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Epimers Switch Galectin-9 Domain Selectivity : 3 N-Aryl Galactosides Bind the C-Terminal and Gulosides Bind the N-Terminal

Mahanti, Mukul LU ; Pal, Kumar Bhaskar ; Sundin, Anders P. LU ; Leffler, Hakon LU and Nilsson, Ulf J. LU (2020) In ACS Medicinal Chemistry Letters 11(1). p.34-39
Abstract

A series of 3-deoxy-3-N-arylated-β-d-galactoside and -guloside derivatives have been synthesized by cesium fluoride/trimetylsilylaryl triflate-mediated benzyne generation and N-arylation of 3-deoxy-3-amino-β-d-galactosides and -gulosides, respectively. Evaluation as ligands to galectin-1, 2, 3, 4N (N-terminal domain), 4C (C-terminal domain), 7, 8N, 8C, 9C, and 9N revealed that the galactosides selectively bound galectin-9C, whereas the gulosides selectively bound galectin-9N. Hence, the N-aryl group induces galectin-9 selectivity and the ligand 3C-configuration acts as an epimeric selectivity switch between the two domains of galectin-9. Furthermore, MD simulations revealed that galacto derivatives in galectin-9C and gulo derivatives in... (More)

A series of 3-deoxy-3-N-arylated-β-d-galactoside and -guloside derivatives have been synthesized by cesium fluoride/trimetylsilylaryl triflate-mediated benzyne generation and N-arylation of 3-deoxy-3-amino-β-d-galactosides and -gulosides, respectively. Evaluation as ligands to galectin-1, 2, 3, 4N (N-terminal domain), 4C (C-terminal domain), 7, 8N, 8C, 9C, and 9N revealed that the galactosides selectively bound galectin-9C, whereas the gulosides selectively bound galectin-9N. Hence, the N-aryl group induces galectin-9 selectivity and the ligand 3C-configuration acts as an epimeric selectivity switch between the two domains of galectin-9. Furthermore, MD simulations revealed that galacto derivatives in galectin-9C and gulo derivatives in galectin-9N find stable poses with specific interactions, which proposes a possible explanation to the gal/gulo 9C/9N selectivity.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
epimers, Galactose, galectin-9, gulose, N-phenyl, selectivity
in
ACS Medicinal Chemistry Letters
volume
11
issue
1
pages
34 - 39
publisher
The American Chemical Society (ACS)
external identifiers
  • pmid:31938460
  • scopus:85076853871
ISSN
1948-5875
DOI
10.1021/acsmedchemlett.9b00396
language
English
LU publication?
yes
id
f00fefdd-3441-405d-a521-8f6044b727d3
date added to LUP
2020-01-14 12:29:15
date last changed
2024-04-02 22:32:27
@article{f00fefdd-3441-405d-a521-8f6044b727d3,
  abstract     = {{<p>A series of 3-deoxy-3-N-arylated-β-d-galactoside and -guloside derivatives have been synthesized by cesium fluoride/trimetylsilylaryl triflate-mediated benzyne generation and N-arylation of 3-deoxy-3-amino-β-d-galactosides and -gulosides, respectively. Evaluation as ligands to galectin-1, 2, 3, 4N (N-terminal domain), 4C (C-terminal domain), 7, 8N, 8C, 9C, and 9N revealed that the galactosides selectively bound galectin-9C, whereas the gulosides selectively bound galectin-9N. Hence, the N-aryl group induces galectin-9 selectivity and the ligand 3C-configuration acts as an epimeric selectivity switch between the two domains of galectin-9. Furthermore, MD simulations revealed that galacto derivatives in galectin-9C and gulo derivatives in galectin-9N find stable poses with specific interactions, which proposes a possible explanation to the gal/gulo 9C/9N selectivity.</p>}},
  author       = {{Mahanti, Mukul and Pal, Kumar Bhaskar and Sundin, Anders P. and Leffler, Hakon and Nilsson, Ulf J.}},
  issn         = {{1948-5875}},
  keywords     = {{epimers; Galactose; galectin-9; gulose; N-phenyl; selectivity}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{34--39}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{ACS Medicinal Chemistry Letters}},
  title        = {{Epimers Switch Galectin-9 Domain Selectivity : 3 N-Aryl Galactosides Bind the C-Terminal and Gulosides Bind the N-Terminal}},
  url          = {{http://dx.doi.org/10.1021/acsmedchemlett.9b00396}},
  doi          = {{10.1021/acsmedchemlett.9b00396}},
  volume       = {{11}},
  year         = {{2020}},
}