α-Hydroxytropolones: A New Class of Potent Inhibitors of Inositol Monophosphatase and Other Bimetallic Enzymes

Abstract

Mono- and polyhydroxytropolones are potent competitive inhibitors of inositol monophosphatase. Modeling studies indicate that this inhibition occurs most probably through a novel mode of action involving the chelation of the two magnesium ions in the active site. This is consistent with experimental data. Inhibition occurs when at least three oxygen atoms are present on the seven-membered ring, and only if they are contiguous to one another. In addition, those oxygens should not be protected. The corresponding six-membered rings showed no activity. Other bimetallic enzymes such as alkaline phosphatase (APase) or dopamine β-monooxygenase (DBM) are also inhibited (in a competitive or uncompetitive manner) by hydroxytropolones.