The Role of Charge in Polyamine Analogue Recognition

Article abstract of DOI:10.1021/jm00013a003

A series of analogues and homologues of N¹,N¹²-diethylspermine (DESPM) was synthesized, and their biological properties were evaluated.These tetraamines include a simple linear analogue of DESPM, N¹,N¹²-bis(2,2,2-trifluoroethyl)spermine (FDESPM), the cyclic analogues of DESPM, N,N'-bis(4-piperidinylmethyl)-1,4-diaminobutane and N,N'-bis<2-(4-piperidinyl)ethyl>-1,4-diaminobutane , and their aromatic counterparts, N,N'-bis(4-pyridylmethyl)-1,4-diaminobutane and N,N'-bis<2-(4-pyridyl)ethyl>-1,4-diaminobutane .The analogues FDESPM, PIP(4,4,4), and PYR(4,4,4) have distances between their nitrogen atoms almost identical to those of DESPM.The longer analogues PIP(5,4,5) and PYR(5,4,5) are very similar in the spacing of their amino groups.However, the pK_a of the nitrogens in the groups differ; thus, the extent of protonation and the charge characteristics among the members of the groups differ.A comparison of the biological properties of these compounds clearly demonstrates that the tetraamines must be charged to be "recognized" by the cell.Analogues with low nitrogen pK_a's such that the nitrogens are poorly protonated at physiological pH do not compete well with spermidine for uptake and, as expected, have high 96 h IC50 values and have little effect on S-adenosylmethionine decarboxylase, ornithine decarboxylase, and spermidine/spermine N¹-acetyltransferase activities and on intracellular polyamine pools.