title: Inhibition of macrophage activation and suppression of graft rejection by DTCM-glutarimide, a novel piperidine derived from the antibiotic 9-methylstreptimidone.
abstract: OBJECTIVE
  We have previously synthesized a novel piperidine compound, 3-[(dodecylthiocarbonyl)methyl]glutarimide (DTCM-glutarimide), that inhibits LPS-induced NO production, and in the present research we studied further the anti-inflammatory activity of DTCM-glutarimide in a macrophage cell line and in mice bearing transplanted hearts.
  
  
  METHODS
  Mouse macrophage-like RAW264.7 cells were employed for the evaluation of cellular inflammatory activity. DTCM-glutarimide was synthesized in our laboratory. The AP-1 activity was measured by nuclear translocation and phosphorylation. For the heart transplantation experiment, male C57BL/6 (H-2b) and BALB/c (H-2d) mice were used as donor and recipient, respectively. DTCM-glutarimide was administered intraperitoneally.
  
  
  RESULTS
  DTCM-glutarimide inhibited the LPS-induced expression of iNOS and COX-2 in macrophages; but, unexpectedly, it did not inhibit LPS-induced NF-κB activation. Instead, it inhibited the nuclear translocation of both c-Jun and c-Fos. It also inhibited LPS-induced c-Jun phosphorylation. Moreover, it inhibited the mixed lymphocyte reaction in primary cultures of mouse spleen cells; and furthermore, in mice it prolonged the graft survival in heart transplantation experiments.
  
  
  CONCLUSIONS
  The novel piperidine compound, DTCM-glutarimide, was found to be a new inhibitor of macrophage activation, inhibiting AP-1 activity. It also inhibited graft rejection in mice, and thus may be a candidate for an anti-inflammatory agent.
authors.affiliation: Center for Chemical Biology, School of Fundamental Science and Technology, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, 223-0061, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeiri
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tachibana
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kaneda
authors.forename: Ayumi
authors.initials: A
authors.lastname: Ito
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Shigeru
authors.initials: S
authors.lastname: Nishiyama
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Goto
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Yamashita
authors.forename: Susumu
authors.initials: S
authors.lastname: Shibasaki
authors.forename: Gentaro
authors.initials: G
authors.lastname: Hirokata
authors.forename: Michitaka
authors.initials: M
authors.lastname: Ozaki
authors.forename: Satoru
authors.initials: S
authors.lastname: Todo
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010881:Piperidones / Q000737:chemistry* / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010881:Piperidones; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; C008497:9-methylstreptimidone; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D048031:JNK Mitogen-Activated Protein Kinases; C007864:glutarimide