Studies on aldose reductase inhibitors from fungi. I. Citrinin and related benzopyran derivatives.
The fungal metabolites, citrinin (4,6-dihydro-8-hydroxy-3,4,5-trimethyl-6- oxo-3H-2-benzopyran-7-carboxylic acid) and DHMI (3,4-dihydro-6-methoxy-3,7-dimethyl-1H-2-benzopyran-8-ol), as well as certain synthetic derivatives, have been evaluated for aldose reductase inhibitory activity using a rat lens enzyme preparation. Citrinin and its reduction product, dihydrocitrinin, were found to have significant activity (IC50 approximately 10 microM), whereas the other compounds were 3-10 times less potent. Kinetic studies showed that citrinin was not an irreversible inhibitor of the enzyme, as might be expected of a quinone methide. Spectroscopic (NMR) evidence is presented for the existence of citrinin predominantly in the form of its hemi-acetal in aqueous solutions, suggesting that it is this benzo[c]pyran derivative which interacts with the enzyme, rather than the quinone methide form.
Deruiter
J
J
Department of Pharmacal Sciences, School of Pharmacy, Auburn University, AL 36849.
Jacyno
J M
JM
Davis
R A
RA
Cutler
H G
HG
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002953:Citrinin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005123:Eye / Q000201:enzymology; D005658:Fungi / Q000378:metabolism; D007700:Kinetics; D010407:Penicillium / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship
D001578:Benzopyrans; D002953:Citrinin; C082706:3,4-dihydro-6-methoxy-3,7-dimethyl-1H-benzopyran-8-ol; C082705:dihydrocitrinin; D000449:Aldehyde Reductase