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1.
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
2.
Chembiochem ; 24(23): e202300480, 2023 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-37715738

RESUMEN

Selective covalent labelling of enzymes using small molecule probes has advanced the scopes of protein profiling. The covalent bond formation to a specific target is the key step of activity-based protein profiling (ABPP), a method which has become an indispensable tool for measuring enzyme activity in complex matrices. With respect to carbohydrate processing enzymes, strategies for ABPP so far involve labelling the active site of the enzyme, which results in permanent loss of activity. Here, we report in a proof of concept study the use of ligand-directed chemistry (LDC) for labelling glycoside hydrolases near - but not in - the active site. During the labelling process, the competitive inhibitor is cleaved from the probe, departs the active site and the enzyme maintains its catalytic activity. To this end, we designed a building block synthetic concept for small molecule probes containing iminosugar-based reversible inhibitors for labelling of two model ß-glucosidases. The results indicate that the LDC approach can be adaptable for covalent proximity labelling of glycoside hydrolases.


Asunto(s)
Carbohidratos , Glicósido Hidrolasas , Glicósido Hidrolasas/metabolismo , Prueba de Estudio Conceptual , Ligandos
3.
Bioorg Chem ; 140: 106819, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37666109

RESUMEN

A new class of compounds inhibiting de-O-glycosylation of proteins has been identified. Highly substituted diaminocyclopentanes are impressively selective reversible non-transition state O-ß-N-acetyl-d-glucosaminidase (O-GlcNAcase) inhibitors. The ease of preparative access and remarkable biological activities provide highly viable leads for the development of anti-tau-phosphorylation agents with a view to eventually ameliorating Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer , beta-N-Acetilhexosaminidasas , Humanos , Hexosaminidasas , Glicosilación
4.
Chem Rec ; 21(11): 2980-2989, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34816592

RESUMEN

A short survey on selected ß-galactosidase inhibitors as potential pharmacological chaperones for GM1 -gangliosidosis and Morquio B associated mutants of human lysosomal ß-galactosidase is provided highlighting recent developments in this particular area of lysosomal storage disorders and orphan diseases.


Asunto(s)
Gangliosidosis , Gangliosidosis GM1 , Mucopolisacaridosis IV , beta-Galactosidasa/antagonistas & inhibidores , Gangliosidosis GM1/tratamiento farmacológico , Humanos , Lisosomas , Mucopolisacaridosis IV/tratamiento farmacológico
5.
Molecules ; 25(20)2020 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-33050585

RESUMEN

The scope of a series of N-alkylated iminosugar based inhibitors in the d-gluco as well as d-xylo configuration towards their interaction with human lysosomal ß-glucocerebrosidase has been evaluated. A versatile synthetic toolbox has been developed for the synthesis of N-alkylated iminosugar scaffolds conjugated to a variety of terminal groups via a benzoic acid ester linker. The terminal groups such as nitrile, azide, alkyne, nonafluoro-tert-butyl and amino substituents enable follow-up chemistry as well as visualisation experiments. All compounds showed promising inhibitory properties as well as selectivities for ß-glucosidases, some exhibiting activities in the low nanomolar range for ß-glucocerebrosidase.


Asunto(s)
Glucosilceramidasa/metabolismo , Lisosomas/enzimología , Ácido Benzoico/metabolismo , Humanos , Cinética , Espectroscopía de Resonancia Magnética , Estructura Molecular
6.
Molecules ; 25(17)2020 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-32899288

RESUMEN

Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid ß-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent ß-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a "strategic" hydroxyl group. New compounds have revealed highly promising activities with a range of ß-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease.


Asunto(s)
Ciclopentanos/farmacología , Galactosidasas/metabolismo , Iminopiranosas/farmacología , Lisosomas/enzimología , Chaperonas Moleculares/metabolismo , Cristalización , Ciclopentanos/síntesis química , Ciclopentanos/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Galactosidasas/antagonistas & inhibidores , Humanos , Iminopiranosas/síntesis química , Iminopiranosas/química , Ligandos , Lisosomas/efectos de los fármacos , Conformación Molecular , Proteínas Mutantes/metabolismo
7.
Int J Mol Sci ; 20(19)2019 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-31554271

RESUMEN

In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.


Asunto(s)
Apoptosis/efectos de los fármacos , Quimiocina CXCL12/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Receptores CXCR4/metabolismo , Transducción de Señal/efectos de los fármacos , Aminoquinolinas , Antineoplásicos/farmacología , Bencimidazoles , Biomarcadores , Butilaminas , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quimiocina CXCL12/genética , Exones , Femenino , Expresión Génica , Compuestos Heterocíclicos con 1 Anillo/farmacología , Humanos , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Masculino , Mutación , Estadificación de Neoplasias , Pronóstico , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética
8.
Molecules ; 23(3)2018 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-29558439

RESUMEN

From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d-galacto configuration are potent inhibitors of the GH20 ß-d-hexosaminidases probed and may bear potential as regulators of N-acetyl-d-hexosaminidase activities in vivo.


Asunto(s)
Ciclopentanos/farmacología , Inhibidores Enzimáticos/farmacología , beta-N-Acetilhexosaminidasas/antagonistas & inhibidores , Cristalografía por Rayos X , Ciclopentanos/síntesis química , Ciclopentanos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Conformación Molecular , beta-N-Acetilhexosaminidasas/metabolismo
9.
European J Org Chem ; 2016(25): 4328-4337, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27840588

RESUMEN

The Amadori rearrangement was investigated for the synthesis of C-glycosyl-type neoglycoconjugates. Various amines including diamines, amino-functionalized glycosides, lysine derivatives, and peptides were conjugated with two different heptoses to generate non-natural C-glycosyl-type glycoconjugates of the d-gluco and d-manno series. With these studies, the scope and limitations of the Amadori rearrangement as a conjugation method have been exemplified with respect to the carbohydrate substrate, as well as the amino components.

10.
Proc Natl Acad Sci U S A ; 109(3): 781-6, 2012 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-22219371

RESUMEN

N-linked glycans play key roles in protein folding, stability, and function. Biosynthetic modification of N-linked glycans, within the endoplasmic reticulum, features sequential trimming and readornment steps. One unusual enzyme, endo-α-mannosidase, cleaves mannoside linkages internally within an N-linked glycan chain, short circuiting the classical N-glycan biosynthetic pathway. Here, using two bacterial orthologs, we present the first structural and mechanistic dissection of endo-α-mannosidase. Structures solved at resolutions 1.7-2.1 Å reveal a (ß/α)(8) barrel fold in which the catalytic center is present in a long substrate-binding groove, consistent with cleavage within the N-glycan chain. Enzymatic cleavage of authentic Glc(1/3)Man(9)GlcNAc(2) yields Glc(1/3)-Man. Using the bespoke substrate α-Glc-1,3-α-Man fluoride, the enzyme was shown to act with retention of anomeric configuration. Complexes with the established endo-α-mannosidase inhibitor α-Glc-1,3-deoxymannonojirimycin and a newly developed inhibitor, α-Glc-1,3-isofagomine, and with the reducing-end product α-1,2-mannobiose structurally define the -2 to +2 subsites of the enzyme. These structural and mechanistic data provide a foundation upon which to develop new enzyme inhibitors targeting the hijacking of N-glycan synthesis in viral disease and cancer.


Asunto(s)
Bacteroides/enzimología , Polisacáridos/química , Polisacáridos/metabolismo , alfa-Manosidasa/metabolismo , Biocatálisis , Conformación de Carbohidratos , Dominio Catalítico , Secuencia Conservada , Humanos , Cinética , Ligandos , Modelos Moleculares , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Electricidad Estática , alfa-Manosidasa/antagonistas & inhibidores
11.
Beilstein J Org Chem ; 11: 1096-1104, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26199665

RESUMEN

The Amadori rearrangement was employed for the synthesis of C-glycosyl-type D-mannoside analogues, namely 1-propargylamino- and 1-phenylamino-1-deoxy-α-D-manno-heptopyranose. They were investigated as ligands of type 1-fimbriated E. coli bacteria by means of molecular docking and bacterial adhesion studies. It turns out that Amadori rearrangement products have a limited activity as inhibitors of bacterial adhesion because the ß-C-glycosidically linked aglycone considerably hampers complexation within the carbohydrate binding site of the type 1-fimbrial lectin FimH.

12.
Bioorg Med Chem Lett ; 24(12): 2777-80, 2014 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-24803362

RESUMEN

A new Staudinger/aza Wittig/Strecker multicomponent reaction sequence to C-1-cyano iminoalditols has been developed. When applied to 5-azidodeoxy-d-xylose and -d-glucose as substrates the method leads smoothly in good yield and with excellent stereoselectivity to respectively, 1,5-dideoxy-1,5-imino-d-idurono nitrile and 2,6-didesoxy-2,6-imino-d-glycero-d-ido-heptononitrile.


Asunto(s)
Iminopiranosas/síntesis química , Nitrilos/química , Compuestos Aza/química , Cristalografía por Rayos X , Iminopiranosas/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Estereoisomerismo
13.
Carbohydr Res ; 544: 109239, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39142016

RESUMEN

Isoiminosugars are highly biological active substances. Herein, we report a concise synthetic approach for this class of compounds. The key step relies on a stereospecific 1,2-hydride shift in O-2 tosylated glycopyranosides leading to C-2 branched glycofuranosides. This approach enables a 4-step synthesis of powerful ß-galactosidase inhibitor 4-epi-isofagomine starting from a simple d-glucopyranoside.


Asunto(s)
beta-Galactosidasa , beta-Galactosidasa/antagonistas & inhibidores , beta-Galactosidasa/metabolismo , beta-Galactosidasa/química , Iminoazúcares/síntesis química , Iminoazúcares/química , Estereoisomerismo , Iminopiranosas/química , Iminopiranosas/síntesis química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología
14.
Carbohydr Polym ; 326: 121633, 2024 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-38142079

RESUMEN

Polysaccharides are among the most abundant bioresources on earth and consequently need to play a pivotal role when addressing existential scientific challenges like climate change and the shift from fossil-based to sustainable biobased materials. The Research Roadmap 2040 of the European Polysaccharide Network of Excellence (EPNOE) provides an expert's view on how future research and development strategies need to evolve to fully exploit the vast potential of polysaccharides as renewable bioresources. It is addressed to academic researchers, companies, as well as policymakers and covers five strategic areas that are of great importance in the context of polysaccharide related research: (I) Materials & Engineering, (II) Food & Nutrition, (III) Biomedical Applications, (IV) Chemistry, Biology & Physics, and (V) Skills & Education. Each section summarizes the state of research, identifies challenges that are currently faced, project achievements and developments that are expected in the upcoming 20 years, and finally provides outlines on how future research activities need to evolve.


Asunto(s)
Polisacáridos
15.
Bioorg Med Chem Lett ; 23(11): 3393-5, 2013 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-23608762

RESUMEN

Yarrowia lipolytica short chain dehydrogenase/reductase (YlSDR) was expressed in Escherichia coli, purified and characterized in vitro. The substrate scope for YlSDR mediated oxidation was investigated with alcohols and unprotected carbohydrates spectrophotometrically, revealing a preference for secondary compared to primary alcohols. In reduction direction, YlSDR was highly active on ribulose and fructose, suggesting that the enzyme is a mannitol-2-dehydrogenase. In order to explore substrate tolerance especially for space-demanding, lipophilic protecting groups, 5-O-trityl-D-ribitol and 5-O-trityl-α,ß-D-ribose were investigated as substrates: YlSDR oxidized 5-O-trityl-D-ribitol and 5-O-trityl-α,ß-D-ribose and reduced the latter at the expense of NADP(H).


Asunto(s)
Ácido Graso Sintasas/metabolismo , NADH NADPH Oxidorreductasas/metabolismo , Pentosas/metabolismo , Ribitol/metabolismo , Yarrowia/enzimología , Escherichia coli/metabolismo , Ácido Graso Sintasas/genética , Fructosa/metabolismo , Cinética , Manitol Deshidrogenasas/genética , Manitol Deshidrogenasas/metabolismo , NADH NADPH Oxidorreductasas/genética , NADP/metabolismo , Oxidación-Reducción , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Ribosa/metabolismo , Especificidad por Sustrato
16.
J Inherit Metab Dis ; 35(3): 495-503, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22033734

RESUMEN

Unlike replacement therapy by infusion of exogenous recombinant lysosomal enzymes, pharmacological chaperones aim at a gain of function of endogenous gene products. Deficits resulting from missense mutations may become treatable by small, competitive inhibitors binding to the catalytical site and thus correcting the erroneous conformation of mutant enzymes. This may prevent their premature degradation and normalize intracellular trafficking as well as biological half-life. A major limitation currently arises from the huge number of individual missense mutations and the lack of knowledge on the structural requirements for specific interaction with mutant protein domains. Our previous work on mutations of the ß-galactosidase (ß-gal) gene, causing GM1 gangliosidosis (GM1) and Morquio B disease (MBD), respectively, characterized clinical phenotypes as well as biosynthesis, intracellular transport and subcellular localization of mutants. We recently identified an effective chaperone, DL-HexDGJ (Methyl 6-{[N(2)-(dansyl)-N(6)-(1,5-dideoxy-D-galactitol-1,5-diyl)- L-lysyl]amino} hexanoate), among a series of N-modified 1-deoxygalactonojirimycin derivatives carrying a dansyl group in its N-acyl moiety. Using novel and flexible synthetic routes, we now report on the effects of two oligofluoroalkyl-derivatives of 1-deoxygalactonojirimycin, Ph(TFM)(2)OHex-DGJ (N-(α,α-di-trifluoromethyl) benzyloxyhexyl-1,5-dideoxy-1,5-imino-D: -galactitol) and (TFM)(3)OHex-DGJ (N-(Nonafluoro-tert-butyloxy)hexyl-1,5-dideoxy-1,5-imino-D: -galactitol) on the ß-gal activity of GM1 and MBD fibroblasts. Both compounds are competitive inhibitors and increase the residual enzyme activities up to tenfold over base line activity in GM1 fibroblasts with chaperone-sensitive mutations. Western blots showed that this was due to a normalization of protein transport and intralysosomal maturation. The fact that the novel compounds were effective at very low concentrations (0.5-10 µM) in the cell culture medium as well as their novel chemical character suggest future testing in animal models. This may contribute to new aspects for efficient and personalized small molecule treatment of lysosomal storage diseases.


Asunto(s)
Gangliosidosis GM1/genética , Mucopolisacaridosis IV/genética , Alcoholes del Azúcar/química , beta-Galactosidasa/genética , Alelos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Exones , Gangliosidosis GM1/tratamiento farmacológico , Genotipo , Humanos , Enfermedades por Almacenamiento Lisosomal/terapia , Lisosomas/metabolismo , Modelos Químicos , Modelos Genéticos , Chaperonas Moleculares/metabolismo , Mucopolisacaridosis IV/tratamiento farmacológico , Mutación , Fenotipo
17.
Beilstein J Org Chem ; 8: 1619-1629, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23209494

RESUMEN

The Amadori rearrangement was investigated as a potential method for the conjugation of carbohydrate moieties to suitable amino components. Starting from selected aldoheptoses, which are readily available by means of the Kiliani-Fischer C-elongation reaction of the corresponding aldohexoses, glycoconjugates presenting D-gluco, D-manno and D-galacto as well as GlcNAc motifs have been synthesised. Following this strategy, non-natural C-glycosyl type glycoconjugates, which can be utilised as building blocks for the composition of larger molecular constructions, are available by a very short synthetic approach.

19.
Organometallics ; 40(9): 1185-1189, 2021 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-34054184

RESUMEN

A convenient synthetic method to obtain d-galactose-substituted acylsilanes and acylgermanes is described. These acyl group 14 compounds are easily accessible in good yields. Their structural properties were analyzed by a combination of NMR, single crystal X-ray crystallography, and UV/vis spectroscopy. A d-galactose-substituted tetraacylgermane represents a new interesting visible light photoinitiator based on its absorption properties as well as its high solubility.

20.
RSC Adv ; 11(26): 15943-15951, 2021 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-35481199

RESUMEN

A set of cyclopentanoid α-galactosidase ligands was prepared from a partially protected ω-eno-aldose via a reliable (2 + 3)-cycloaddition protocol with slightly modified conditions. The obtained N-benzylisoxazolidine ring was selectively opened and the configuration of the hydroxymethylgroup was inverted. Consecutive deprotection provided an aminocyclopentane, which was N-alkylated to furnish a set of potential α-galactosidase inhibitors. Their glycosidase inhibitory activities were screened with a panel of standard glycosidases of biological significance.

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