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Semi-synthetic derivates of quercetin as antioxidants and aldose reductase inhibitors in prevention of diabetic complications: preclinical study in vitro The etiology of diabetic complications is multi-factorial since multiple hyperglycemia-dependent mechanisms contribute to their development. Oxidative stress and the polyol pathway are considered to have key roles in the etiology of diabetic complications. Therapeutic approaches interfering with the pathological processes at molecular level, e.g. based on antioxidants (AOs) and aldose reductase inhibitors (ARIs), are needed to attenuate the noxious effects of glucose. Innovative „multi-target“ strategies are focused on a rational design of chemical entities able to affect simultaneously multiple key mechanisms. This approach increases the chance of successful therapeutic intervention, decreases the risk of side effects and is economical. ARIs possessing AO activity would therefore seem to be desirable. Recently, considerable attention has been devoted to the search for phytochemical therapeutics. The flavonol quercetin is the most widely consumed flavonoid in the human diet. Quercetin and other flavonoids have been shown to exert protective effects against eye lens opacification in rats under conditions of experimental diabetes. The aim of this study was to provide new derivatives of quercetin with improved aldose reductase inhibitory activity and antioxidant capacity endowed with high selectivity and optimal biological availability. A series of novel semi-synthetic derivates of quercetin was designed and synthesized, namely 3,7-bis-hydroxy-2-(3´-hydroxy-4´-(2-chloro-1,4-naphtoquinone-3-oxy)phenyl)-5-hydroxy-chro-men-4-one (1), 3,7-di-hydroxy-2-(4´-hydroxy-3´-(chloropivaloyloxy)phenyl)-5-hydroxy-chro-men-4-one (2), and 3,7-di-hydroxy-2-(3´-hydroxy-4´-(4-O-acetylferuloyloxy)phenyl)-5-hydroxy-chro-men-4-one (3). In vitro inhibition of aldose reductase isolated from rat eye lenses was determined by a conventional method. Kinetic analysis of the most potent compound (1) with the value of IC50 = 2.09 ± 0.57 μM, showed noncompetitive inhibition. Selectivity with respect to the closely related aldehyde reductase isolated from rat kidneys was determined by measuring the corresponding inhibitory activities, giving the value of IC50 = 11.1 ± 1.1 μM for compound 1. However lower selectivity was recorded for the other two derivatives and quercetin itself. Antioxidant action of the compounds was documented in a DPPH test by determining the initial velocity of radical quenching. Significantly increased antiradical activity was recorded for compounds 1 and 2 in comparison with quercetin, the activities being comparable with that of standard trolox. Derivative 3 showed negligible effect on DPPH. At the organ level, aldose reductase inhibitory action of the most efficient derivative was assessed in isolated rat eye lenses and the sciatic nerve incubated with high glucose, by determining sorbitol accumulation. Molecular docking simulations into the aldose reductase active site performed for the most efficient derivative 1 indicated crucial interactions with specific amino acid residues. To conclude, the results obtained, along with the properties implicit to ‘drug-likeness’, inferred from simple molecular descriptors by applying the criteria of Lipinski’s ‘rule of five’, rendered the novel quercetin derivatives potential drugs with expected good bioavailability. Acknowledgement The work was supported by The Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic for the Structural Funds of EU, OP R&D of ERDF by realization of the Project „Evaluation of natural substances and their selection for prevention and treatment of lifestyle diseases” (ITMS 26240220040).
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