A novel class of zinc-binding inhibitors for the phosphatidylcholine-preferring phospholipase C from Bacillus cereus

The phospholipase C (PLC) isozymes catalyze the hydrolysis of phospholipids to provide diacylglycerol (DAG) and a phosphorylated headgroup. Because DA G; has been implicated in cellular signal transduction cascades in mammalia n systems, there has been considerable interest in the development of inhib itors of these enzymes. Toward this end, we have discovered that the cyclic N,N'-dihydroxyureas 6-10 inhibit the phosphatidylcholine preferring PLC fr om Bacillus cereus (PLCBc). This class of inhibitors is believed to functio n by the bidentate chelation of the N,N'-dihydroxyurea array to one or more of the zinc ions at the active site of the enzyme. Because the affinities of these compounds correlate with the pK(a)s of the N-OH hydroxyl groups, i t is apparent that one or both of the hydroxyl groups must be ionized for e ffective coordination to the zinc ions. It is also apparent that there may be rather strict steric requirements for these inhibitors.