A Novel Class of Zinc-Binding Inhibitors for the Phosphatidylcholine-Preferring Phospholipase C from Bacillus c ereus

• Published in: Journal of organic chemistry Vol. 65; no. 15; pp. 4509 - 4514
• Main Authors: Martin, Stephen F, Follows, Bruce C, Hergenrother, Paul J, Franklin, Christopher L
• Format: Journal Article
• Language: English
• Published: American Chemical Society 28-07-2000
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo9915731

The phospholipase C (PLC) isozymes catalyze the hydrolysis of phospholipids to provide diacylglycerol (DAG) and a phosphorylated headgroup. Because DAG has been implicated in cellular signal transduction cascades in mammalian systems, there has been considerable interest in the development of inhibitors of these enzymes. Toward this end, we have discovered that the cyclic N,N‘-dihydroxyureas 6−10 inhibit the phosphatidylcholine preferring PLC from Bacillus cereus (PLC Bc ). This class of inhibitors is believed to function 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 as of the N−OH hydroxyl groups, it is apparent that one or both of the hydroxyl groups must be ionized for effective coordination to the zinc ions. It is also apparent that there may be rather strict steric requirements for these inhibitors.