Studies on Aldose Reductase Inhibitors from Fungi. II. Moniliformin and Small Ring Analogues

The fungal metabolite moniliformin and several small ring analogues were evaluated for potential substrate and inhibitory activity in the rat lens aldose reductase (AR) assay. Even though all of these compounds possess carbonyl moieties and structural similarities to AR substrates, none were found to function as substrates over a concentration range of 1.0 mM to 10 mu M. All of the compounds did display inhibitory activity with IC(50)s ranging from 19-110 mu M. The most inhibitory compounds were the four-membered ring moniliformin (IC50 19 mu M), the five-membered analogue croconic acid (IC50 28 mu M) and six-membered derivative tetrahydroxy p-benzoquinone (IC50 23 mu M). Modification of moniliformin by methylation (methyl moniliformin) or hydroxylation (squaric acid) resulted in a significant decline in inhibitory activity. All of the compounds evaluated except moniliformin displayed uncompetitive, non-competitive or mixed-type kinetics relative to the substrate (glyceraldehyde) and cofactor (NADPH), kinetic profiles commonly observed for inhibitors of AR.