title: Impact of stereochemistry on the biological activity of novel oleandomycin derivatives.
abstract: A set of 8-methylene-, 8-methyl-, and 8-methyl-9-dihydro-oleandomycin derivatives having different combinations of stereochemistries at positions C-8 and/or C-9 have been prepared in a chemoselective and stereoselective manner and tested in vitro for antibacterial activity and inhibition of IL-6 production. Configurations of the stereocenters at C-8 and C-9 were determined using 2D NMR techniques. We have shown that change of stereochemistry at these positions can exert a major influence on antibacterial activity as well as IL-6 inhibition, providing novel macrolide derivatives with diminished antibacterial and potent anti-inflammatory activity. In addition, the anti-inflammatory activity observed in vitro was confirmed in an in vivo model of lipopolysaccharide-induced inflammation.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb, Prilaz b. Filipovića 29, Zagreb, Croatia.
authors.forename: Jurica
authors.initials: J
authors.lastname: Bauer
authors.forename: Mark
authors.initials: M
authors.lastname: Vine
authors.forename: Ilija
authors.initials: I
authors.lastname: Corić
authors.forename: Martina
authors.initials: M
authors.lastname: Bosnar
authors.forename: Ivanka
authors.initials: I
authors.lastname: Pašalić
authors.forename: Gordana
authors.initials: G
authors.lastname: Turkalj
authors.forename: Gorjana
authors.initials: G
authors.lastname: Lazarevski
authors.forename: Ognjen
authors.initials: O
authors.lastname: Culić
authors.forename: Goran
authors.initials: G
authors.lastname: Kragol
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009504:Neutrophils / Q000187:drug effects; D009827:Oleandomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009827:Oleandomycin