Alpha-methyl polyamines: efficient synthesis and tolerance studies in vivo and in vitro. First evidence for dormant stereospecificity of polyamine oxidase.
Efficient syntheses of metabolically stable alpha-methylspermidine 1, alpha-methylspermine 2, and bis-alpha,alpha'-methylated spermine 3 starting from ethyl 3-aminobutyrate are described. The biological tolerance for these compounds was tested in wild-type mice and transgenic mice carrying the metallothionein promoter-driven spermidine/spermine N(1)-acetyltransferase gene (MT-SSAT). The efficient substitution of natural polyamines by their derivatives was confirmed in vivo with the rats harboring the same MT-SSAT transgene and in vitro with the immortalized fibroblasts derived from these animals. Enantiomers of previously unknown 1-amino-8-acetamido-5-azanonane dihydrochloride 4 were synthesized starting from enantiomerically pure (R)- and (S)-alaninols. The studies with recombinant human polyamine oxidase (PAO) showed that PAO (usually splits achiral substrates) strongly favors the (R)-isomer of 4 that demonstrates for the first time that the enzyme has hidden potency for stereospecificity.
Järvinen
Aki J
AJ
Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland.
Cerrada-Gimenez
Marc
M
Grigorenko
Nikolay A
NA
Khomutov
Alex R
AR
Vepsäläinen
Jouko J
JJ
Sinervirta
Riitta M
RM
Keinänen
Tuomo A
TA
Alhonen
Leena I
LI
Jänne
Juhani E
JE
D000818:Animals; D030801:Animals, Genetically Modified; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000187:drug effects* / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects; D051381:Rats; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D013095:Spermidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013096:Spermine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D000097667:Polyamine Oxidase
D000587:Oxidoreductases Acting on CH-NH Group Donors; D011994:Recombinant Proteins; D013095:Spermidine; D013096:Spermine; D000097667:Polyamine Oxidase; C502957:alpha-methylspermine; C073193:1-methylspermidine; C073195:1,12-dimethylspermine