New CD1d agonists: Synthesis and biological activity of 6″-triazole-substituted α-galactosyl ceramides

Peter J. Jervis; Lisa M. Graham; Erin L. Foster; Liam R. Cox; Steven A. Porcelli; Gurdyal S. Besra

doi:10.1016/j.bmcl.2012.05.009

New CD1d agonists: Synthesis and biological activity of 6″-triazole-substituted α-galactosyl ceramides

Peter J. Jervis, Lisa M. Graham, Erin L. Foster, Liam R. Cox, Steven A. Porcelli, Gurdyal S. Besra

Microbiology & Immunology

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

Huisgen [3+2] dipolar cycloaddition of 6″-azido-6″-deoxy- α-galactosyl ceramide 11 with a range of alkynes (or a benzyne precursor) yielded a series of triazole-containing α-galactosyl ceramide (α-GalCer) analogues in high yield. These α-GalCer analogues and the precursor azide 11 were tested for their ability to activate iNKT cells and stimulate IL-2 cytokine secretion in vitro, and IFN-γ and IL-4 cytokine secretion in vivo. Some of these analogues, specifically 11, 12b, 12f and 13, were more potent IL-2 stimulators than the prototypical CD1d agonist, α-GalCer 1. In terms of any cytokine bias, most of the triazole-containing analogues exhibited a small Th2 cytokine-biasing response relative to that shown by α-GalCer 1. In contrast, the cycloaddition precursor, namely azide 11, provided a small Th1 cytokine-biasing response.

Original language	English (US)
Pages (from-to)	4348-4352
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	13
DOIs	https://doi.org/10.1016/j.bmcl.2012.05.009
State	Published - Jul 1 2012

Keywords

CD1d
Click chemistry
Triazole
iNKT cell
α-GalCer

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2012.05.009

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title = "New CD1d agonists: Synthesis and biological activity of 6″-triazole-substituted α-galactosyl ceramides",

abstract = "Huisgen [3+2] dipolar cycloaddition of 6″-azido-6″-deoxy- α-galactosyl ceramide 11 with a range of alkynes (or a benzyne precursor) yielded a series of triazole-containing α-galactosyl ceramide (α-GalCer) analogues in high yield. These α-GalCer analogues and the precursor azide 11 were tested for their ability to activate iNKT cells and stimulate IL-2 cytokine secretion in vitro, and IFN-γ and IL-4 cytokine secretion in vivo. Some of these analogues, specifically 11, 12b, 12f and 13, were more potent IL-2 stimulators than the prototypical CD1d agonist, α-GalCer 1. In terms of any cytokine bias, most of the triazole-containing analogues exhibited a small Th2 cytokine-biasing response relative to that shown by α-GalCer 1. In contrast, the cycloaddition precursor, namely azide 11, provided a small Th1 cytokine-biasing response.",

keywords = "CD1d, Click chemistry, Triazole, iNKT cell, α-GalCer",

author = "Jervis, {Peter J.} and Graham, {Lisa M.} and Foster, {Erin L.} and Cox, {Liam R.} and Porcelli, {Steven A.} and Besra, {Gurdyal S.}",

note = "Funding Information: G.S.B. acknowledges support in the form of a Personal Research Chair from Mr. James Bardrick, Royal Society Wolfson Research Merit Award, as a former Lister Institute-Jenner Research Fellow; The Wellcome Trust (084923/B/08/Z) for funding (to P.J.J.). The NMR spectrometers used in this research were funded in part through Birmingham Science City: Innovative Uses for Advanced Materials in the Modern World (West Midlands Centre for Advanced Materials Project 2), with support from Advantage West Midlands and part-funded by the European Regional Development Fund. ",

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doi = "10.1016/j.bmcl.2012.05.009",

language = "English (US)",

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T2 - Synthesis and biological activity of 6″-triazole-substituted α-galactosyl ceramides

AU - Jervis, Peter J.

AU - Graham, Lisa M.

AU - Foster, Erin L.

AU - Cox, Liam R.

AU - Porcelli, Steven A.

AU - Besra, Gurdyal S.

N1 - Funding Information: G.S.B. acknowledges support in the form of a Personal Research Chair from Mr. James Bardrick, Royal Society Wolfson Research Merit Award, as a former Lister Institute-Jenner Research Fellow; The Wellcome Trust (084923/B/08/Z) for funding (to P.J.J.). The NMR spectrometers used in this research were funded in part through Birmingham Science City: Innovative Uses for Advanced Materials in the Modern World (West Midlands Centre for Advanced Materials Project 2), with support from Advantage West Midlands and part-funded by the European Regional Development Fund.

PY - 2012/7/1

Y1 - 2012/7/1

N2 - Huisgen [3+2] dipolar cycloaddition of 6″-azido-6″-deoxy- α-galactosyl ceramide 11 with a range of alkynes (or a benzyne precursor) yielded a series of triazole-containing α-galactosyl ceramide (α-GalCer) analogues in high yield. These α-GalCer analogues and the precursor azide 11 were tested for their ability to activate iNKT cells and stimulate IL-2 cytokine secretion in vitro, and IFN-γ and IL-4 cytokine secretion in vivo. Some of these analogues, specifically 11, 12b, 12f and 13, were more potent IL-2 stimulators than the prototypical CD1d agonist, α-GalCer 1. In terms of any cytokine bias, most of the triazole-containing analogues exhibited a small Th2 cytokine-biasing response relative to that shown by α-GalCer 1. In contrast, the cycloaddition precursor, namely azide 11, provided a small Th1 cytokine-biasing response.

AB - Huisgen [3+2] dipolar cycloaddition of 6″-azido-6″-deoxy- α-galactosyl ceramide 11 with a range of alkynes (or a benzyne precursor) yielded a series of triazole-containing α-galactosyl ceramide (α-GalCer) analogues in high yield. These α-GalCer analogues and the precursor azide 11 were tested for their ability to activate iNKT cells and stimulate IL-2 cytokine secretion in vitro, and IFN-γ and IL-4 cytokine secretion in vivo. Some of these analogues, specifically 11, 12b, 12f and 13, were more potent IL-2 stimulators than the prototypical CD1d agonist, α-GalCer 1. In terms of any cytokine bias, most of the triazole-containing analogues exhibited a small Th2 cytokine-biasing response relative to that shown by α-GalCer 1. In contrast, the cycloaddition precursor, namely azide 11, provided a small Th1 cytokine-biasing response.

KW - CD1d

KW - Click chemistry

KW - Triazole

KW - iNKT cell

KW - α-GalCer

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ER -

New CD1d agonists: Synthesis and biological activity of 6″-triazole-substituted α-galactosyl ceramides

Abstract

Keywords

ASJC Scopus subject areas

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