Synthesis of flavonoids and their effects on aldose reductase and sorbitol accumulation in streptozotocin-induced diabetic rat tissues.
Aldose reductase, the key enzyme of the polyol pathway, and oxidative stress are known to play important roles in the complications of diabetes. A drug with potent inhibition of aldose reductase and oxidative stress, therefore, would be a most promising drug for the prevention of diabetic complications. The purpose of this study was to develop new compounds with these dual-effects through synthesis of chalcone derivatives and by examining the structure-activity relationships on the inhibition of rat lens aldose reductase as well as on antioxidant effects. A series of 35 flavonoid derivatives were synthesized by Winget's condensation, oxidation, and reduction of appropriate acetophenones with appropriate benzaldehydes. The inhibitory activity of these derivatives on rat lens aldose reductase and their antioxidant effects, measured using Cu2+ chelation and radical scavenging activities on 1,1-diphenyl-picrylhydrazyl in-vitro, were evaluated. Their effect on sorbitol accumulation in the red blood cells, lenses and sciatic nerves of streptozotocin-induced diabetic rats was also estimated. Among the new flavonoid derivatives synthesized, those with the 2',4'-dihydroxyl groups in the A ring such as 2,4,2',4'-tetrahydroxychalcone (22), 2,2',4'-trihydroxychalcone (11), 2',4'-dihydroxy-2,4-dimethylchalcone (21) and 3,4,2',4'-tetrahydroxychalcone (18) were found to possess the highest rat lens aldose reductase inhibitory activity in-vitro, their IC50 values (concentration of inhibitors giving 50% inhibition of enzyme activity) being 1.6 x 10(-7), 3.8 x 10(-7), 4.0 x 10(-7) and 4.6 x 10(-7) M, respectively. All of the chalcones tested except 3, 18, 23 with o-dihydroxy or hydroquinone moiety showed a weak free radical scavenging activity. In the in-vivo experiments, however, compound 18 with o-dihydroxy moiety in the B ring showed the strongest inhibitory activity in the accumulation of sorbitol in the tissues. It also showed the strongest activity in transition metal chelation and free radical scavenging activity. Of the 35 4,2'-dihydroxyl and 2',4'-dihydroxyl derivatives of flavonoid synthesized, including chalcone, flavone, flavanone, flavonol and dihydrochalcone, some chalcone derivatives synthesized were found to possess aldose reductase inhibition and antioxidant activities in-vitro as well as inhibition in the accumulation of sorbitol in the tissues in-vivo. 3,4,2',4'-Tetrahydroxychalcone (18, butein) was the most promising compound for the prevention or treatment of diabetic complications.
Lim
S S
SS
Natural Products Research Institute, Seoul National University, Korea.
Jung
S H
SH
Ji
J
J
Shin
K H
KH
Keum
S R
SR
D000449:Aldehyde Reductase / Q000378:metabolism*; D000818:Animals; D002599:Chalcone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D005419:Flavonoids / Q000138:chemical synthesis* / Q000494:pharmacology*; D016166:Free Radical Scavengers; D007908:Lens, Crystalline / Q000737:chemistry / Q000201:enzymology; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000737:chemistry / Q000201:enzymology; D013012:Sorbitol / Q000493:pharmacokinetics*; D013311:Streptozocin / Q000008:administration & dosage / Q000009:adverse effects
D005419:Flavonoids; D016166:Free Radical Scavengers; D013012:Sorbitol; D002599:Chalcone; D013311:Streptozocin; D000449:Aldehyde Reductase