Synthesis and Evaluation of Acyl-Chain- and Galactose-6′′-Modified Analogues of α-GalCer for NKT Cell Activation

Authors

  • Ming-Han Hsieh,

    1. School of Pharmacy, College of Medicine, National Taiwan University, 1, Jen-Ai Road, Section 1, Taipei 100 (Taiwan)
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Dr. Jung-Tung Hung,

    1. Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115 (Taiwan)
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Ya-Wen Liw,

    1. School of Pharmacy, College of Medicine, National Taiwan University, 1, Jen-Ai Road, Section 1, Taipei 100 (Taiwan)
    Search for more papers by this author
  • Yin-Jen Lu,

    1. School of Pharmacy, College of Medicine, National Taiwan University, 1, Jen-Ai Road, Section 1, Taipei 100 (Taiwan)
    Search for more papers by this author
  • Prof. Dr. Chi-Huey Wong,

    Corresponding author
    1. Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115 (Taiwan)
    • Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115 (Taiwan)
    Search for more papers by this author
  • Prof. Dr. Alice L. Yu,

    Corresponding author
    1. Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115 (Taiwan)
    • Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115 (Taiwan)
    Search for more papers by this author
  • Prof. Dr. Pi-Hui Liang

    Corresponding author
    1. School of Pharmacy, College of Medicine, National Taiwan University, 1, Jen-Ai Road, Section 1, Taipei 100 (Taiwan)
    2. Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115 (Taiwan)
    • School of Pharmacy, College of Medicine, National Taiwan University, 1, Jen-Ai Road, Section 1, Taipei 100 (Taiwan)
    Search for more papers by this author

Abstract

α-GalCer is an immunostimulating glycolipid that binds to CD1d molecules and activates invariant natural killer T (iNKT) cells. Here we report a scaled-up synthesis of α-GalCer analogues with modifications in the acyl side chain and/or at the galactose 6′′-position, together with their evaluation in vitro and in vivo. Analogues containing 11-phenylundecanoyl acyl side chains with aromatic substitutions (14, 1621) and Gal-6′′-phenylacetamide-substituted α-GalCer analogues bearing p-nitro- (32), p-tert-butyl (34), or o-, m-, or p-methyl groups (4042) displayed higher IFN-γ/IL-4 secretion ratios than α-GalCer in vitro. In mice, compound 16, with an 11-(3,4-difluorophenyl)undecanoyl acyl chain, induced significant proliferation of NK and DC cells, which should be beneficial in killing tumors and priming the immune response. These new glycolipids might prove useful as adjuvants or anticancer agents.

Ancillary