1.
Bum-Erdene, Khuchtumur, et al.
(författare)
Novel Selective Galectin-3 Antagonists Are Cytotoxic to Acute Lymphoblastic Leukemia
2022
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 65:8, s. 5975-5989
Tidskriftsartikel (refereegranskat) abstract
Galectin-3 is a β-galactoside-specific, carbohydrate-recognizing protein (lectin) that is strongly implicated in cancer development, metastasis, and drug resistance. Galectin-3 promotes migration and ability to withstand drug treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells. Due to high amino acid conservation among galectins and the shallow nature of their glycan-binding site, the design of selective potent antagonists targeting galectin-3 is challenging. Herein, we report the design and synthesis of novel taloside-based antagonists of galectin-3 with enhanced affinity and selectivity. The molecules were optimized by in silico docking, selectivity was established against four galectins, and the binding modes were confirmed by elucidation of X-ray crystal structures. Critically, the specific inhibition of galectin-3-induced BCP-ALL cell agglutination was demonstrated. The compounds decreased the viability of ALL cells even when grown in the presence of protective stromal cells. We conclude that these compounds are promising leads for therapeutics, targeting the tumor-supportive activities of galectin-3 in cancer.
2.
Bum-Erdene, Khuchtumur, et al.
(författare)
Structural characterisation of human galectin-4 N-terminal carbohydrate recognition domain in complex with glycerol, lactose, 3 '-sulfo-lactose, and 2 '-fucosyllactose
2016
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
Tidskriftsartikel (refereegranskat) abstract
Galectin-4 is a tandem-repeat galectin with two distinct carbohydrate recognition domains (CRD). Galectin-4 is expressed mainly in the alimentary tract and is proposed to function as a lipid raft and adherens junction stabilizer by its glycan cross-linking capacity. Galectin-4 plays divergent roles in cancer and inflammatory conditions, either promoting or inhibiting each disease progression, depending on the specific pathological condition. The study of galectin-4's ligand-binding profile may help decipher its roles under specific conditions. Here we present the X-ray structures of human galectin-4 N-terminal CRD (galectin-4N) bound to different saccharide ligands. Galectin-4's overall fold and its core interactions to lactose are similar to other galectin CRDs. Galectin-4N recognises the sulfate cap of 3'-sulfated glycans by a weak interaction through Arg45 and two water-mediated hydrogen bonds via Trp84 and Asn49. When galectin-4N interacts with the H-antigen mimic, 2'-fucosyllactose, an interaction is formed between the ring oxygen of fucose and Arg45. The extended binding site of galectin-4N may not be well suited to the A/B-antigen determinants, alpha-GalNAc/alpha-Gal, specifically due to clashes with residue Phe47. Overall, galectin-4N favours sulfated glycans whilst galectin-4C prefers blood group determinants. However, the two CRDs of galectin-4 can, to a less extent, recognise each other's ligands.
3.
Dahlqvist, Alexander, et al.
(författare)
Aminopyrimidine-galactose hybrids are highly selective galectin-3 inhibitors
2019
Ingår i: MedChemComm. - : Royal Society of Chemistry (RSC). - 2040-2503 .- 2040-2511. ; 10:6, s. 913-925
Tidskriftsartikel (refereegranskat) abstract
Galectins are a family of carbohydrate recognition proteins involved in, among other things, modulating cell signalling and cell-environment interactions, giving them roles in several pathologies like cancer and idiopathic lung fibrosis. Hence, developing new galectin inhibitors with high affinity and high selectivity is important to be able to target such diseases. Most existing galectin inhibitors have a disaccharide scaffold, but there has been success as of late in developing monogalactoside inhibitors such as α-arylthioglycosides. Here, we report aminopyrimidine-derivatised galactosides as good galectin-3 inhibitors with affinities down to 1.7 μM and a more than 300-fold selectivity over galectin-1. Mutant studies replacing Arg144 in galectin-3 with lysine and serine support the hypothesis that the binding of the derivatives involves interactions with Arg144. Molecular dynamics simulations converged to stable poses of the inhibitor aminopyrimidine moiety with polar interactions with Asp148 and Ser237, while the aryl-aminopyrimidine ring stacked onto the side chain of Arg144. Hence, combining an aminopyrimidine motif with a phenyl α-thiogalactoside motif offers an attractive route towards highly selective galectin-3 inhibitors.
4.
Dahlqvist, Alexander, et al.
(författare)
C1-Galactopyranosyl Heterocycle Structure Guides Selectivity : Triazoles Prefer Galectin-1 and Oxazoles Prefer Galectin-3
2019
Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 4:4, s. 7047-7053
Tidskriftsartikel (refereegranskat) abstract
Galectins are carbohydrate-recognizing proteins involved in many different pathological processes, including cancer and immune-related disorders. Inhibitors of galectins have evolved from natural oligosaccharides toward more drug-like truncated galactoside scaffolds that only retain key specific interactions of the galactose scaffolds with the galectin carbohydrate recognition domains. In this context, C1-galactosides are attractive and stable scaffolds, and this work reports that the synthesis of novel C1-galactopyranosyl heteroaryl derivatives as galectin inhibitors, in which galectin selectivity is governed by the composition of the heterocycle and affinity, is driven by the structure of the aryl substituent to give compounds selective for either galectin-1 or galectin-3. The affinities are close to or better than those of lactose and other natural galectin-binding disaccharides, selectivities induced by the C1-heteroaryl groups are superior to lactose, and compound hydrolytic stabilities and drug-like properties are potentially better than those of natural saccharides. Hence, C1-galactopyranosyl heteroaryls constitute a class of promising starting scaffolds for galectin inhibition, in which a natural ligand pyranose has been replaced by more than fivefold selectivity-inducing heteroaryl rings leading to affinities of 90 μM toward galectin-3 for a C1-galactopyranosyl naphthyloxazole and 170 μM toward galectin-1 for a C1-galactopyranosyl 2-fluorophenyltriazole.
5.
Dahlqvist, Alexander, et al.
(författare)
Stereo- And regioselective hydroboration of 1-exo-methylene pyranoses : Discovery of aryltriazolylmethyl C-galactopyranosides as selective galectin-1 inhibitors
2019
Ingår i: Beilstein Journal of Organic Chemistry. - : Beilstein Institut. - 1860-5397. ; 15, s. 1046-1060
Tidskriftsartikel (refereegranskat) abstract
Galectins are carbohydrate recognition proteins that bind carbohydrates containing galactose and are involved in cell signaling and cellular interactions, involving them in several diseases. We present the synthesis of (aryltriazolyl)methyl galactopyranoside galectin inhibitors using a highly diastereoselective hydroboration of C1-exo-methylene pyranosides giving inhibitors with fourfold or better selectivity for galectin-1 over galectin-3, -4C (C-terminal CRD), -4N (N-terminal CRD), -7, -8C, -8N, -9C, and -9N and dissociation constants down to 170 μM.
6.
Delaine, Tamara, et al.
(författare)
Galectin-3-Binding Glycomimetics that Strongly Reduce Bleomycin-Induced Lung Fibrosis and Modulate Intracellular Glycan Recognition
2016
Ingår i: ChemBioChem. - : Wiley. - 1439-4227. ; 17:18, s. 1759-1770
Tidskriftsartikel (refereegranskat) abstract
Discovery of glycan-competitive galectin-3-binding compounds that attenuate lung fibrosis in a murine model and that block intracellular galectin-3 accumulation at damaged vesicles, hence revealing galectin-3-glycan interactions involved in fibrosis progression and in intracellular galectin-3 activities, is reported. 3,3'-Bis-(4-aryltriazol-1-yl)thiodigalactosides were synthesized and evaluated as antagonists of galectin-1, -2, -3, and -4 N-terminal, -4 C-terminal, -7 and -8 N-terminal, -9 N-terminal, and -9 C-terminal domains. Compounds displaying low-nanomolar affinities for galectins-1 and -3 were identified in a competitive fluorescence anisotropy assay. X-ray structural analysis of selected compounds in complex with galectin-3, together with galectin-3 mutant binding experiments, revealed that both the aryltriazolyl moieties and fluoro substituents on the compounds are involved in key interactions responsible for exceptional affinities towards galectin-3. The most potent galectin-3 antagonist was demonstrated to act in an assay monitoring galectin-3 accumulation upon amitriptyline-induced vesicle damage, visualizing a biochemically/medically relevant intracellular lectin-carbohydrate binding event and that it can be blocked by a small molecule. The same antagonist administered intratracheally attenuated bleomycin-induced pulmonary fibrosis in a mouse model with a dose/response profile comparing favorably with that of oral administration of the marketed antifibrotic compound pirfenidone.
7.
Delaine, Tamara, et al.
(författare)
Galectin-inhibitory thiodigalactoside ester derivatives have antimigratory effects in cultured lung and prostate cancer cells.
2008
Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 51:24, s. 8109-8114
Tidskriftsartikel (refereegranskat) abstract
Aromatic 3,3'-diesters of thiodigalactoside were synthesized in a rapid three-step sequence from commercially available thiodigalactoside and evaluated as inhibitors of cancer- and immunity-related galectins. For each of galectins-1, -3, -7, and -9N-terminal domain, aromatic 3,3'-diesters of thiodigalactoside were found to have affinities in the low micromolar range, which represents a 7-70 fold enhancement over thiodigalactoside itself. No significant improvement was found for galectin-8 N-terminal domain. Two of the compounds were selected for testing in cell culture and were shown to have potent antimigratory effects on human PC-3 prostate and human A549 nonsmall-cell lung cancer cells.
8.
Hassan, Mujtaba, et al.
(författare)
Benzimidazole–galactosides bind selectively to the Galectin-8 N-Terminal domain : Structure-based design and optimisation
2021
Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234. ; 223
Tidskriftsartikel (refereegranskat) abstract
We have obtained the X-ray crystal structure of the galectin-8 N-terminal domain (galectin-8N) with a previously reported quinoline–galactoside ligand at a resolution of 1.6 Å. Based on this X-ray structure, a collection of galactosides derivatised at O3 with triazole, benzimidazole, benzothiazole, and benzoxazole moieties were designed and synthesised. This led to the discovery of a 3-O-(N-methylbenzimidazolylmethyl)–galactoside with a Kd of 1.8 μM for galectin-8N, the most potent selective synthetic galectin-8N ligand to date. Molecular dynamics simulations showed that benzimidazole–galactoside derivatives bind the non-conserved amino acid Gln47, accounting for the higher selectivity for galectin-8N. Galectin-8 is a carbohydrate-binding protein that plays a key role in pathological lymphangiogenesis, modulation of the immune system, and autophagy. Thus, the benzimidazole-derivatised galactosides represent promising compounds for studies of the pathological implications of galectin-8, as well as a starting point for the development of anti-tumour and anti-inflammatory therapeutics targeting galectin-8.
9.
Lázár, László, et al.
(författare)
Strong Binding of C-Glycosylic1,2-Thiodisaccharides to Galectin-3─Enthalpy-Driven Affinity Enhancement by Water-Mediated Hydrogen Bonds
2023
Ingår i: Journal of Medicinal Chemistry. - 1520-4804. ; 66:17, s. 12420-12431
Tidskriftsartikel (refereegranskat) abstract
Galectin-3 is involved in multiple pathways of many diseases, including cancer, fibrosis, and diabetes, and it is a validated pharmaceutical target for the development of novel therapeutic agents to address unmet medical needs. Novel 1,2-thiodisaccharides with a C-glycosylic functionality were synthesized by the photoinitiated thiol-ene click reaction of O-peracylated 1-C-substituted glycals and 1-thio-glycopyranoses. Subsequent global deprotection yielded test compounds, which were studied for their binding to human galectin-3 by fluorescence polarization and isothermal titration calorimetry to show low micromolar K d values. The best inhibitor displayed a K d value of 8.0 μM. An analysis of the thermodynamic binding parameters revealed that the binding Gibbs free energy (Δ G) of the new inhibitors was dominated by enthalpy (Δ H). The binding mode of the four most efficient 1,2-thiodisaccharides was also studied by X-ray crystallography that uncovered the unique role of water-mediated hydrogen bonds in conferring enthalpy-driven affinity enhancement for the new inhibitors. This 1,2-thiodisaccharide-type scaffold represents a new lead for galectin-3 inhibitor discovery and offers several possibilities for further development.
10.
Mahanti, Mukul, et al.
(författare)
Epimers Switch Galectin-9 Domain Selectivity : 3 N-Aryl Galactosides Bind the C-Terminal and Gulosides Bind the N-Terminal
2020
Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 11:1, s. 34-39
Tidskriftsartikel (refereegranskat) 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 galectin-9N find stable poses with specific interactions, which proposes a possible explanation to the gal/gulo 9C/9N selectivity.
