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

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Abstract

Herein, we report the design and synthesis of the novel 12-membered non-antibiotic macrolide (8R,9S)-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, (8R,9S)-4″,13-O-diacetyl-8,9-dihydro-6,9-epoxy-8,9-anhydropseudoerythromycin A (EM911), was found to be twice as effective as EM900.

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Acknowledgments

We thank Dr. Hideaki Hanaki and Dr. Hidehiro Matsui for measurement of MIC values of EM900 analogues. We also thank Ms. Akiko Nakagawa and Ms. Noriko Sato for various instrumental analyses.

References and notes (21)

  • S. Ōmura et al.

    Motilide, motilin-like macrolide

  • P.J. Atkins et al.

    Int. J. Pharmaceut.

    (1986)
  • H. Gouda et al.

    Bioorg. Med. Chem. Lett.

    (2006)
  • S. Pal

    Tetrahedron

    (2006)
  • J.M. McGuire et al.

    Antibiot. Chemother.

    (1952)
  • Z. Itoh et al.

    Am. J. Physiol.

    (1984)
  • S. Ōmura et al.

    J. Antibiot.

    (1985)
  • S. Ōmura et al.

    J. Med. Chem.

    (1987)
  • K. Tsuzuki et al.

    Chem. Pharm. Bull.

    (1989)
  • T. Sunazuka et al.

    Chem. Pharm. Bull.

    (1989)
There are more references available in the full text version of this article.

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