Synthetic Galectin Inhibitors Selective O-galactosyl aldoximes, multivalent lactosides and galactose-mimicking mannosides

Johan Tejler

Research output: ThesisDoctoral Thesis (compilation)

127 Downloads (Pure)

Abstract

This thesis describes the design, synthesis and evaluation of synthetic inhibitors for the carbohydrate binding proteins called galectins. Potent and selective inhibitors can be used as important research tools in the endeavor to chart the true role of galectins in biological events such as cancer and inflammation and possibly as lead for future galectin targeting drugs.

A panel of O-galactosyl aldoximes was synthesized and inhibitors with high affinity and selectivity for galectin-3 and -7 were identified. The best inhibitor for galectin-3, O-(?-D-galactopyranosyl)-indole-3-carbaldoxime, was combined with previously optimized galectin-3 targeting triazoles, in a fragment based approach, to give 3C-triazol-1-yl-O-galactopyranosyl aldoximes with high affinity and selectivity for galectin-3 (Kd down to 11 µM).

Furthermore, a glycoside clustering effect was observed for multivalent lactose containing inhibitors and galectin-1. The mechanisms behind this were investigated using mutated galectin-1, lacking the possibility to dimerize.

Finally, 1H-[1,2,3]-triazol-1-yl mannosides, with synthetic advantages over galactose based inhibitors, were synthesized and the 4-benzylaminocarbonyl-1H-[1,2,3]-triazol-1-yl ?-D-mannopyranoside (Kd=540 µM, for galectin-9N) compared favorably with its galactoside counterpart.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Department of Chemistry
Supervisors/Advisors
  • Nilsson, Ulf, Supervisor
  • Leffler, Hakon, Supervisor
Award date2006 Dec 20
Publisher
ISBN (Print)91-7422-133-7
Publication statusPublished - 2006

Bibliographical note

Defence details

Date: 2006-12-20
Time: 09:30
Place: Kemicentrum, sal K:C

External reviewer(s)

Name: Pieters, Roland
Title: Dr.
Affiliation: Dept. of Medicinal Chemistry and Chemical Biology, Utrecht University

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<div class="article_info">Johan Tejler, Hakon Leffler and Ulf, J Nilsson. <span class="article_issue_date">2005</span>. <span class="article_title">Synthesis of O-galactosyl aldoximes as potent LacNAc-mimetic galectin-3 inhibitors</span> <span class="journal_series_title">Bioorganic & Medicinal Chemistry Letters</span>, <span class="journal_volume">vol 15</span> <span class="journal_pages">pp 2343-2345</span>. <span class="journal_distributor">Elsevier</span></div>
<div class="article_info">Johan Tejler, Bader Salameh, Hakon Leffler and Ulf, J Nilsson. <span class="article_issue_date"></span>. <span class="article_title">A fragment based approach towards triazole-substituted O-galactosyl aldoximes as selective and low micromolar small molecule galectin-3 inhibitors</span> (manuscript)</div>
<div class="article_info">Johan Tejler, Erik Tullberg, Torbjörn Frejd, Hakon Leffler and Ulf, J Nilsson. <span class="article_issue_date">2006</span>. <span class="article_title">Synthesis of multivalent lactose derivatives by 1,3-dipolar cycloadditions: selective galectin-1 inhibition</span> <span class="journal_series_title">Carbohydrate Research</span>, <span class="journal_volume">vol 341</span> <span class="journal_pages">pp 1353-1362</span>. <span class="journal_distributor">Elsevier</span></div>
<div class="article_info">Emma Salomonsson, Johan Tejler, Erik Tullberg, Anders Sundin, Areej Khabut, Torbjörn Frejd, Yura Lobsanov, James Rini, Ulf, J Nilsson and Hakon Leffler. <span class="article_issue_date"></span>. <span class="article_title">Interaction of a divalent lactose ligand with monomeric galectin-1. Mechanisms contributing to the glycoside clustering effect</span> (manuscript)</div>
<div class="article_info">Johan Tejler, Fredrik Skogman, Hakon Leffler and Ulf, J Nilsson. <span class="article_issue_date"></span>. <span class="article_title">Synthesis of galactose-mimicking 1H-(1,2,3-triazol-1-yl)-mannosides as selective galectin-3 and 9N inhibitors</span> (manuscript)</div>


The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Department of Chemistry (011001220), Organic chemistry (S/LTH) (011001240)

Subject classification (UKÄ)

  • Chemical Sciences

Free keywords

  • Proteiner
  • enzymology
  • Proteins
  • Glycomimetic
  • Fragment based
  • Cluster effect
  • Multivalence
  • Triazole
  • Inhibitor
  • Aldoxime
  • enzymologi
  • Organic chemistry
  • Organisk kemi
  • Galectin
  • Lectin

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