ACS Medicinal Chemistry Letters
Letter
(13) Morita, M.; Motoki, K.; Akimoto, K.; Natori, T.; Sakai, T.; Sawa,
E.; Yamaji, K.; Koezuka, Y.; Kobayashi, E.; Fukushima, H. Structure-
activity relationship of α-galactosylceramides against B16-bearing mice.
J. Med. Chem. 1995, 38, 2176−2187.
(14) Takeda, K.; Hayakawa, Y.; Van Kaer, L.; Matsuda, H.; Yagita,
H.; Okumura, K. Critical contribution of liver natural killer T cells to a
murine model of hepatitis. Proc. Natl. Acad. Sci. U.S.A. 2000, 97,
5498−5530.
(15) Hayakawa, Y.; Rovero, S.; Forni, G.; Smyth, M. J. α-
galactosylceramide (KRN7000) suppression of chemical- and
oncogene-dependent carcinogenesis. Proc. Natl. Acad. Sci. U.S.A.
2003, 100, 9464−9469.
(16) Chang, D. H.; Osman, K.; Connolly, J.; Kukreja, A.; Krasovsky,
J.; Pack, M.; Hutchinson, A.; Geller, M.; Liu, N.; Annable, R.; Shay, J.;
Kirchhoff, K.; Nishi, N.; Ando, Y.; Hayashi, K.; Hassoun, H.; Steinman,
R. M.; Dhodapkar, M. V. Sustained expansion of NKT cells and
antigen-specific T cells after injection of α-galactosyl-ceramide loaded
mature dendritic cells in cancer patients. J. Exp. Med. 2005, 201,
1503−1517.
(17) Uchida, T.; Horiguchi, S.; Tanaka, Y.; Yamamoto, H.; Kunii, N.;
Motohashi, S.; Taniguchi, M.; Nakayama, T.; Okamoto, Y. Phase I
study of α-galactosylceramide-pulsed antigen presenting cells admin-
istration to the nasal submucosa in unresectable or recurrent head and
neck cancer. Cancer Immunol. Immun. 2008, 57, 337−345.
(18) Ko, S. Y.; Ko, H. J.; Chang, W. S.; Park, S. H.; Kweon, M. N.;
Kang, C. Y. α-Galactosylceramide can act as a nasal vaccine adjuvant
inducing protective immune responses against viral infection and
tumor. J. Immunol. 2005, 175, 3309−3317.
(19) Kaer, L. V. α-Galactosylceramide therapy for autoimmune
diseases: prospects and obstacles. Nat. Rev. Immunol. 2005, 5, 31−42.
(20) Sharif, S.; Arreaza, G. A.; Zucker, P.; Mi, Q.-S.; Sondhi, J.;
Naidenko, O. V.; Kronenberg, M.; Koezuka, Y.; Delovitch, T. L.;
Gombert, J.-M.; Leite-de-Moraes, M.; Gouarin, C.; Zhu, R.; Hameg,
A.; Nakayama, T.; Taniguchi, M.; Lepault, F.; Lehuen, A.; Bach, J.-F.;
Herbelin, A. Activation of natural killer T cells by α-galactosylceramide
treatment prevents the onset and recurrence of autoimmune Type 1
diabetes. Nat. Med. 2001, 7, 1057−1062.
(21) Burdin, N.; Brossay, L.; Kronenberg, M. Immunization with α-
galactosylceramide polarizes CD1-reactive NK T cells towards Th2
cytokine synthesis. Eur. J. Immunol. 1999, 29, 2014−2025.
(22) Berkers, C. R.; Ovaa, H. Immunotherapeutic potential for
ceramide-based activators of iNKT cells. Trends Pharmacol. Sci. 2005,
26, 252−257.
(23) Banchet-Cadeddu, A.; Henon, E.; Dauchez, M.; Renault, J.-H.;
Monneaux, F.; Haudrechy, A. The stimulating adventure of KRN
7000. Org. Biomol. Chem. 2011, 9, 3080−3104.
(24) Tashiro, T. Structure-activity relationship studies of novel
glycosphingolipids that stimulate natural killer T-cells. Biosci.
Biotechnol. Biochem. 2012, 76, 1055−1067.
(25) Baek, D. J.; Seo, J. H.; Lim, C.; Kim, J. H.; Chung, D. H.; Cho,
W. J.; Kang, C. Y.; Kim, S. The 3-deoxy analogue of α-GalCer:
disclosing the role of the 4-hydroxyl group for CD1d-mediated NKT
cell activation. ACS Med. Chem. Lett. 2011, 2, 544−548.
(26) Kim, Y.; Kim, J.; Oh, K.; Lee, D. S.; Park, S. B. Heteroaromatic
moieties in the sphingosine backbone of α-galactosylceramides for
noncovalent interactions with CD1d. ACS Med. Chem. Lett. 2012, 3,
151−154.
(27) Lim, C.; Kim, J. H.; Baek, D. J.; Lee, J. Y.; Cho, M.; Lee, Y. S.;
Kang, C. Y.; Chung, D. H.; Cho, W. J.; Kim, S. Design and evaluation
of ω-hydroxy fatty acids containing α-GalCer analogues for CD1d-
mediated NKT cell activation. ACS Med. Chem. Lett. 2014, 5, 331−
335.
(28) Chang, Y. J.; Huang, J. R.; Tsai, Y. C.; Hung, J. T.; Wu, D.;
Fujio, M.; Wong, C. H.; Yu, A. L. Potent immune-modulating and
anticancer effects of NKT cell stimulatory glycolipids. Proc. Natl. Acad.
Sci. U.S.A. 2007, 104, 10299−10304.
(29) Brossay, L.; Naidenko, O.; Burdin, N.; Matsuda, J.; Sakai, T.;
Kronenberg, M. Cutting edge: structural requirements for galacto-
Funding
This work was supported in partial by the MOST of China
(Projects 2012ZX09502001 and 2012CB822101) and NNSF of
China (Projects 21372254, 21321004, and 31322020). We
thank Dr. Yuan Li and Dr. Shao-Xiang Xiong from Institute of
Chemistry Chinese Academy of Sciences for mass spectrum
performance.
Notes
The authors declare no competing financial interest.
ABBREVIATIONS
■
KRN7000, (2S,3S,4R)-1-O-(α-D-galactopyranosyl)-2-(N-hexa-
cosanoylamino)-1,3,4-octadecanetriol; iNKT, invariant natural
killer T cells; Th1, T helper 1; Th2, T helper 1; IFN-γ,
interferon γ; TNF-α, tumor necrosis factor-α; IF-2, interleukin-
2; IL-4, interleukin-4; IL-10, interleukin-10; α-GalCer, α-
galactosylceramide; TCR, T cell receptor; MS, mass spectrum;
PBS-25, (2S,3S,4R)-1-O-(α-D-galacto pyranosyl)-2-(N-octanoy-
lamino)-1,3,4-octadecanetriol; α-GalCer 566, (2S,3S,4R)-1-O-
(α-D-galactopyranosyl)-2-(N-tetradecanoylamino)-1,3,4-octade-
canetriol; NEt3, triethylamine; THF, tetrahydrofuran; CCl3CN,
trichloroacetonitrile; DBU, 1,8-diazabicyclo(5.4.0)undec-7-ene;
TMSOTf, trimethylsilyl trifluoromethanesulfonate; ELISA,
enzyme linked immunosorbent assay; BFA, brefeldin A; APC,
adenomatous polyposis coli; PMA-I, phorbol 12-myristate 13-
acetate ionomycin
REFERENCES
■
(1) Bendelac, A.; Savage, P. B.; Teyton, L. The biology of NKT cells.
Annu. Rev. Immunol. 2007, 25, 297−336.
(2) Hong, C.; Park, S.-H. Application of natural killer T cells in
antitumor immunotherapy. Crit. Rev. Immun. 2007, 27, 511−525.
(3) Motohashi, S.; Nakayama, T. Clinical applications of natural killer
T cell−based immunotherapy for cancer. Cancer Sci. 2008, 99, 638−
645.
(4) Berzofsky, J. A.; Terabe, M. The contrasting roles of NKT cells in
tumor immunity. Curr. Mol. Med. 2009, 9, 667−672.
(5) Behar, S. M.; Porcelli, S. A. CD1-restricted T cells in host defense
to infectious diseases. Curr. Top. Microbiol. Immun. 2007, 314, 215−
250.
(6) Tupin, E.; Kinjo, Y.; Kronenberg, M. The unique role of natural
killer T cells in the response to microorganisms. Nat. Rev. Microbiol.
2007, 5, 405−417.
(7) Natori, T.; Morita, M.; Akimoto, K.; Koezuka, Y. Agelasphins,
novel antitumor and immunostimulatory cerebrosides from the marine
sponge Agelas mauritianus. Tetrahedron 1994, 50, 2771−2784.
(8) Crowe, N. Y.; Uldrich, A. P.; Kyparissoudis, K.; Hammond, K. J.
L.; Hayakawa, Y.; Sidobre, S.; Keating, R.; Kronenberg, M.; Smyth, M.
J.; Godfrey, D. I. Glycolipid antigen drives rapid expansion and
sustained cytokine production by NKT cells. J. Immunol. 2003, 171,
4020−4027.
(9) Carnaud, C.; Lee, D.; Donnars, O.; Park, S.-H.; Beavis, A.;
Koezuka, Y.; Bendelac, A. Cutting edge: cross-talk between cells of the
innate immune system: NKT cells rapidly activate NK cells. J.
Immunol. 1999, 163, 4647−4650.
(10) Godfrey, D. I.; MacDonald, H. R.; Kronenberg, M.; Smyth, M.
J.; VanKaer, L. NKT cells: what’s in a name? Nat. Rev. Immunol. 2004,
4, 231−237.
(11) Gonzalez-Aseguinolaza, G.; VanKaer, L.; Bergmann, C. C.;
Wilson, J. M.; Schmieg, J.; Kronenberg, M.; Nakayama, T.; Taniguchi,
M.; Koezuka, Y.; Tsuji, M. Natural killer T cell ligand α-
galactosylceramide enhances protective immunity induced by malaria
vaccines. J. Exp. Med. 2002, 195, 617−624.
(12) Miyamoto, K.; Miyake, S.; Yamamura, T. A synthetic glycolipid
prevents autoimmune encephalomyelitis by inducing Th2 bias of
natural killer T cells. Nature 2001, 413, 531−534.
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