Spirohydantoin inhibitors of aldose reductase inhibit iron- and copper-catalysed ascorbate oxidation in vitro.
Transition metal-catalysed oxidations have been implicated in the complications of diabetes. We report here that some experimental inhibitors of the enzyme aldose reductase (implicated in diabetes mellitus via its ability to catalyse glucose reduction to sorbitol) are also potent inhibitors of transition metal-catalysed ascorbate oxidation. The inhibition appears to be dependent upon the presence of a spirohydantoin group. It is conceivable that the copper- and iron-binding capacity of these compounds may contribute to some of their observed biological effects and may provide a starting point for a new generation of experimental drugs for the treatment of diabetes mellitus.
Jiang
Z Y
ZY
Department of Clinical Pharmacology, University College and Middlesex School of Medicine, London, U.K.
Zhou
Q L
QL
Eaton
J W
JW
Koppenol
W H
WH
Hunt
J V
JV
Wolff
S P
SP
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000378:metabolism*; D003300:Copper / Q000494:pharmacology*; D003920:Diabetes Mellitus / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D005449:Fluorenes / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006827:Hydantoins / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D048289:Imidazolidines; D007501:Iron / Q000494:pharmacology*; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship
D000975:Antioxidants; D005449:Fluorenes; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; C052241:imirestat; D003300:Copper; D007501:Iron; D000449:Aldehyde Reductase; C026411:sorbinil; D001205:Ascorbic Acid