Stereospecific Synthesis and Biological Evaluation of KRN7000 Analogues with Thio-modifications at the Acyl Moiety

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Jul 17

PMID 39015265

Authors

Tianhui Hao

Tian Mi

Qinyu Chu

Wenjing Ma

Xi Cheng

Yi Zang

Jia Li

Tiehai Li

Affiliations

Soon will be listed here.

Abstract

α-Galactosylceramide (KRN7000 or α-GalCer) analogues terminated with phenyl (Ph) groups at the acyl moiety possess more potency than KRN7000 to activate invariant natural killer T (iNKT) cells for inducing a T helper 1 (Th1)-biased immune response. However, biological activities of phenyl glycolipids with thio-modifications at the acyl moiety remain unknown, and facile approaches for highly stereoselective synthesis of KRN7000 and its analogues are rather scarce. Herein, we exploited 4,6-di---butylsilylene (DTBS)-directed stereospecific galactosylation to efficiently synthesize various α-GalCer analogues bearing thioamide, terminal thiophenyl and dual modifications at the acyl moiety. Biological evaluations suggest that a new analogue S34 featuring a terminal Ph-S-Ph-F group exhibits a more superior Th1-biased immune response in mice. Molecular docking analysis revealed that the introduction of a sulfur atom influences vital hydrogen bonding interactions between glycolipids and the cluster of differentiation 1d (CDld), thus adjusting the stability of the glycolipid-CDld complex.

References

Chen X, Zhang R, Wang X, Yin X, Wang J, Wang Y . Peptide-free Synthetic Nicotine Vaccine Candidates with α-Galactosylceramide as Adjuvant. Mol Pharm. 2019; 16(4):1467-1476. DOI: 10.1021/acs.molpharmaceut.8b01095. View

Nadas J, Li C, Wang P . Computational structure activity relationship studies on the CD1d/glycolipid/TCR complex using AMBER and AUTODOCK. J Chem Inf Model. 2009; 49(2):410-23. DOI: 10.1021/ci8002705. View

Li X, Fujio M, Imamura M, Wu D, Vasan S, Wong C . Design of a potent CD1d-binding NKT cell ligand as a vaccine adjuvant. Proc Natl Acad Sci U S A. 2010; 107(29):13010-5. PMC: 2919905. DOI: 10.1073/pnas.1006662107. View

Liu Z, Guo J . NKT-cell glycolipid agonist as adjuvant in synthetic vaccine. Carbohydr Res. 2017; 452:78-90. DOI: 10.1016/j.carres.2017.10.006. View

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

Ma J, He P, Zhao C, Ren Q, Dong Z, Qiu J . A Designed -GalCer Analog Promotes Considerable Th1 Cytokine Response by Activating the CD1d-iNKT Axis and CD11b-Positive Monocytes/Macrophages. Adv Sci (Weinh). 2020; 7(14):2000609. PMC: 7375225. DOI: 10.1002/advs.202000609. View

Saavedra-Avila N, Pigni N, Caldwell D, Chena-Becerra F, Intano Jr J, Ng T . A Humanized Mouse Model Coupled with Computational Analysis Identifies Potent Glycolipid Agonist of Invariant NKT Cells. ACS Chem Biol. 2024; 19(4):926-937. PMC: 11075374. DOI: 10.1021/acschembio.3c00736. View

Shiozaki M, Tashiro T, Koshino H, Nakagawa R, Inoue S, Shigeura T . Synthesis and biological activity of ester and ether analogues of alpha-galactosylceramide (KRN7000). Carbohydr Res. 2010; 345(12):1663-84. DOI: 10.1016/j.carres.2010.05.003. View

Birkholz A, Girardi E, Wingender G, Khurana A, Wang J, Zhao M . A Novel Glycolipid Antigen for NKT Cells That Preferentially Induces IFN-γ Production. J Immunol. 2015; 195(3):924-33. PMC: 4506857. DOI: 10.4049/jimmunol.1500070. View

10.

Liu Y, Xu X, Gao Q, Yan S, Li Y, Ding N . Rapid access to 6″-functionalized α-galactosyl ceramides by using 2-naphthylmethyl ether as the permanent protecting group. Bioorg Med Chem Lett. 2017; 27(8):1795-1798. DOI: 10.1016/j.bmcl.2017.02.055. View

11.

Pellicci D, Patel O, Kjer-Nielsen L, Pang S, Sullivan L, Kyparissoudis K . Differential recognition of CD1d-alpha-galactosyl ceramide by the V beta 8.2 and V beta 7 semi-invariant NKT T cell receptors. Immunity. 2009; 31(1):47-59. PMC: 2765864. DOI: 10.1016/j.immuni.2009.04.018. View

12.

Yu K, Im J, Molano A, Dutronc Y, Illarionov P, Forestier C . Modulation of CD1d-restricted NKT cell responses by using N-acyl variants of alpha-galactosylceramides. Proc Natl Acad Sci U S A. 2005; 102(9):3383-8. PMC: 552918. DOI: 10.1073/pnas.0407488102. 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.

Wu T, Lin K, Wu Y, Huang J, Hung J, Wu J . Phenyl Glycolipids with Different Glycosyl Groups Exhibit Marked Differences in Murine and Human iNKT Cell Activation. ACS Chem Biol. 2016; 11(12):3431-3441. DOI: 10.1021/acschembio.6b00650. View

15.

Golten S, Patinec A, Akoumany K, Rocher J, Graton J, Jacquemin D . 3,4-Dideoxy-3,3,4,4-tetrafluoro- and 4-OH epimeric 3-deoxy-3,3-difluoro-α-GalCer analogues: Synthesis and biological evaluation on human iNKT cells stimulation. Eur J Med Chem. 2019; 178:195-213. DOI: 10.1016/j.ejmech.2019.05.069. View

16.

Wojno J, Jukes J, Ghadbane H, Shepherd D, Besra G, Cerundolo V . Amide analogues of CD1d agonists modulate iNKT-cell-mediated cytokine production. ACS Chem Biol. 2012; 7(5):847-55. PMC: 3409616. DOI: 10.1021/cb2005017. View

17.

Berkers C, Ovaa H . Immunotherapeutic potential for ceramide-based activators of iNKT cells. Trends Pharmacol Sci. 2005; 26(5):252-7. DOI: 10.1016/j.tips.2005.03.005. View

18.

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

19.

Kishi J, Inuki S, Kashiwabara E, Suzuki T, Dohmae N, Fujimoto Y . Design and Discovery of Covalent α-GalCer Derivatives as Potent CD1d Ligands. ACS Chem Biol. 2020; 15(2):353-359. DOI: 10.1021/acschembio.9b00700. View

20.

Brennan P, Brigl M, Brenner M . Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol. 2013; 13(2):101-17. DOI: 10.1038/nri3369. View