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 (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)-Et(2)-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.
Weisell
Janne
J
Department of Biosciences, University of Eastern Finland, Kuopio, Finland. Janne.Weisell@uef.fi
Hyvönen
Mervi T
MT
Häkkinen
Merja R
MR
Grigorenko
Nikolay A
NA
Pietilä
Marko
M
Lampinen
Anita
A
Kochetkov
Sergey N
SN
Alhonen
Leena
L
Vepsäläinen
Jouko
J
Keinänen
Tuomo A
TA
Khomutov
Alex R
AR
D000123:Acetyltransferases / Q000737:chemistry / Q000235:genetics; D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D051379:Mice; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D013096:Spermine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D015317:Biogenic Polyamines; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011994:Recombinant Proteins; D013096:Spermine; D000097667:Polyamine Oxidase; D000099228:Diamine N-Acetyltransferase; C502960:1,12-diamino-3,6,9-triazadodecane