title: Synthesis and in vitro evaluation of anti-inflammatory activity of ester and amine derivatives of indoline in RAW 264.7 and peritoneal macrophages.
abstract: A prolonged increase in pro-inflammatory cytokines, TNF-α and IL-6 occurs in inflammatory diseases. Although existing therapies like steroids and TNF-α antagonists are effective they may cause serious adverse effects. We describe the preparation and evaluation for anti-inflammatory activity of 11 novel derivatives of indoline carbamates with a propionic ester, 2-aminoethyl, 3-aminopropyl 2-(dimethylamino)ethyl or 3-(dimethylamino)propyl group in positions 3 or 1. Compounds 25, 26 and 29 were previously shown to inhibit acetylcholinesterase with IC50s ranging from 0.4 to 55μM and to prevent cytotoxicity induced by reactive oxygen species in a concentration range of 100pM-1μM. Compounds 25, 26, 29, 9, 10, 17 and 18, reduced NO, TNF-α and IL-6 at concentrations of 1-10pM in LPS-activated RAW-264.7 and mouse peritoneal macrophages. The reduction in cytokines by compound 25 was associated with an increase in IκBα degradation and a decrease in the phosphorylation of p38 but not that of ERK.
  
  
  CONCLUSIONS
  Indoline derivatives substituted at position 3 with chains carrying ester or amino groups may have potential for the treatment of chronic inflammatory and neurodegenerative diseases.
authors.affiliation: Department of Chemistry, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Furman
authors.affiliation: Department of Chemistry, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Elinor
authors.initials: E
authors.lastname: Nissim-Bardugo
authors.affiliation: Department of Chemistry, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Shani
authors.initials: S
authors.lastname: Zeeli
authors.affiliation: Department of Chemistry, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Weitman
authors.affiliation: Department of Chemistry, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Abraham
authors.initials: A
authors.lastname: Nudelman
authors.affiliation: Institute of Drug Research, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem 91120, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Finkin-Groner
authors.affiliation: Institute of Drug Research, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem 91120, Israel.
authors.forename: Dorit
authors.initials: D
authors.lastname: Moradov
authors.affiliation: Institute of Drug Research, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem 91120, Israel.
authors.forename: Helena
authors.initials: H
authors.lastname: Shifrin
authors.affiliation: Institute of Drug Research, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem 91120, Israel.
authors.forename: Donna
authors.initials: D
authors.lastname: Schorer-Apelbaum
authors.affiliation: Institute of Drug Research, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem 91120, Israel. Electronic address: martar@ekmd.huji.ac.il.
authors.forename: Marta
authors.initials: M
authors.lastname: Weinstock
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000588:Amines; D000893:Anti-Inflammatory Agents; D004952:Esters; D007211:Indoles; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C057812:indoline; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Acetylcholinesterase inhibition; IL-6; Nitric oxide; TNF-α; p38