Syntheses and Biological Activities of KRN7000 Analogues Having Aromatic Residues in the Acyl and Backbone Chains with Varying Stereochemistry

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2010 Jan 12

PMID 20061147

Citations 9

Authors

Jeong-Ju Park

Ji Hyung Lee

Kyung-Chang Seo

Gabriel Bricard

Manjunatha M Venkataswamy

Steven A Porcelli

Sung-Kee Chung

Affiliations

Soon will be listed here.

Abstract

KRN7000 is an important ligand identified for CD1d protein of APC, and KRN7000/CD1d complex can stimulate NKT cells to release a broad range of bioactive cytokines. In an effort to understand the structure-activity relationships, we have carried out syntheses of 26 new KRN7000 analogues incorporating aromatic residues in either or both side chains. Structural variations of the phytosphingosine moiety also include varying stereochemistry at C3 and C4, and 4-deoxy and 3,4-dideoxy versions. Their biological activities are described.

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References

Chang Y, Choi J, Ding S, Prieschl E, Baumruker T, Lee J . The synthesis and biological characterization of a ceramide library. J Am Chem Soc. 2002; 124(9):1856-7. DOI: 10.1021/ja017576o. View

Borg N, Wun K, Kjer-Nielsen L, Wilce M, Pellicci D, Koh R . CD1d-lipid-antigen recognition by the semi-invariant NKT T-cell receptor. Nature. 2007; 448(7149):44-9. DOI: 10.1038/nature05907. View

Koch M, Stronge V, Shepherd D, Gadola S, Mathew B, Ritter G . The crystal structure of human CD1d with and without alpha-galactosylceramide. Nat Immunol. 2005; 6(8):819-26. DOI: 10.1038/ni1225. View

Fujio M, Wu D, Garcia-Navarro R, Ho D, Tsuji M, Wong C . Structure-based discovery of glycolipids for CD1d-mediated NKT cell activation: tuning the adjuvant versus immunosuppression activity. J Am Chem Soc. 2006; 128(28):9022-3. DOI: 10.1021/ja062740z. View

Chang Y, Huang J, Tsai Y, Hung J, Wu D, Fujio M . Potent immune-modulating and anticancer effects of NKT cell stimulatory glycolipids. Proc Natl Acad Sci U S A. 2007; 104(25):10299-304. PMC: 1965507. DOI: 10.1073/pnas.0703824104. View

Goff R, Gao Y, Mattner J, Zhou D, Yin N, Cantu 3rd C . Effects of lipid chain lengths in alpha-galactosylceramides on cytokine release by natural killer T cells. J Am Chem Soc. 2004; 126(42):13602-3. DOI: 10.1021/ja045385q. View

Li X, Chen G, Garcia-Navarro R, Franck R, Tsuji M . Identification of C-glycoside analogues that display a potent biological activity against murine and human invariant natural killer T cells. Immunology. 2009; 127(2):216-225. PMC: 2691787. DOI: 10.1111/j.1365-2567.2008.02943.x. View

Kronenberg M . Toward an understanding of NKT cell biology: progress and paradoxes. Annu Rev Immunol. 2005; 23:877-900. DOI: 10.1146/annurev.immunol.23.021704.115742. View

Lee A, Farrand K, Dickgreber N, Hayman C, Jurs S, Hermans I . Novel synthesis of alpha-galactosyl-ceramides and confirmation of their powerful NKT cell agonist activity. Carbohydr Res. 2006; 341(17):2785-98. DOI: 10.1016/j.carres.2006.09.006. View

10.

Wu D, Xing G, Poles M, Horowitz A, Kinjo Y, Sullivan B . Bacterial glycolipids and analogs as antigens for CD1d-restricted NKT cells. Proc Natl Acad Sci U S A. 2005; 102(5):1351-6. PMC: 547854. DOI: 10.1073/pnas.0408696102. View

11.

Tsuji M . Glycolipids and phospholipids as natural CD1d-binding NKT cell ligands. Cell Mol Life Sci. 2006; 63(16):1889-98. PMC: 11136056. DOI: 10.1007/s00018-006-6073-z. View

12.

Li X, Shiratsuchi T, Chen G, Dellabona P, Casorati G, Franck R . Invariant TCR rather than CD1d shapes the preferential activities of C-glycoside analogues against human versus murine invariant NKT cells. J Immunol. 2009; 183(7):4415-21. PMC: 3603359. DOI: 10.4049/jimmunol.0901021. View

13.

Du W, Gervay-Hague J . Efficient synthesis of alpha-galactosyl ceramide analogues using glycosyl iodide donors. Org Lett. 2005; 7(10):2063-5. DOI: 10.1021/ol050659f. View

14.

Fuji N, Ueda Y, Fujiwara H, Toh T, Yoshimura T, Yamagishi H . Antitumor effect of alpha-galactosylceramide (KRN7000) on spontaneous hepatic metastases requires endogenous interleukin 12 in the liver. Clin Cancer Res. 2000; 6(8):3380-7. View

15.

Brossay L, Naidenko O, Burdin N, Matsuda J, Sakai T, Kronenberg M . Structural requirements for galactosylceramide recognition by CD1-restricted NK T cells. J Immunol. 1998; 161(10):5124-8. View

16.

Sidobre S, Hammond K, Benazet-Sidobre L, Maltsev S, Richardson S, Ndonye R . The T cell antigen receptor expressed by Valpha14i NKT cells has a unique mode of glycosphingolipid antigen recognition. Proc Natl Acad Sci U S A. 2004; 101(33):12254-9. PMC: 514465. DOI: 10.1073/pnas.0404632101. View

17.

Zajonc D, Cantu 3rd C, Mattner J, Zhou D, Savage P, Bendelac A . Structure and function of a potent agonist for the semi-invariant natural killer T cell receptor. Nat Immunol. 2005; 6(8):810-8. PMC: 2045075. DOI: 10.1038/ni1224. View

18.

Van Kaer L . alpha-Galactosylceramide therapy for autoimmune diseases: prospects and obstacles. Nat Rev Immunol. 2005; 5(1):31-42. DOI: 10.1038/nri1531. View

19.

Stronge V, Salio M, Jones E, Cerundolo V . A closer look at CD1d molecules: new horizons in studying NKT cells. Trends Immunol. 2007; 28(10):455-62. DOI: 10.1016/j.it.2007.08.002. View

20.

Zhou X, Forestier C, Goff R, Li C, Teyton L, Bendelac A . Synthesis and NKT cell stimulating properties of fluorophore- and biotin-appended 6"-amino-6"-deoxy-galactosylceramides. Org Lett. 2002; 4(8):1267-70. DOI: 10.1021/ol025565+. View