Synthesis and Biochemical Evaluation of Adenosylspermidine, a Nucleoside-Polyamine Adduct Inhibitor of Spermidine Synthase

John R. Lakanen, Anthony Pegg, James K. Coward

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Abstract

The synthesis of a new class of multisubstrate adduct inhibitors of polyamine biosynthesis has been investigated. The first target compound, designed to inhibit spermidine synthase, was obtained and proved to be a very potent inhibitor of that enzyme. Two synthetic routes to effect the coupling of the polyamine spermidine to the nucleoside adenosine were studied. The first route involved a proposed Wittig or Julia olefination reaction to form the critical 5′-6′ carbon-carbon bond between the nucleoside and polyamine moieties This route failed due to a facile β-elimination of a portion of the side chain from a carbanion intermediate during either coupling reaction. A second route involved a reductive amination approach and proved to be successful. The new inhibitor, given the trivial name adenosylspermidine, is the most potent inhibitor of spermidine synthase prepared to date.

Original languageEnglish (US)
Pages (from-to)2714-2727
Number of pages14
JournalJournal of Medicinal Chemistry
Volume38
Issue number14
DOIs
Publication statusPublished - Jul 1 1995

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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