Synthesis and evaluation of some stable multisubstrate adducts as specific inhibitors of spermidine synthase

Abstract

A new series of aminopropyltransferase inhibitors was designed in which the nucleophilic aminopropyl acceptor is attached to the aminopropyl donor, S-adenosyl-1-(methylthio)-3-propylamine (decarboxylated S-adenosylmethionine), to form a multisubstrate adduct. S-Adenosyl-1,8-diamino-3-thiooctane and the corresponding methylsulfonium salt were synthesized. Several compounds of this type were assayed as inhibitors of spermidine synthase, and both were potent inhibitors of the enzyme. The thioether is the most potent inhibitor of spermidine synthase described to date and is almost totally devoid of inhibitory activity against the closely related aminopropyltransferase, spermine synthase. This type of compound should have use as a specific inhibitor of spermidine biosynthesis in vivo.