. Due to the saturation of hexokinase, excess glucose is metabolized
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