Synthesis of tricyclic carbohydrate–benzene hybrids as selective inhibitors of galectin-1 and galectin-8 N-terminal domains

Wu, Chunxia; Yong, Can; Zhong, Qiuju; Wang, Zhouyu; Nilsson, Ulf J.; Zhang, Yuanyuan

doi:10.1039/d0ra03144e

Cited by 10 publications

(8 citation statements)

References 34 publications

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“…The popularity of this deiodosilylation approach with iodine monochloride to access other important, high‐value organic molecules including access to tricyclic carbohydrate‐benzene hybrids [10b] or alternatively towards Hagfeldt donor organic dyes [10c] has also recently been reported last year.…”

Section: Halogenation Of Arenes/alkenes/alkynes Using Iodine Monochloridementioning

confidence: 98%

Reactivity and Applications of Iodine Monochloride in Synthetic Approaches

2021

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Over the last half‐decade, routes towards accessing halogenated compounds of value such as bioactive pharmaceuticals, organic building blocks has been of interest to the synthetic community. The demand for new methodologies to access important compounds has surged over the period. Amongst the halogenating agents available in a chemist's toolbox, one reagent in particular, iodine monochloride (ICl), is relatively under employed in comparison to alternatives such as molecular iodine for example. In this Minireview, we document the most recent applications (2015–2020) of ICl in synthetic organic transformations, namely halogenations including iodinations and chlorination reactions, cyclizations, metathesis reactions as well as oxidation processes. Furthermore, its versatile nature and interesting properties will be discussed, through its advantages and downfalls over other halogenating reagents, and discussions where relevant to compare modes of reactivity and mechanistic insights is presented.

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Section: Halogenation Of Arenes/alkenes/alkynes Using Iodine Monochloridementioning

confidence: 98%

Reactivity and Applications of Iodine Monochloride in Synthetic Approaches

2021

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“…The discovery of a selective tricyclic galactalbenzene hybrid 3 has been described, which has an affinity of 180 μM for galectin-8N. [23] However, this compound is only twofold selective over galectin-1. Another reported galectin-8N ligand is galactomalonate 4, with a micromolar affinity for galectin-8N but no reported affinities for other galectins.…”

Section: Introductionmentioning

confidence: 99%

Selective Galectin‐8N Ligands: The Design and Synthesis of Phthalazinone‐d‐Galactals

et al. 2021

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Ligand selectivity among the highly conserved galectins has been an ever-challenging objective. For galectin-8, a protein prevalent in both pathology and tissue distribution, we report phthalazinone-galactals that show excellent selectivity for the galectin-8N-terminal domain. A dissection of structure-activity relationships of the phthalazinone and an extensive molecular dynamics meta-analysis accompany the discovery of the selective galectin-8N ligands presented here. These selective compounds will facilitate the study of galectin-8 biology and may have pharmaceutical relevance in the wide range of galectin-8 associated pathologies.

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“…Of particular note is a recently reported tricyclic galactose-benzene hybrid 2 ( K d = 180 μM) which has about 2-fold selectivity over galectin-1 and a high 23-fold selectivity over galectin-3 ( Figure 1 ). 21 Published docking analyses of compound 2 in complex with galectin-8N suggested that the endocyclic double bond at the junction between the 3,4-dihydropyran ring and the adjacent phenyl ring of 2 lies within 3.5 Å to the electropositive side chain guanidinium ion of Arg45. 21 This distance would allow for an interaction between the double bond and Arg45.…”

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confidence: 99%

“… 21 Published docking analyses of compound 2 in complex with galectin-8N suggested that the endocyclic double bond at the junction between the 3,4-dihydropyran ring and the adjacent phenyl ring of 2 lies within 3.5 Å to the electropositive side chain guanidinium ion of Arg45. 21 This distance would allow for an interaction between the double bond and Arg45. Furthermore, the phenyl moieties of compound 2 were solvent-exposed and not in contact with galectin-8N amino acid side chains.…”

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confidence: 99%

“…Furthermore, the phenyl moieties of compound 2 were solvent-exposed and not in contact with galectin-8N amino acid side chains. 21 Therefore, we hypothesized that the endocyclic double bond of compound 2 possibly accounts for the higher affinity and selectivity of the compound for galectin-8N through interaction with Arg45 while none of its phenyl rings engage in specific interactions with the neighboring residues. Hence, the d -galactal 3 represents the minimum active fragment of compound 2 .…”

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confidence: 99%

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Structure-Guided Design of d-Galactal Derivatives with High Affinity and Selectivity for the Galectin-8 N-Terminal Domain

Hassan

Baussière

Guzelj

et al. 2021

ACS Med. Chem. Lett.

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Galectin-8 is a carbohydrate-binding protein that plays a crucial role in tumor progression and metastasis, antibacterial autophagy, modulation of the immune system, and bone remodeling. The design, synthesis, and protein affinity evaluation of a set of C-3 substituted benzimidazole and quinoline D-galactal derivatives identified a D-galactal-benzimidazole hybrid as a selective ligand for the galectin-8 N-terminal domain (galectin-8N), with a K d of 48 μM and 15-fold selectivity over galectin-3 and even better selectivity over the other mammalian galectins. X-ray structural analysis of galectin-8N in complex with one benzimidazole-and one quinoline-galactal derivative at 1.52 and 2.1 Å together with molecular dynamics simulations and quantum mechanical calculations of galectin-8N in complex with the benzimidazole derivative revealed orbital overlap between a NH LUMO of Arg45 with electron rich HOMOs of the olefin and O4 of the D-galactal. Such overlap is hypothesized to contribute to the high affinity of the D-galactal-derived ligands for galectin-8N. A (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4sulfophenyl)-2H-tetrazolium) (MTS) assay evaluation of the D-galactal-benzimidazole hybrid and an analogous galactoside derivative on a panel of cell lines with MTS assay showed no effect on cell viability up to 100 μM concentration. A subsequent functional assay using the MDA-MB-231 cell line demonstrated that the D-galactal-benzimidazole hybrid and the analogous galactoside derivative reduced the secretion of the proinflammatory cytokines interleukin-6 (IL-6) and IL-8 in a dose-dependent manner. Therefore, these compounds represent potential probes for galectin-8N pharmacology investigations and possibly promising leads for the design and synthesis of potent and selective galectin-8 inhibitors as potential antitumor and anti-inflammatory agents.

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Synthesis of tricyclic carbohydrate–benzene hybrids as selective inhibitors of galectin-1 and galectin-8 N-terminal domains

Abstract: Fused tricyclic carbohydrate–benzene hybrids carrying substituents at C10 and/or C11 were designed, synthesized and evaluated as inhibitors for galectin-1 and the N-terminal domain of galectin-8.

Cited by 10 publications

References 34 publications

Reactivity and Applications of Iodine Monochloride in Synthetic Approaches

Reactivity and Applications of Iodine Monochloride in Synthetic Approaches

Selective Galectin‐8N Ligands: The Design and Synthesis of Phthalazinone‐d‐Galactals

Structure-Guided Design of d-Galactal Derivatives with High Affinity and Selectivity for the Galectin-8 N-Terminal Domain

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