Novel 12-membered non-antibiotic macrolides from erythromycin A; EM900 series as novel leads for anti-inflammatory and/or immunomodulatory agents

• Published in: Bioorganic & medicinal chemistry letters 2011-06, Vol.21 (11), p.3373-3376
• Main Authors: Sugawara, Akihiro, Sueki, Akito, Hirose, Tomoyasu, Nagai, Kenichiro, Gouda, Hiroaki, Hirono, Shuichi, Shima, Hideaki, Akagawa, Kiyoko S., Ōmura, Satoshi, Sunazuka, Toshiaki
• Format: Article
• Language: English
• Subjects: (8 R,9 S)-8,9-Dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A ( EM900); 14-Membered non-antibiotic macrolide; Anti-inflammatory agent; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; antibacterial properties; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Differentiation - drug effects; Cells, Cultured; chemistry; Cytotoxicity; Differentiation; Diffuse panbronchiolitis; Drug Design; Erythromycin; Erythromycin - analogs & derivatives; Erythromycin - chemical synthesis; Erythromycin - chemistry; Erythromycin - pharmacology; Humans; Immunologic Factors - chemical synthesis; Immunologic Factors - chemistry; Immunologic Factors - pharmacology; Immunomodulation; Immunomodulation - drug effects; Immunomodulators; Immunomodulatory agent; Inflammation; Macrolides - chemical synthesis; Macrolides - chemistry; Macrolides - pharmacology; Macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - immunology; Medical sciences; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Monocytes; Pharmacology. Drug treatments
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.04.004

▪ Herein, we report the design and synthesis of the novel 12-membered non-antibiotic macrolide (8 R,9 S)-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A ( EM900), which was found to be a potent anti-inflammatory and/or immunomodulatory agent, capable of promoting monocyte to macrophage differentiation. This molecule shows improved acid stability, does not exhibit any anti-bacterial activity and has relatively low cytotoxicity against THP-1 cells. In addition, one of its analogues, (8 R,9 S)-4″,13- O-diacetyl-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A ( EM911), was found to be twice as effective as EM900.