STUDIES ON ALDOSE REDUCTASE INHIBITORS FROM FUNGI .2. MONILIFORMIN AND SMALL RING ANALOGS

The fungal metabolite moniliformin and several small ring analogues we re evaluated for potential substrate and inhibitory activity in the ra t lens aldose reductase (AR) assay. Even though all of these compounds possess carbonyl moieties and structural similarities to AR substrate s, none were found to function as substrates over a concentration rang e of 1.0 mM to 10 mu M. All of the compounds did display inhibitory ac tivity with IC(50)s ranging from 19-110 mu M. The most inhibitory comp ounds were the four-membered ring moniliformin (IC50 19 mu M), the fiv e-membered analogue croconic acid (IC50 28 mu M) and six-membered deri vative tetrahydroxy p-benzoquinone (IC50 23 mu M). Modification of mon iliformin by methylation (methyl moniliformin) or hydroxylation (squar ic acid) resulted in a significant decline in inhibitory activity. All of the compounds evaluated except moniliformin displayed uncompetitiv e, non-competitive or mixed-type kinetics relative to the substrate (g lyceraldehyde) and cofactor (NADPH), kinetic profiles commonly observe d for inhibitors of AR.