Synthesis and Biological Evaluation of S-Adenosyl-l,12-diamino-3-thio-9-azadodecane, a Multisubstrate Adduct Inhibitor of Spermine Synthase

Patrick M. Woster, Alison Y. Black, Keith J. Duff, James K. Coward, Anthony E. Pegg

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

As part of a continuing search for specific inhibitors of the enzymes involved in polyamine biosynthesis, we have designed and synthesized a multisubstrate adduct inhibitor, S-adenosyl-l,12-diamino-3-thio-9-azadodecane (AdoDATAD), in which critical portions of the nucleophilic aminopropyl acceptor are covalently linked to critical portions of the electrophilic aminopropyl donor to form a potent and specific inhibitor of spermine synthase. In addition, the corresponding desamino analogue which was designed to lack activity against spermine synthase on the basis of substrate structure-activity data has been synthesized as a control. Preliminary biological results demonstrate that AdoDATAD is a potent and specific inhibitor of mammalian spermine synthase in vitro, while being almost completely devoid of inhibitory activity toward the closely related aminopropyltransferase spermidine synthase. The desamino analogue, as predicted, showed no inhibitory activity against either enzyme. AdoDATAD represents an important addition to the arsenal of specific enzyme inhibitors available for blockade of the polyamine biosynthetic pathway at specific sites.

Original languageEnglish (US)
Pages (from-to)1300-1307
Number of pages8
JournalJournal of Medicinal Chemistry
Volume32
Issue number6
DOIs
StatePublished - Jun 1 1989

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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