Synthesis and Biological Characterization of Novel Charge-Deficient Spermine Analogues

Biogenic polyamines, spermidine and spermine, are positively charged at physiological pH. They are present in all cells and essential for their growth and viability. Here we synthesized three novel derivatives of the isosteric charge-deficient spermine analogue 1,12-diamino-3,6,9-triazadodecane (Spm...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-08, Vol.53 (15), p.5738-5748
Main Authors: Weisell, Janne, Hyvönen, Mervi T, Häkkinen, Merja R, Grigorenko, Nikolay A, Pietilä, Marko, Lampinen, Anita, Kochetkov, Sergey N, Alhonen, Leena, Vepsäläinen, Jouko, Keinänen, Tuomo A, Khomutov, Alex R
Format: Article
Language:English
Subjects:
Acetyltransferases - chemistry
Acetyltransferases - genetics
Alternative Splicing - drug effects
Animals
Biogenic Polyamines - metabolism
Cell Line, Tumor
Cell Proliferation - drug effects
Fibroblasts - drug effects
Fibroblasts - metabolism
Humans
Kinetics
Mice
Oxidoreductases Acting on CH-NH Group Donors - chemistry
Polyamine Oxidase
Recombinant Proteins - chemistry
Spermine - analogs & derivatives
Spermine - chemical synthesis
Spermine - chemistry
Spermine - pharmacology
Structure-Activity Relationship
Substrate Specificity
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Summary:Biogenic polyamines, spermidine and spermine, are positively charged at physiological pH. They are present in all cells and essential for their growth and viability. Here we synthesized three novel derivatives of the isosteric charge-deficient spermine analogue 1,12-diamino-3,6,9-triazadodecane (SpmTrien, 5a) that are N 1-Ac-SpmTrien (5c), N 12-Ac-SpmTrien (5b), and N 1,N 12-diethyl-1,12-diamino-3,6,9-triazadodecane (N 1,N 12-Et2-SpmTrien, 5d). 5a and 5d readily accumulated in DU145 cells at the same concentration range as natural polyamines and moderately competed for the uptake with putrescine (1) but not with spermine (4a) or spermidine (2). 5a efficiently down-regulated ornithine decarboxylase and decreased polyamine levels, while 5d proved to be inefficient, compared with N 1,N 11 -diethylnorspermine (6). None of the tested analogues were substrates for human recombinant spermine oxidase, but those having free aminoterminus, including 1,8-diamino-3,6-diazaoctane (Trien, 3a), were acetylated by mouse recombinant spermidine/spermine N 1-acetyltransferase. 5a was acetylated to 5c and 5b, and the latter was further metabolized by acetylpolyamine oxidase to 3a, a drug used to treat Wilson’s disease. Thus, 5a is a bioactive precursor of 3a with enhanced bioavailability.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm100439p