title: Design, synthesis and biological evaluation of novel desmuramyldipeptide analogs.
abstract: A series of novel desmuramyldipeptides have been designed and synthesized as part of our search for therapeutically useful muramyldipeptide (MDP) analogs. Their immunomodulatory properties were initially assessed in vitro, evaluating their effect on lipopolysaccharide (LPS)-induced cytokine release in THP-1 cells. Following the initial screening, selected compounds were further investigated for immunomodulatory properties using LPS and phorbol 12-myristate 13-acetate (PMA)/ionomycin-stimulated human peripheral blood mononuclear cells. The results confirmed the immunomodulatory properties of some of the synthesized desmuramyldipeptide analogs. Taken together, presented data confirmed the immunostimulatory effect of compound 44, MDP derivative incorporating a pyrido-fused [1,2]-benzisothiazole moiety, while for compounds 32 and 39, indole scaffold-based derivatives of MDP, an immunosuppressive effect was observed. Further studies will be necessary to address their potential therapeutic use as immunomodulatory drugs, both as immunostimulants or anti-inflammatory agents.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
authors.forename: Žiga
authors.initials: Ž
authors.lastname: Jakopin
authors.forename: Emanuela
authors.initials: E
authors.lastname: Corsini
authors.forename: Martina
authors.initials: M
authors.lastname: Gobec
authors.forename: Irena
authors.initials: I
authors.lastname: Mlinarič-Raščan
authors.forename: Marija Sollner
authors.initials: MS
authors.lastname: Dolenc
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000138:chemical synthesis* / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D008070:Lipopolysaccharides; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate