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
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.