Novel isosteric charge-deficient spermine analogue--1,12-diamino-3,6,9-triazadodecane: synthesis, pK(a) measurement and biological activity.
Ionic interactions are essential for the biological functions of the polyamines spermidine and spermine in mammalian physiology. Here, we describe a simple gram scale method to prepare 1,12-diamino-3,6,9-triazadodecane (SpmTrien), an isosteric charge-deficient spermine analogue. The protonation sites of SpmTrien were determined at pH range of 2.2-11.0 using two-dimensional (1)H-(15)N NMR spectroscopy, which proved to be more feasible than conventional methods. The macroscopic pK(a) values of SpmTrien (3.3, 6.3, 8.5, 9.5 and 10.3) are significantly lower than those of 1,12-diamino-4,9-diazadodecane (spermine). The effects of SpmTrien and its parent molecule, 1,8-diamino-3,6-diazaoctane (Trien), on cell growth and polyamine metabolism were investigated in DU145 prostate carcinoma cells. SpmTrien downregulated the biosynthetic enzymes ornithine decarboxylase (ODC) and S-adenosyl-L: -methionine decarboxylase and decreased intracellular polyamine levels, whereas the effects of Trien alone were minor. Interestingly, both SpmTrien and Trien were able to partially overcome growth arrest induced by an ODC inhibitor, alpha-difluoromethylornithine, indicating that they are able to mimic some functions of the natural polyamines. Thus, SpmTrien is a novel tool to influence polyamine interaction sites at the molecular level and offers a new means to study the contribution of the protonation of spermine amino group(s) in the regulation of polyamine-dependent biological processes.
Weisell
Janne
J
Laboratory of Chemistry, Department of Biosciences, University of Kuopio, Kuopio, Finland. Janne.Weisell@uku.fi
Hyvönen
Mervi T
MT
Vepsäläinen
Jouko
J
Alhonen
Leena
L
Keinänen
Tuomo A
TA
Khomutov
Alex R
AR
Soininen
Pasi
P
D002262:Carboxy-Lyases / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C502960:1,12-diamino-3,6,9-triazadodecane; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D013096:Spermine; D002262:Carboxy-Lyases; D009955:Ornithine Decarboxylase; C066836:methionine decarboxylase