title: Investigations on the immunosuppressive activity of derivatives of mycophenolic acid in immature dendritic cells.
abstract: The main activity of mycophenolic acid 1 (MPA) and its analogs is the inhibition of proliferation of T cells. Here, we hypothesized that MPA and its conjugates inhibits also the activity of antigen-presenting cells (APC) including dendritic cells (DCs). We tested the effect of novel amino acid derivatives of MPA and conjugates of MPA with acridines/acridones on DCs by flow cytometry, ELISA and MLR assay. Both acridines/acridone derivatives could inhibit the maturation of DC, as shown by the decreased expression of B7 family receptors. It was confirmed in the mixed leucocyte reaction (MLR), in which T cells challenged with DCs pretreated with the analogs showed decreased proliferation and reduced cytokine secretion. The most interesting activity in this series of studies, that is, the suppression of CD86 receptor expression, decreased cytokine production and suppressed mixed leucocyte reaction, exhibited (mycophenoyl-N-3-propyl)-9-acridone-4-carboxamide ester 5a and (mycophenoyl-N-5-pentyl)-9-acridone-4-carboxamide ester 5b. These compounds reduced also the secretion of IL-2 and IL-15. In addition, they increased secretion of suppressive IL-10. Equally promising results were obtained for the N-mycophenoyl-D-glutamic acid 4b, which previously gave the highest value of selectivity. Acridone derivatives of MPA are therefore good immunosuppressive drug candidates for further testing.
authors.affiliation: Department of Organic Chemistry, Gdansk University of Technology, ul. G. Narutowicza 11/12, 80-233 Gdansk, Poland; Department of Clinical Immunology and Transplantology, Medical University of Gdansk, ul. Debinki 7, 80-211 Gdansk, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Iwaszkiewicz-Grzes
authors.affiliation: Department of Organic Chemistry, Gdansk University of Technology, ul. G. Narutowicza 11/12, 80-233 Gdansk, Poland. Electronic address: grzchole@pg.gda.pl.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Cholewinski
authors.affiliation: Department of Analytical Chemistry, Gdansk University of Technology, ul. G. Narutowicza 11/12, 80-233 Gdansk, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Kot-Wasik
authors.affiliation: Department of Clinical Immunology and Transplantology, Medical University of Gdansk, ul. Debinki 7, 80-211 Gdansk, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Trzonkowski
authors.affiliation: Department of Organic Chemistry, Gdansk University of Technology, ul. G. Narutowicza 11/12, 80-233 Gdansk, Poland.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Dzierzbicka
mesh_terms: D054831:Acridones / Q000737:chemistry; D001327:Autoimmune Diseases / Q000188:drug therapy*; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006084:Graft Rejection / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D016377:Organ Transplantation; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D054831:Acridones; D051940:B7-2 Antigen; C508609:IL10 protein, human; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016753:Interleukin-10; D009173:Mycophenolic Acid
keywords: Acridines; Acridones; Amino acids; Dendritic cells; Immunosuppressants; Mycophenolic acid