Synthesis of flavonoids and their effects on aldose reductase and sorbitolaccumulation in streptozotocin-induced diabetic rat tissues

Citation
Ss. Lim et al., Synthesis of flavonoids and their effects on aldose reductase and sorbitolaccumulation in streptozotocin-induced diabetic rat tissues, J PHARM PHA, 53(5), 2001, pp. 653-668
Citations number
41
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACY AND PHARMACOLOGY
ISSN journal
0022-3573 → ACNP
Volume
53
Issue
5
Year of publication
2001
Pages
653 - 668
Database
ISI
SICI code
0022-3573(200105)53:5<653:SOFATE>2.0.ZU;2-W
Abstract
Aldose reductase, the key enzyme of the polyol pathway, and oxidative stres s are known to play important roles in the complications of diabetes. A dru g with potent inhibition of aldose reductase and oxidative stress, therefor e, would be a most promising drug for the prevention of diabetic complicati ons. The purpose of this study was to develop new compounds with these dual -effects through synthesis of chalcone derivatives and by examining the str ucture-activity relationships on the inhibition of rat lens aldose reductas e as well as on antioxidant effects. A series of 35 flavonoid derivatives w ere synthesized by Winget's condensation, oxidation, and reduction of appro priate acetophenones with appropriate benzaldehydes. The inhibitory activit y of these derivatives on rat lens aldose reductase and their antioxidant e ffects, measured using Cu2+ chelation and radical scavenging activities on 1,1-diphenyl-picrylhydrazyl in-vitro. were evaluated. Their effect on sorbi tol accumulation in the red blood cells, lenses and sciatic nerves of strep tozotocin-induced diabetic rats was also estimated. Among the new flavonoid derivatives synthesized, those with the 2',4'-dihydroxyl groups in the A r ing 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'-tetrahydroxy chalcone (18) were found to possess the highest rat lens aldose reductase i nhibitory 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 teste d except 3, 18, 23 with o-dihydroxy or hydroquinone moiety showed a weak fr ee radical scavenging activity. In the in-vivo experiments, however, compou nd 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 th e strongest activity in transition metal chelation and free radical scaveng ing activity. Of the 35 4,2'-dihydroxyl and 2',4'-dihydroxyl derivatives of flavonoid synthesized, including chalcone, flavone, flavanone, flavonol an d dihydrochalcone, some chalcone derivatives synthesized were found to poss ess 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.