title: The role of charge in polyamine analogue recognition.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, J. Hillis Miller Health Center, Gainesville 32610, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Bergeron
authors.forename: J S
authors.initials: JS
authors.lastname: McManis
authors.forename: W R
authors.initials: WR
authors.lastname: Weimar
authors.forename: K M
authors.initials: KM
authors.lastname: Schreier
authors.forename: F
authors.initials: F
authors.lastname: Gao
authors.forename: Q
authors.initials: Q
authors.lastname: Wu
authors.forename: J
authors.initials: J
authors.lastname: Ortiz-Ocasio
authors.forename: G R
authors.initials: GR
authors.lastname: Luchetta
authors.forename: C
authors.initials: C
authors.lastname: Porter
authors.forename: J R
authors.initials: JR
authors.lastname: Vinson
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors; D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors; D000818:Animals; D004563:Electrochemistry; D007700:Kinetics; D051379:Mice; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000737:chemistry* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D012437:Adenosylmethionine Decarboxylase; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D000099228:Diamine N-Acetyltransferase