Design and Synthesis of Inhibitors of N8-Acetylspermidine Deacetylase

Article abstract of DOI:10.1021/jm00125a010

Analogues of N⁸-acetylspermidine (1) were synthesized as potential inhibitors of the cytoplasmic enzyme N⁸-acetylspermidine deacetylase.The compounds were assayed for their ability to inhibit the deacetylation of 1 in a cytosolic fraction from rat liver.The apparent K_i values were determined by Dixon plots.The apparent K_m of 1 for this enzyme is 11.0 μM.It was found that compounds which lacked the N1 or the N4 of spermidine were less effective at competing for the enzyme than the substrate.All compounds with acyl substituents larger than acetyl were less potent inhibitors than the corresponding acetylated derivatives.Thus, the enzyme's selectivity as a deacetylase seems to be attributable to steric hindrance which occurs with larger acyl groups.The N8 of the substrate is not essential for its binding to the enzyme.Replacement of N8 with a CH2 group gives the ketone 14, which has an apparent K_i of 0.18 μM, 60-fold lower than the apparent K_m of 1.The inhibitory potency of 14 is retained in compounds substituted at the N1 position.The N¹,N¹-dimethyl and the N¹,N¹-diethyl analogues (15 and 16) of 14 have apparent K_i values of 0.096 and 0.10 μM, respectively.These agents are the most potent inhibitors of N⁸-acetylspermidine deacetylase reported, and they are promising tools for use in determining the physiological function of N⁸-acetylspermidine deacetylase.