MONOARYLDIHYDROXYTROPOLONES AND BISARYLDIHYDROXYTROPOLONES AS POTENT INHIBITORS OF INOSITOL MONOPHOSPHATASE

The first successful preparation of mono- and disubstituted 3,7-dihydr oxytropolone involves a four-step synthetic scheme. Thus, bromination of 3,7-dihydroxytropolone (8) followed by permethylation of the result ant products furnished gram quantities of intermediates 13-18. Single or double Suzuki coupling reactions between these permethylated monobr omo- and dibromodihydroxytropolone derivatives and a variety of boroni c acids delivered the expected products whose deprotection yielded the desired compounds 1a-u and 26a-n, usually in fair to good yields. Tro polones 1 and 26 were found to be potent; inhibitors of inositol monop hosphatase with IC50 values in the low-micromolar range. The results a re discussed in the context of the recently described novel mode of in hibition of the enzyme by 3,7-dihydroxytropolones.