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

The title compound (1c), was designed and synthesized based on mechanistic data concerning enzyme-catalyzed alkyl transfer reactions, applied in this case to aminopropyl transferases. The inhibition by 1c 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 1c. Similar, although not as marked, specifity between the two aminopropyltransferases was observed with the corresponding methyl sulfonium salt, 2c. Studies with structurally related compounds support the hypothesis that the strong inhibition of spermidine synthase by 1c derives from the incorporation in this compound of important features of the transition-state structure of this enzyme-catalyzed reaction.