Synthesis and biological activities of amino acids functionalized α-GalCer analogues

Weiwei Ma; Jingjing Bi; Chuanfang Zhao; Zhiguo Zhang; Tongxin Liu; Guisheng Zhang

doi:10.1016/j.bmc.2019.115141

Synthesis and biological activities of amino acids functionalized α-GalCer analogues

Bioorg Med Chem. 2020 Jan 1;28(1):115141. doi: 10.1016/j.bmc.2019.115141. Epub 2019 Oct 28.

Authors

Weiwei Ma¹, Jingjing Bi², Chuanfang Zhao³, Zhiguo Zhang¹, Tongxin Liu¹, Guisheng Zhang⁴

Affiliations

¹ Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China.
² Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China. Electronic address: bijingjing2008@126.com.
³ School of Chemical Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China. Electronic address: zgs@htu.cn.

PMID: 31786009
DOI: 10.1016/j.bmc.2019.115141

Abstract

Invariant natural killer T-cells (iNKT-cells) are promising targets for manipulating the immune system, which can rapidly release a large amount of Th1 and Th2 cytokines upon the engagement of their T cell receptor with glycolipid antigens presented by CD1d. In this paper, we wish to report a novel series of α-GalCer analogues which were synthesized by incorporation of l-amino acid methyl esters in the C-6' position of glycolipid. The evaluation of these synthetic analogues for their capacities to stimulate iNKT-cells into producing Th1 and Th2 cytokines both in vitro and in vivo indicated that they were potent CD1d ligands and could stimulate murine spleen cells into a higher release of the Th1 cytokine IFN-γ in vitro. In vivo, Gly-α-GalCer (1) and Lys-α-GalCer (3) showed more Th1-biased responses than α-GalCer, especially analogue 3 showed the highest selectivity for IFN-γ production (IFN-γ/IL-4 = 5.32) compared with α-GalCer (IFN-γ/IL-4 = 2.5) in vivo. These novel α-GalCer analogues might be used as efficient X-ray crystallographic probes to reveal the relationship between glycolipids and CD1d proteins in α-GalCer/CD1d complexes and pave the way for developing new potent immunostimulating agents.

Keywords: Amino acids functionalized α-GalCers; Th1 response; iNKT cells; α-GalCer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adjuvants, Immunologic / chemical synthesis
Adjuvants, Immunologic / chemistry
Adjuvants, Immunologic / pharmacology*
Amino Acids / chemistry
Amino Acids / pharmacology*
Animals
Cell Proliferation / drug effects
Cytokines / biosynthesis*
Cytokines / immunology
Dose-Response Relationship, Drug
Female
Galactosylceramides / chemical synthesis
Galactosylceramides / chemistry
Galactosylceramides / pharmacology*
Mice
Mice, Inbred C57BL
Molecular Structure
Natural Killer T-Cells / drug effects*
Natural Killer T-Cells / immunology
Spleen / drug effects
Spleen / immunology
Structure-Activity Relationship

Substances

Adjuvants, Immunologic
Amino Acids
Cytokines
Galactosylceramides
alpha-galactosylceramide