title: Synthesis and biological characterization of novel charge-deficient spermine analogues.
abstract: 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.
authors.affiliation: Department of Biosciences, University of Eastern Finland, Kuopio, Finland. Janne.Weisell@uef.fi
authors.forename: Janne
authors.initials: J
authors.lastname: Weisell
authors.forename: Mervi T
authors.initials: MT
authors.lastname: Hyvönen
authors.forename: Merja R
authors.initials: MR
authors.lastname: Häkkinen
authors.forename: Nikolay A
authors.initials: NA
authors.lastname: Grigorenko
authors.forename: Marko
authors.initials: M
authors.lastname: Pietilä
authors.forename: Anita
authors.initials: A
authors.lastname: Lampinen
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Kochetkov
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
authors.forename: Jouko
authors.initials: J
authors.lastname: Vepsäläinen
authors.forename: Tuomo A
authors.initials: TA
authors.lastname: Keinänen
authors.forename: Alex R
authors.initials: AR
authors.lastname: Khomutov
mesh_terms: 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
chemical_list: 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