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1.
Angew Chem Int Ed Engl ; 57(19): 5257-5261, 2018 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-29480525

RESUMEN

Cysteine-reactive small molecules are used as chemical probes of biological systems and as medicines. Identifying high-quality covalent ligands requires comprehensive kinetic analysis to distinguish selective binders from pan-reactive compounds. Quantitative irreversible tethering (qIT), a general method for screening cysteine-reactive small molecules based upon the maximization of kinetic selectivity, is described. This method was applied prospectively to discover covalent fragments that target the clinically important cell cycle regulator Cdk2. Crystal structures of the inhibitor complexes validate the approach and guide further optimization. The power of this technique is highlighted by the identification of a Cdk2-selective allosteric (type IV) kinase inhibitor whose novel mode-of-action could be exploited therapeutically.


Asunto(s)
Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Cisteína/farmacología , Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Ligandos , Inhibidores de Proteínas Quinasas/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Quinasa 2 Dependiente de la Ciclina/metabolismo , Cisteína/química , Cinética , Estructura Molecular , Inhibidores de Proteínas Quinasas/análisis , Inhibidores de Proteínas Quinasas/síntesis química , Bibliotecas de Moléculas Pequeñas/análisis , Bibliotecas de Moléculas Pequeñas/síntesis química
2.
Beilstein J Org Chem ; 12: 1440-6, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27559395

RESUMEN

Vaccines against S. pneumoniae, one of the most prevalent bacterial infections causing severe disease, rely on isolated capsular polysaccharide (CPS) that are conjugated to proteins. Such isolates contain a heterogeneous oligosaccharide mixture of different chain lengths and frame shifts. Access to defined synthetic S. pneumoniae CPS structures is desirable. Known syntheses of S. pneumoniae serotype 3 CPS rely on a time-consuming and low-yielding late-stage oxidation step, or use disaccharide building blocks which limits variability. Herein, we report the first iterative automated glycan assembly (AGA) of a conjugation-ready S. pneumoniae serotype 3 CPS trisaccharide. This oligosaccharide was assembled using a novel glucuronic acid building block to circumvent the need for a late-stage oxidation. The introduction of a washing step with the activator prior to each glycosylation cycle greatly increased the yields by neutralizing any residual base from deprotection steps in the synthetic cycle. This process improvement is applicable to AGA of many other oligosaccharides.

3.
Org Lett ; 17(15): 3670-3, 2015 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-26161847

RESUMEN

The use of versatile alkynyl-building blocks that are activated by gold(I)-catalysis is demonstrated to efficiently generate a variety of glycosides in continuous flow. The application of a continuous flow setting to gold(I)-catalyzed glycosylations enables very short reaction times and excellent control of the reaction conditions.


Asunto(s)
Alquinos/química , Glicósidos/síntesis química , Oro/química , Catálisis , Ciclización , Glicósidos/química , Glicosilación , Isocumarinas/química , Estructura Molecular , Estereoisomerismo
4.
J Am Chem Soc ; 137(8): 2848-51, 2015 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-25668389

RESUMEN

Legionaminic acid is a nine-carbon diamino monosaccharide that is found coating the surface of various bacterial human pathogens. Its unique structure makes it a valuable biological probe, but access via isolation is difficult and no practical synthesis has been reported. We describe a stereoselective synthesis that yields a legionaminic acid building block as well as linker-equipped conjugation-ready legionaminic acid starting from cheap d-threonine. To set the desired amino and hydroxyl group pattern of the target, we designed a concise sequence of stereoselective reactions. The key transformations rely on chelation-controlled organometallic additions and a Petasis multicomponent reaction. The legionaminic acid was synthesized in a form that enables attachment to surfaces. Glycan microarray containing legionaminic acid revealed that human antibodies bind the synthetic glycoside. The synthetic bacterial monosaccharide is a valuable probe to detect an immune response to bacterial pathogens such as Legionella pneumophila, the causative agent of Legionnaire's disease.


Asunto(s)
Pruebas Serológicas/métodos , Ácidos Siálicos/síntesis química , Técnicas de Química Sintética , Glicósidos/inmunología , Humanos , Análisis por Micromatrices , Ácidos Siálicos/química , Estereoisomerismo , Treonina/química
5.
Chemistry ; 19(37): 12497-503, 2013 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-23950082

RESUMEN

ß-Glucans are a group of structurally heterogeneous polysaccharides found in bacteria, fungi, algae and plants. ß-(1,3)-D-Glucans have been studied in most detail due to their impact on the immune system of vertebrates. The studies into the immunomodulatory properties of these glucans are typically carried out with isolates that contain a heterogeneous mixture of polysaccharides of different chain lengths and varying degrees of branching. In order to determine the structure-activity relationship of ß-(1,3)-glucans, access to homogeneous, structurally-defined samples of these oligosaccharides that are only available through chemical synthesis is required. The syntheses of ß-glucans reported to date rely on the classical solution-phase approach. We describe the first automated solid-phase synthesis of a ß-glucan oligosaccharide that was made possible by innovating and optimizing the linker and glycosylating agent combination. A ß-(1,3)-glucan dodecasaccharide was assembled in 56 h in a stereoselective fashion with an average yield of 88% per step. This automated approach provides means for the fast and efficient assembly of linker-functionalized mono- to dodecasaccharide ß-(1,3)-glucans required for biological studies.


Asunto(s)
Polisacáridos/química , Polisacáridos/síntesis química , beta-Glucanos/química , beta-Glucanos/síntesis química , Aminación , Animales , Hongos , Glicosilación , Plantas , Técnicas de Síntesis en Fase Sólida , Relación Estructura-Actividad
6.
Chem Commun (Camb) ; 48(98): 11987-9, 2012 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-23128386

RESUMEN

A chemoenzymatic synthesis of sialic acid from inexpensive N-acetyl-D-glucosamine is described. In a three-step Wittig-protection-ozonolysis strategy manno-configured aldehydes are obtained. Treatment with oxaloacetate in the presence of macrophomate synthase affords the signature α-keto-γ-hydroxy acid moiety with high diastereoselectivity.


Asunto(s)
Complejos Multienzimáticos/metabolismo , Ácido N-Acetilneuramínico/biosíntesis , Conformación de Carbohidratos , Complejos Multienzimáticos/química , Ácido N-Acetilneuramínico/química
7.
Chemistry ; 18(34): 10701-14, 2012 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-22777749

RESUMEN

The hydrodefluorination (HDF) of fluoroalkenes in the presence of a variety of titanium catalysts was studied with respect to scope, selectivity, and mechanism. Optimization revealed that the catalyst requires low steric bulk and high electron density; secondary silanes serve as the preferred hydride source. A broad range of substrates yield partially fluorinated alkenes, such as previously unknown (Z)-1,2-(difluorovinyl)ferrocene. Mechanistic studies indicate a titanium(III) hydride as the active species, which forms a titanium(III) fluoride by H/F exchange with the substrate. The HDF step can follow both an insertion/elimination and a σ-bond metathesis mechanism; the E/Z selectivity is controlled by the substrate. The catalysts' ineffieciency towards fluoroallenes was rationalized by studying their reactivity towards Group 6 hydride complexes.

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