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

Johan Tejler

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

Johan Tejler

Centre for Analysis and Synthesis

Research output: Thesis › Doctoral Thesis (compilation)

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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 language	English
Qualification	Doctor
Awarding Institution	Department of Chemistry
Supervisors/Advisors	Nilsson, Ulf, Supervisor Leffler, Hakon, Supervisor
Award date	2006 Dec 20
Publisher	Lund University, The Center for Chemistry and Chemical Engineering, Division of organic chemistry
ISBN (Print)	91-7422-133-7
Publication status	Published - 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

---

<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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Johan_Tejler_kappa

Cite this

@phdthesis{b6ff30e0edb849edaa35690c75bd96e3,

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

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.",

keywords = "Proteiner, enzymology, Proteins, Glycomimetic, Fragment based, Cluster effect, Multivalence, Triazole, Inhibitor, Aldoxime, enzymologi, Organic chemistry, Organisk kemi, Galectin, Lectin",

author = "Johan Tejler",

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 --- <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, Torbj{\"o}rn 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, Torbj{\"o}rn 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)",

year = "2006",

language = "English",

isbn = "91-7422-133-7",

publisher = "Lund University, The Center for Chemistry and Chemical Engineering, Division of organic chemistry",

type = "Doctoral Thesis (compilation)",

school = "Department of Chemistry",

}

TY - THES

T1 - Synthetic Galectin Inhibitors Selective O-galactosyl aldoximes, multivalent lactosides and galactose-mimicking mannosides

AU - Tejler, Johan

N1 - 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 --- <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)

PY - 2006

Y1 - 2006

N2 - 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.

AB - 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.

KW - Proteiner

KW - enzymology

KW - Proteins

KW - Glycomimetic

KW - Fragment based

KW - Cluster effect

KW - Multivalence

KW - Triazole

KW - Inhibitor

KW - Aldoxime

KW - enzymologi

KW - Organic chemistry

KW - Organisk kemi

KW - Galectin

KW - Lectin

M3 - Doctoral Thesis (compilation)

SN - 91-7422-133-7

PB - Lund University, The Center for Chemistry and Chemical Engineering, Division of organic chemistry

ER -

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

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

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