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1.
Bioorg Med Chem ; 94: 117480, 2023 Oct 30.
Article in English | MEDLINE | ID: mdl-37774448

ABSTRACT

Galectins, a family of endogenous glycan-binding proteins, play crucial roles in a broad range of physiological and pathological processes. Galectin-1 (Gal-1), a proto-type member of this family, is overexpressed in several cancers and plays critical roles in tumor-immune escape, angiogenesis and metastasis. Thus, generation of high-affinity Gal-1 inhibitors emerges as an attractive therapeutic approach for a wide range of neoplastic conditions. Small-molecule carbohydrate inhibitors based on lactose (Lac) and N-acetyllactosamine (LacNAc) structures have been tested showing different results. In this study, we evaluated Lac- and LacNAc-based compounds with specific chemical modifications at key positions as Gal-1 ligands by competitive solid-phase assays (SPA) and isothermal titration calorimetry (ITC). Both assays showed excellent correlation, highlighting that lactosides bearing bulky aromatic groups at the anomeric carbon and sulfate groups at the O3' position exhibited the highest binding affinities. To dissect the atomistic determinants for preferential affinity of the different tested Gal-1 ligands, molecular docking simulations were conducted and PRODIGY-LIG structure-based method was employed to predict binding affinity in protein-ligand complexes. Notably, calculated binding free energies derived from the molecular docking were in accordance with experimental values determined by SPA and ITC, showing excellent correlation between theoretical and experimental approaches. Moreover, this analysis showed that 3'-O-sulfate groups interact with residues of the Gal-1 subsite B, mainly with Asn33, while the ester groups of the aromatic anomeric group interact with Gly69 and Thr70 at Gal-1 subsite E, extending deeper into the pocket, which could account for the enhanced binding affinity. This study contributes to the rational design of highly optimized Gal-1 inhibitors to be further studied in cancer models and other pathologic conditions.

2.
ACS Omega ; 8(30): 26793-26805, 2023 Aug 01.
Article in English | MEDLINE | ID: mdl-37546669

ABSTRACT

Hexahydro-3-alkyl-3H-oxazolo[3,4-a]pyridines 4-15 for the quantitative analysis of various aldehydes were obtained in good yield via the condensation reaction of 2-hydroxymethylpiperidine (2-HMP) with aldehydes under mild conditions. When acrolein was used, the bicyclic 17 was obtained. This novel compound has suitable physical characteristics for an analytical standard. The hexahydro-3-vinyl-3H-oxazolo[3,4-a]pyridine 16 can be obtained at higher temperatures using an excess of acrolein (3 equiv). Following the same procedure as for 16, but with an excess of 2-HMP (2 equiv), a diastereomeric mixture of 18/19, which are both bisadducts of 2-HMP with acrolein, was obtained. The latter mixture can be easily converted into pure 18. Mechanistically, a thorough 1H-NMR study did not show any evidence that the condensation reaction proceeded via an enamine. The reaction probably proceeded through an elusive hemiaminal and fleeting iminium ion, which underwent subsequent cyclization to give hexahydro-3-alkyl-3H-oxazolo[3,4-a]pyridines 4-16. The reaction pathways for the preparation of 4-18 are described.

3.
Molecules ; 26(1)2020 Dec 29.
Article in English | MEDLINE | ID: mdl-33383774

ABSTRACT

Vanillin-based lactoside derivatives were synthetized using phase-transfer catalyzed reactions from per-O-acetylated lactosyl bromide. The aldehyde group of the vanillin moiety was then modified to generate a series of related analogs having variable functionalities in the para- position of the aromatic residue. The corresponding unprotected lactosides, obtained by Zemplén transesterification, were regioselectively 3'-O-sulfated using tin chemistry activation followed by treatment with sulfur trioxide-trimethylamine complex (Men3N-SO3). Additional derivatives were also prepared from the vanillin's aldehyde using a Knoevenagel reaction to provide extended α, ß-unsaturated carboxylic acid which was next reduced to the saturated counterpart.


Subject(s)
Benzaldehydes/chemistry , Galectins/antagonists & inhibitors , Glycosides/chemistry , Sulfates/chemistry , Benzaldehydes/chemical synthesis , Benzaldehydes/pharmacology , Catalysis , Chemistry Techniques, Synthetic , Galectins/metabolism , Glycosides/chemical synthesis , Glycosides/pharmacology , Humans , Molecular Docking Simulation , Stereoisomerism , Sulfates/chemical synthesis , Sulfates/pharmacology
4.
Histochem Cell Biol ; 147(2): 285-301, 2017 Feb.
Article in English | MEDLINE | ID: mdl-28013366

ABSTRACT

A hallmark of endogenous lectins is their ability to select a few distinct glycoconjugates as counterreceptors for functional pairing from the natural abundance of cellular glycoproteins and glycolipids. As a consequence, assays to assess inhibition of lectin binding should necessarily come as close as possible to the physiological situation, to characterize an impact of a synthetic compound on biorelevant binding with pharmaceutical perspective. We here introduce in a proof-of-principle manner work with sections of paraffin-embedded tissue (jejunum, epididymis) and labeled adhesion/growth-regulatory galectins, harboring one (galectin-1 and galectin-3) or two (galectin-8) types of lectin domain. Six pairs of synthetic lactosides from tailoring of the headgroup (3'-O-sulfation) and the aglycone (ß-methyl to aromatic S- and O-linked extensions) as well as three bi- to tetravalent glycoclusters were used as test compounds. Varying extents of reduction in staining intensity by synthetic compounds relative to unsubstituted/free lactose proved the applicability and sensitivity of the method. Flanking cytofluorimetric assays on lectin binding to native cells gave similar grading, excluding a major impact of tissue fixation. The experiments revealed cell/tissue binding of galectin-8 preferentially via one domain, depending on the cell type so that the effect of an inhibitor in a certain context cannot be extrapolated to other cells/tissues. Moreover, the work with the other galectins attests that this assay enables comprehensive analysis of the galectin network in serial tissue sections to determine overlaps and regional differences in inhibitory profiles.


Subject(s)
Galectins/chemistry , Galectins/metabolism , Flow Cytometry , Galectins/classification , Glycosides/chemical synthesis , Glycosides/chemistry , Glycosides/metabolism , Humans , Lectins/chemistry , Lectins/metabolism , Protein Binding
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