Specific and potent inhibition of spermidine synthase by the transition-state analog,S-adenosyl-3-thio-1,8-diaminooctane

The title compound ($\text{1}\text{c}$), was designed and synthesized based on mechanistic data concerning enzyme-catalyzed alkyl transfer reactions, applied in this case to aminopropyl transferases. The inhibition by $\text{1}\text{c}$ of one such enzyme, spermidine synthase, was both potent (I₅₀ = 4 × 10^?7M) and specific. A closely related aminopropyltransferase, spermine synthase was only minimally affected by high concentrations of $\text{1}\text{c}$. Similar, although not as marked, specifity between the two aminopropyltransferases was observed with the corresponding methyl sulfonium salt, $\text{2}\text{c}$. Studies with structurally related compounds support the hypothesis that the strong inhibition of spermidine synthase by $\text{1}\text{c}$ derives from the incorporation in this compound of important features of the transition-state structure of this enzyme-catalyzed reaction.