Synthesis and biochemical evaluation of adenosylspermidine, a nucleoside-polyamine adduct inhibitor of spermidine synthase.
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 beta-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.
Lakanen
J R
JR
Department of Chemistry, University of Michigan, Ann Arbor 48109-1055, USA.
Pegg
A E
AE
Coward
J K
JK
D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D000882:Haplorhini; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013095:Spermidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011436:Spermidine Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
C094871:adenosylspermidine; D011436:Spermidine Synthase; D000241:Adenosine; D013095:Spermidine