title: Non-antibiotic 12-membered macrolides: design, synthesis and biological evaluation in a cigarette-smoking model.
abstract: The 14-membered macrolide erythromycin A expresses three distinct biological properties, including antibacterial activity, gastrointestinal motor-stimulating activity and anti-inflammatory and/or immunomodulatory effects. Although low-dose, long-term therapy using 14- and 15-membered macrolides displaying anti-inflammatory and/or immunomodulatory activity effectively treats diffuse panbronchiolitis and chronic sinusitis, bacterial resistance may emerge. To address this issue, we developed the 12-membered non-antibiotic macrolide (8R,9S)-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM900) that promotes monocyte to macrophage differentiation, a marker for anti-inflammatory and/or immunomodulatory effects, without possessing antibacterial activity. In this article, we report that the new macrolide derivative (8R,9S) -de(3'-N-methyl)-3'-N-(p-chlorobenzyl)-de(3-O-cladinosyl)-3-dehydro-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A 12,13-carbonate (EM939) exhibited stronger promotive activity for monocyte to macrophage differentiation than that of the parent compound EM900 in addition to reduced cytotoxicity toward THP-1 cells and antibacterial inactivity. In a cigarette-smoking model used to simulate chronic obstructive pulmonary disease (COPD), the EM900 derivatives significantly attenuated lung and alveolar inflations, functionally and histologically, via oral administration. Because of these marked therapeutic effects, non-antibiotic EM900 derivatives may become central to the treatment of chronic inflammatory diseases such as COPD.
authors.affiliation: The Kitasato Institute and Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sugawara
authors.affiliation: The Kitasato Institute and Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Shima
authors.affiliation: The Kitasato Institute and Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Sueki
authors.affiliation: The Kitasato Institute and Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Hirose
authors.affiliation: The Kitasato Institute and Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Matsui
authors.affiliation: The Kitasato Institute and Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakano
authors.affiliation: The Kitasato Institute and Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hanaki
authors.affiliation: The Kitasato Institute and Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Kiyoko S
authors.initials: KS
authors.lastname: Akagawa
authors.affiliation: The Kitasato Institute and Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ōmura
authors.affiliation: The Kitasato Institute and Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sunazuka
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D004917:Erythromycin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D008168:Lung / Q000473:pathology; D018942:Macrolides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008826:Microbial Sensitivity Tests; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000209:etiology; D012907:Smoking / Q000009:adverse effects
chemical_list: C560918:(8R,9S)-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A; D000893:Anti-Inflammatory Agents; C000614360:EM939; D018942:Macrolides; D004917:Erythromycin