The role of charge in polyamine analog recognition

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-piper...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 38; no. 13; pp. 2278 - 2285
Main Authors:	Bergeron, Raymond J, McManis, James S, Weimar, William R, Schreier, Kathy, Gao, Fenglan, Wu, Qianhong, Ortiz-Ocasio, Jackqueline, Luchetta, Gabriel R, Porter, Carl, Vinson, J. R. Timothy
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 01-06-1995
Subjects:	Acetyltransferases - antagonists & inhibitors Adenosylmethionine Decarboxylase - antagonists & inhibitors Animals Antineoplastic agents Biological and medical sciences Electrochemistry General aspects Kinetics Medical sciences Mice Ornithine Decarboxylase Inhibitors Pharmacology. Drug treatments Polyamines - chemistry Polyamines - pharmacology Tumor Cells, Cultured Antineoplastic agent Acyltransferases Polyamine Enzyme Aliphatic compound Transferases Enzyme inhibitor Lyases L1210-Leukemia Ornithine decarboxylase In vitro Pyridine derivatives Adenosylmethionine decarboxylase Carbon-carbon lyases Structure activity relation Carboxy-lyases Established cell line Piperidine derivatives Diamine N-acetyltransferase Chemical synthesis
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Summary:	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 [PIP(4,4,4)] and N,N'-bis[2-(4-piperidinyl)ethyl]-1,4-diaminobutane [PIP(5,4,5)], and their aromatic counterparts, N,N'-bis-(4-pyridylmethyl)-1,4-diaminobutane [PYR(4,4,4)] and N,N'-bis[2-(4-pyridyl)ethyl]-1,4-diaminobutane [PYR(5,4,5)]. 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 pKa 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 pKa'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.
Bibliography:	ark:/67375/TPS-TC6GZHJF-H istex:F4FAA465EBC2419A6B4423C52E264802BE175F6B ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm00013a003