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Quinoline-galactose hybrids bind selectively with high affinity to a galectin-8 N-terminal domain

Pal, Kumar Bhaskar; Mahanti, Mukul LU ; Huang, Xiaoli LU ; Persson, Stella; Sundin, Anders P. LU ; Zetterberg, Fredrik R.; Oredsson, Stina LU ; Leffler, Hakon LU and Nilsson, Ulf J. LU (2018) In Organic and Biomolecular Chemistry 16(34). p.6295-6305
Abstract

Quinolines, indolizines, and coumarins are well known structural elements in many biologically active molecules. In this report, we have developed straightforward methods to incorporate quinoline, indolizine, and coumarin structures into galactoside derivatives under robust reaction conditions for the discovery of glycomimetic inhibitors of the galectin family of proteins that are involved in immunological and tumor-promoting biological processes. Evaluation of the quinoline, indolizine and coumarin-derivatised galactosides as inhibitors of the human galectin-1, 2, 3, 4N (N-terminal domain), 4C (C-terminal domain), 7, 8N, 8C, 9N, and 9C revealed quinoline derivatives that selectively bound galectin-8N, a galectin with key roles in... (More)

Quinolines, indolizines, and coumarins are well known structural elements in many biologically active molecules. In this report, we have developed straightforward methods to incorporate quinoline, indolizine, and coumarin structures into galactoside derivatives under robust reaction conditions for the discovery of glycomimetic inhibitors of the galectin family of proteins that are involved in immunological and tumor-promoting biological processes. Evaluation of the quinoline, indolizine and coumarin-derivatised galactosides as inhibitors of the human galectin-1, 2, 3, 4N (N-terminal domain), 4C (C-terminal domain), 7, 8N, 8C, 9N, and 9C revealed quinoline derivatives that selectively bound galectin-8N, a galectin with key roles in lymphangiogenesis, tumor progression, and autophagy, with up to nearly 60-fold affinity improvements relative to methyl β-d-galactopyranoside. Molecular dynamics simulations proposed an interaction mode in which Arg59 had moved 2.5 Å and in which an inhibitor carboxylate and quinoline nitrogen formed structure-stabilizing water-mediated hydrogen bonds. The compounds were demonstrated to be non-toxic in an MTT assay with several breast cancer cell lines and one normal cell line. The improved affinity, selectivity, and low cytotoxicity suggest that the quinoline-galactoside derivatives provide an attractive starting point for the development of galectin-8N inhibitors potentially interfering with pathological lymphangiogenesis, autophagy, and tumor progression.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Organic and Biomolecular Chemistry
volume
16
issue
34
pages
11 pages
publisher
Royal Society of Chemistry
external identifiers
  • scopus:85052703609
ISSN
1477-0520
DOI
10.1039/c8ob01354c
language
English
LU publication?
yes
id
2b0a1932-d70e-4796-879c-e8428714d775
date added to LUP
2018-09-28 08:47:35
date last changed
2019-01-06 14:06:24
@article{2b0a1932-d70e-4796-879c-e8428714d775,
  abstract     = {<p>Quinolines, indolizines, and coumarins are well known structural elements in many biologically active molecules. In this report, we have developed straightforward methods to incorporate quinoline, indolizine, and coumarin structures into galactoside derivatives under robust reaction conditions for the discovery of glycomimetic inhibitors of the galectin family of proteins that are involved in immunological and tumor-promoting biological processes. Evaluation of the quinoline, indolizine and coumarin-derivatised galactosides as inhibitors of the human galectin-1, 2, 3, 4N (N-terminal domain), 4C (C-terminal domain), 7, 8N, 8C, 9N, and 9C revealed quinoline derivatives that selectively bound galectin-8N, a galectin with key roles in lymphangiogenesis, tumor progression, and autophagy, with up to nearly 60-fold affinity improvements relative to methyl β-d-galactopyranoside. Molecular dynamics simulations proposed an interaction mode in which Arg59 had moved 2.5 Å and in which an inhibitor carboxylate and quinoline nitrogen formed structure-stabilizing water-mediated hydrogen bonds. The compounds were demonstrated to be non-toxic in an MTT assay with several breast cancer cell lines and one normal cell line. The improved affinity, selectivity, and low cytotoxicity suggest that the quinoline-galactoside derivatives provide an attractive starting point for the development of galectin-8N inhibitors potentially interfering with pathological lymphangiogenesis, autophagy, and tumor progression.</p>},
  author       = {Pal, Kumar Bhaskar and Mahanti, Mukul and Huang, Xiaoli and Persson, Stella and Sundin, Anders P. and Zetterberg, Fredrik R. and Oredsson, Stina and Leffler, Hakon and Nilsson, Ulf J.},
  issn         = {1477-0520},
  language     = {eng},
  month        = {08},
  number       = {34},
  pages        = {6295--6305},
  publisher    = {Royal Society of Chemistry},
  series       = {Organic and Biomolecular Chemistry},
  title        = {Quinoline-galactose hybrids bind selectively with high affinity to a galectin-8 N-terminal domain},
  url          = {http://dx.doi.org/10.1039/c8ob01354c},
  volume       = {16},
  year         = {2018},
}