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1.
Bioorg Chem ; 145: 107231, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38394919

RESUMEN

The binding of human galectins by glycomimetic inhibitors is a promising therapeutic approach. The structurally distinct group of tandem-repeat galectins has scarcely been studied so far, and there is hardly any knowledge on their ligand specificity or their inhibitory potential, particularly concerning non-natural carbohydrates. Here, we present the synthesis of a library of seven 3-O-disubstituted thiodigalactoside-derived glycomimetics and their affinity to two tandem-repeat galectins, Gal-8 and Gal-9. The straightforward synthesis of these glycomimetics involved dibutyltin oxide-catalyzed 3,3́-O-disubstitution of commercially available unprotected thiodigalactoside, and conjugation of various aryl substituents by copper-catalyzed Huisgen azide-alkyne cycloaddition (CuAAC). The inhibitory potential of the prepared glycomimetics for Gal-8 and Gal-9 was assessed, and compared with the established galectins Gal-1 and Gal-3. The introduction of C-3 substituents resulted in an over 40-fold increase in affinity compared with unmodified TDG. The structure-affinity relations within the studied series were discussed using molecular modeling. Furthermore, the prepared glycomimetics were shown to scavenge Gal-8 and Gal-9 from the surface of cancer cells. This pioneering study on the synthetic inhibitors especially of Gal-9 identified lead compounds that may be used in further biomedical research.


Asunto(s)
Galectinas , Tiogalactósidos , Humanos , Unión Proteica , Galectinas/metabolismo , Tiogalactósidos/química , Carbohidratos/química
2.
Bioorg Chem ; 148: 107452, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38763001

RESUMEN

A new class of compounds, namely highly substituted diaminocyclopentane-l-lysine adducts, have been discovered as potent inhibitors of O-GlcNAcase, an enzyme crucial for protein de-O-glycosylation. These inhibitors exhibit exceptional selectivity and reversibility and are the first example of human O-GlcNAcase inhibitors that are structurally related to the transition state of the rate-limiting step with the "aglycon" still in bond-length proximity. The ease of their preparation, remarkable biological activities, stability, and non-toxicity make them promising candidates for the development of anti-tau-phosphorylation agents holding significant potential for the treatment of Alzheimer's disease.


Asunto(s)
Inhibidores Enzimáticos , Lisina , Humanos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Relación Estructura-Actividad , Lisina/química , Lisina/farmacología , beta-N-Acetilhexosaminidasas/antagonistas & inhibidores , beta-N-Acetilhexosaminidasas/metabolismo , Ciclopentanos/química , Ciclopentanos/farmacología , Ciclopentanos/síntesis química , Estructura Molecular , Relación Dosis-Respuesta a Droga
3.
J Agric Food Chem ; 72(28): 15613-15623, 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-38978453

RESUMEN

Here we describe a complex enzymatic approach to the efficient transformation of abundant waste chitin, a byproduct of the food industry, into valuable chitooligomers with a degree of polymerization (DP) ranging from 6 to 11. This method involves a three-step process: initial hydrolysis of chitin using engineered variants of a novel fungal chitinase from Talaromyces flavus to generate low-DP chitooligomers, followed by an extension to the desired DP using the high-yielding Y445N variant of ß-N-acetylhexosaminidase from Aspergillus oryzae, achieving yields of up to 57%. Subsequently, enzymatic deacetylation of chitooligomers with DP 6 and 7 was accomplished using peptidoglycan deacetylase from Bacillus subtilis BsPdaC. The innovative enzymatic procedure demonstrates a sustainable and feasible route for converting waste chitin into unavailable bioactive chitooligomers potentially applicable as natural pesticides in ecological and sustainable agriculture.


Asunto(s)
Aspergillus oryzae , Quitina , Quitinasas , Proteínas Fúngicas , Oligosacáridos , Talaromyces , Quitina/metabolismo , Quitina/química , Quitinasas/metabolismo , Quitinasas/genética , Quitinasas/química , Talaromyces/enzimología , Talaromyces/genética , Talaromyces/química , Talaromyces/metabolismo , Oligosacáridos/metabolismo , Oligosacáridos/química , Hidrólisis , Aspergillus oryzae/enzimología , Aspergillus oryzae/genética , Aspergillus oryzae/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/química , Bacillus subtilis/genética , Bacillus subtilis/enzimología , Bacillus subtilis/química , Bacillus subtilis/metabolismo , Biocatálisis , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/química
4.
Org Lett ; 26(3): 708-712, 2024 01 26.
Artículo en Inglés | MEDLINE | ID: mdl-38227978

RESUMEN

Photooxygenation of flavonoids leads to the release of carbon monoxide (CO). Our structure-photoreactivity study, employing several structurally different flavonoids, including their 13C-labeled analogs, revealed that CO can be produced via two completely orthogonal pathways, depending on their hydroxy group substitution pattern and the reaction conditions. While photooxygenation of the enol 3-OH group has previously been established as the CO liberation channel, we show that the catechol-type hydroxy groups of ring B can predominantly participate in photodecarbonylation.


Asunto(s)
Monóxido de Carbono , Flavonoides , Fotoquímica/métodos
5.
J Med Chem ; 67(11): 9214-9226, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38829964

RESUMEN

Pulmonary hypertension is a cardiovascular disease with a low survival rate. The protein galectin-3 (Gal-3) binding ß-galactosides of cellular glycoproteins plays an important role in the onset and development of this disease. Carbohydrate-based drugs that target Gal-3 represent a new therapeutic strategy in the treatment of pulmonary hypertension. Here, we present the synthesis of novel hydrophilic glycopolymer inhibitors of Gal-3 based on a polyoxazoline chain decorated with carbohydrate ligands. Biolayer interferometry revealed a high binding affinity of these glycopolymers to Gal-3 in the subnanomolar range. In the cell cultures of cardiac fibroblasts and pulmonary artery smooth muscle cells, the most potent glycopolymer 18 (Lac-high) caused a decrease in the expression of markers of tissue remodeling in pulmonary hypertension. The glycopolymers were shown to penetrate into the cells. In a biodistribution and pharmacokinetics study in rats, the glycopolymers accumulated in heart and lung tissues, which are most affected by pulmonary hypertension.


Asunto(s)
Galectina 3 , Hipertensión Pulmonar , Animales , Galectina 3/antagonistas & inhibidores , Galectina 3/metabolismo , Hipertensión Pulmonar/tratamiento farmacológico , Hipertensión Pulmonar/metabolismo , Ratas , Humanos , Distribución Tisular , Masculino , Biomarcadores , Células Cultivadas , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Polímeros/química , Polímeros/farmacología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/metabolismo
6.
ACS Omega ; 9(32): 34938-34950, 2024 Aug 13.
Artículo en Inglés | MEDLINE | ID: mdl-39157108

RESUMEN

In this work, we report the application of Buchwald-Hartwig amination for the preparation of new derivatives of quercetin and luteolin. Our investigation delves into the impact of aniline moiety on antioxidant, and anti-inflammatory activity, cytotoxicity, and the ability of flavonoids to modulate drug-resistance mechanisms in bacteria. The anti-inflammatory activity disappeared after the introduction of aniline into the flavonoids and the cytotoxicity remained low. Although the ability of quercetin and luteolin to modulate bacterial resistance to antibiotics has already been published, this is the first report on the molecular mechanism of this process. Both flavonoids attenuate erythromycin resistance by suppressing the ribosomal methyltransferase encoded by the ermA gene in Staphylococcus aureus. Notably, 4-(trifluoromethyl)anilino quercetin emerged as a potent ErmA inhibitor, likely by interacting with the RNA-binding pocket of ErmA. Additionally, both 4-fluoroanilino derivatives effectively impended the staphylococcal efflux system. All the prepared derivatives exhibited superior activity in modulating gentamicin resistance in S. aureus compared to the parent compounds. Overall, the incorporation of substituted anilines into the flavonoid core significantly enhanced its ability to combat multidrug resistance in bacteria.

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