Fragment-based development of triazole-substituted O-galactosyl aldoximes with fragment-induced affinity and selectivity for galectin-3

Tejler, Johan; Salameh, Bader A.; Leffler, Hakon; Nilsson, Ulf J.

doi:10.1039/b909091f

Cited by 46 publications

(31 citation statements)

References 46 publications

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“…2a) to further improve affinity and thus providing promise for drug development. [83] Collections of O-and C-β-d-galactosides with aglycons incorporating isoxazole-or triazole moieties that would interact with subsite D were found by Roy et al to inhibit galectin-1 with promising mM affinities and with significant selectivity over galectin-3 [68] (Fig. 6).…”

Section: Inhibitors Mimicking Glc or Glcnac Of Natural Ligands -Targementioning

confidence: 95%

Inhibition of Galectins with Small Molecules

Öberg¹,

Leffler²,

Nilsson³

2011

Chimia

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Evidence that the galectin family of proteins plays crucial roles in cancer, inflammation, and immunity has accumulated over the last decade. The galectins have consequently emerged as interesting drug targets. A majority of galectin functions occurs by means of cross-linking glycoproteins and by doing so controlling glycoprotein cellular localization and residence times. The glycoprotein cross-linking occurs when galectin dimers or multimers, or galectins with two binding sites, bind galactose-containing glycans of the glycoproteins. Such galectin-glycan interactions have been successfully blocked with compounds having multivalent presentation of galactose, lactose, or N-acetyllactosamine, with peptides, and with small carbohydrate (galactose) derivatives. This review summarizes and analyzes attempts to develop efficient and selective small-molecule galectin inhibitors through derivatization of monosaccharides, mainly galactosides, with non-carbohydrate structures that protrude into subsites adjacent to the core-conserved galactose-recognizing site of the galectins.

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Section: Inhibitors Mimicking Glc or Glcnac Of Natural Ligands -Targementioning

confidence: 95%

Inhibition of Galectins with Small Molecules

Öberg¹,

Leffler²,

Nilsson³

2011

Chimia

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“…Further evidence has been gathered to support the proposal that it is the quinone methide, formed by two electron reduction of prekinamycin, that is responsible for its cytostatic activity (Khdour & Skibo, 2009). A series of substituted thienopyrimidines have been synthesised and shown to be cytotoxic to a number of cancer cell lines (Snegaroff et al, 2009) and substituted O-galactosyl aldoximes were prepared as selective galectin-3 inhibitors (Tejler et al, 2009). Pyrrolidine 3,4-diols have been reported as -L-fucosidase inhibitors (MorenoClavijo et al, 2009).…”

Section: Bioactivesmentioning

confidence: 97%

Chemical Biology: What is Its Role in Drug Discovery?

Pirrie¹,

Westwood²

2011

Drug Discovery and Development - Present and Future

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“…[137] In addition, the compounds containing indole aldoximes at C1 showed high selectivity for galectin-3, where the indole group could supposedly move into a unique binding groove next to the galactosebinding site. [137] Several C3 triazole-linked [138] and C1 O-or S-linked [139] galactose modifications using aromatic moieties have been reported, but the initial molecules did not achieve the same level of haemagglutination inhibition as the lactosides. A later study found a single C1-butyl-2-enoate modification that was ,2-fold better than lactose and selective for galectin-1 over galectin-3 (Fig.…”

Section: Modified Saccharidesmentioning

confidence: 98%

“…Stemming from the work with arginine tweezers [139,142] and previous work with galactose C1 aldoximes [50,137] (described above), several modifications were made onto the C2 and C3 positions of a taloside scaffold. [51] The taloside is meant to mimic the galactose scaffold with the added benefit of an axial C2 hydroxy group, which points along the surface of galectins, increasing the effect of C2 modifications as opposed to being directed away from the protein surface in the case of galactose.…”

Section: Talose-based Inhibitorsmentioning

confidence: 99%

Inhibitors of Galectins and Implications for Structure-Based Design of Galectin-Specific Therapeutics

2014

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Galectins are a family of galactoside-specific lectins that are involved in a myriad of metabolic and disease processes. Due to roles in cancer and inflammatory and heart diseases, galectins are attractive targets for drug development. Over the last two decades, various strategies have been used to inhibit galectins, including polysaccharide-based therapeutics, multivalent display of saccharides, peptides, peptidomimetics, and saccharide-modifications. Primarily due to galectin carbohydrate binding sites having high sequence identities, the design and development of selective inhibitors targeting particular galectins, thereby addressing specific disease states, is challenging. Furthermore, the use of different inhibition assays by research groups has hindered systematic assessment of the relative selectivity and affinity of inhibitors. This review summarises the status of current inhibitors, strategies, and novel scaffolds that exploit subtle differences in galectin structures that, in conjunction with increasing available data on multiple galectins, is enabling the feasible design of effective and specific inhibitors of galectins. small-molecule crystallography, University of London, UK) undertook post-doctoral research in protein X-ray crystallography and drug-design in academia and industry within Canada, USA, Switzerland and Australia. In 2002 Helen established a protein X-ray crystallography structural biology group at the Institute for Glycomics, Griffith University. As recognition of her international contribution to structural biology and chemistry she was admitted as fellow of the Royal Society of Chemistry (FRSC) in 2006. Her research involves determination of atomic protein structure, analysis of protein-ligand interactions and application of this information in understanding protein function and for structure based drug-design. Her research group has a major focus on lectins critical to disease progression including her research program on galectins that have importance in serious conditions including cancer. Khuchtumur Bum-Erdene completed his Bachelors degree in Chemistry (

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Fragment-based development of triazole-substituted O-galactosyl aldoximes with fragment-induced affinity and selectivity for galectin-3

Cited by 46 publications

References 46 publications

Inhibition of Galectins with Small Molecules

Inhibition of Galectins with Small Molecules

Chemical Biology: What is Its Role in Drug Discovery?

Inhibitors of Galectins and Implications for Structure-Based Design of Galectin-Specific Therapeutics

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