s-adenosyl-3-methylthiopropylamine and 6-heptyne-2-5-diamine

(2R,5R)-6-heptyne-2,5-diamine (MAP; MDL 72175), a potent irreversible inhibitor of L-ornithine decarboxylase (ODC), possesses immunosuppressive activities in vitro as the result of inhibition of lymphocyte polyamine biosynthesis. The effects of MAP were now studied in vivo in MRL-lpr/lpr female mice, an animal model for human systemic lupus erythematosus (SLE). Administration of MAP (0.2% in drinking water; drug intake: 0.25-0.35 g/kg body weight/day) to female mice for 15 weeks, starting 8 weeks after birth, reduced by 47% the number of spleen cells, retarded development of lymphadenopathy and, at that time, markedly prolonged the survival of the mice. At week 23, MAP reduced plasma IgG concentrations by 50% whereas, in contrast, those of IgM were elevated 1.5-fold. No statistically significant effects of MAP were observed on plasma levels of anti-DNA autoantibodies although serum anti-RNP and anti-Sm titres tended downwards during treatment. Neither glomerular lesions nor proteinuria were improved by MAP administration. Finally chronic administration of MAP for 45 weeks prolonged the median survival time from 29.75 to 35.5 weeks.

Topics: Alkynes; Animals; Autoantibodies; Diamines; Female; Immunoglobulin G; Immunoglobulin M; Kidney Glomerulus; Lupus Erythematosus, Systemic; Lymphatic Diseases; Mice; Mice, Inbred Strains; Ornithine Decarboxylase Inhibitors; S-Adenosylmethionine; Splenomegaly; Time Factors

A highly sensitive HPLC method for the determination of decarboxylated S-adenosylmethionine (dc-SAM) by fluorometric detection was developed. The reaction of dc-SAM and its analogs with chloroacetaldehyde leads to the corresponding 1,N6-etheno derivatives. These highly fluorescent derivatives were fully characterized through their proton nuclear magnetic resonance spectra and/or mass spectra. This derivatization procedure has been applied to the analysis of dc-SAM in rat and human urine. After a simple cation exchange column prepurification, the urine extracts were derivatized with chloroacetaldehyde and analyzed by reversed-phase HPLC with fluorometric detection. The method allowed the determination of subpicomole amounts of dc-SAM and was shown to be highly reproducible with the use of decarboxylated S-adenosylethionine as internal standard. The application of the method to the analysis of urine of rats treated with MDL 72175, a potent ornithine decarboxylase inhibitor, showed that the dc-SAM levels increased in a dose-related fashion.

Topics: Alkynes; Animals; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Decarboxylation; Diamines; Humans; Male; Ornithine Decarboxylase Inhibitors; Rats; S-Adenosylmethionine; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet

Treatment with ornithine decarboxylase inhibitors leads to a marked increase of decarboxylated S-adenosylmethionine (dc-SAM) in various tissues, accompanied by the concomitant formation of a metabolite of dc-SAM. This metabolite has been isolated from rat prostate samples by a combination of chromatographic procedures. The use of IH-NMR and of fast atom bombardment mass spectometry and the synthesis of an authentic sample allowed the unambiguous characterization of this unknown compound as the N-acetyl derivative of dc-SAM. A reverse-phase high performance liquid chromatography procedure was developed for the separation of dc-SAM and its N-acetyl derivative into their diastereomers resulting from the chiral sulfonium group.

Topics: Acetylation; Alkynes; Animals; Chromatography, High Pressure Liquid; Diamines; Magnetic Resonance Spectroscopy; Male; Mass Spectrometry; Ornithine Decarboxylase Inhibitors; Prostate; Rats; S-Adenosylmethionine