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

Stephen F. Martin, Bruce C. Follows, Paul J. Hergenrother, Christopher L. Franklin

Research output: Contribution to journalArticle

Abstract

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(a)s 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.

Original languageEnglish (US)
Pages (from-to)4509-4514
Number of pages6
JournalJournal of Organic Chemistry
Volume65
Issue number15
DOIs
StatePublished - Jul 28 2000
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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