J. Deruiter et al., STUDIES ON ALDOSE REDUCTASE INHIBITORS FROM FUNGI .2. MONILIFORMIN AND SMALL RING ANALOGS, Journal of enzyme inhibition, 7(4), 1993, pp. 249-256
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.