title: The use of novel C-methylated spermidine derivatives to investigate the regulation of polyamine metabolism.
abstract: The polyamines are organic polycations present at millimolar concentrations in eukaryotic cells where they participate in the regulation of vital cellular functions including proliferation and differentiation. Biological evaluation of rationally designed polyamine analogs is one of the cornerstones of polyamine research. Here we have synthesized and characterized novel C-methylated spermidine analogs, that is, 2-methylspermidine, 3-methylspermidine, and 8-methylspermidine. 3-Methylspermidine was found to be metabolically stable in DU145 cells, while 8-methylspermidine was a substrate for spermidine/spermine N(1)-acetyltransferase (SSAT) and 2-methylspermidine was a substrate for both SSAT and acetylpolyamine oxidase. All the analogs induced the splicing of the productive mRNA splice variant of SSAT, overcame growth arrest induced by 72-h treatment with ornithine decarboxylase (ODC) inhibitor α-difluoromethylornithine, and were transported via the polyamine transporter. Surprisingly, 2-methylspermidine was a weak downregulator of ODC activity in DU145 cells. Our data demonstrates that it is possible to radically alter the biochemical properties of a polyamine analog by changing the position of the methyl group.
authors.affiliation: AI Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, Kuopio, Finland. mervi.hyvonen@uef.fi
authors.forename: Mervi T
authors.initials: MT
authors.lastname: Hyvönen
authors.forename: Tuomo A
authors.initials: TA
authors.lastname: Keinänen
authors.forename: Maxim
authors.initials: M
authors.lastname: Khomutov
authors.forename: Alina
authors.initials: A
authors.lastname: Simonian
authors.forename: Janne
authors.initials: J
authors.lastname: Weisell
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Kochetkov
authors.forename: Jouko
authors.initials: J
authors.lastname: Vepsäläinen
authors.forename: Leena
authors.initials: L
authors.lastname: Alhonen
authors.forename: Alex R
authors.initials: AR
authors.lastname: Khomutov
mesh_terms: D000123:Acetyltransferases / Q000737:chemistry / Q000235:genetics; D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000518:Eflornithine / Q000494:pharmacology; D006801:Humans; D051379:Mice; D065108:Ornithine Decarboxylase Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000737:chemistry; D011073:Polyamines / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry; D013095:Spermidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D000518:Eflornithine; D065108:Ornithine Decarboxylase Inhibitors; D000587:Oxidoreductases Acting on CH-NH Group Donors; D011073:Polyamines; D012322:RNA Precursors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013095:Spermidine; D000099228:Diamine N-Acetyltransferase; C501650:N(1)-acetylpolyamine oxidase, human