RESUMEN
A stereospecific Mizoroki-Heck cross-coupling of differently substituted glycals with haloarenes resulting in the exclusive formation of either α- or ß-aryl-C-glycosides depending solely on the configuration at C3 was achieved. The reaction was easy to set up because no specific precautions were required concerning moisture or oxygen, and it proceeded by a chirality transfer from C3 to C1. After optimization of cross-coupling conditions, various prepared glycals (7â examples) and arenes (10â examples) were tested, leading stereospecifically to the corresponding aryl-C-glycosides with a carbonyl group at C3, thus opening up new horizons for the total synthesis of glycosylated natural products.
RESUMEN
A new strategy for the synthesis of acyl ß-C-glycosides is described. The reactivity of glyconitriles toward organometallic reagents such as organomagnesium or organolithium derivatives was studied, affording acyl ß-C-glycosides in moderate to good yields. In this study, glycal formation was efficiently prevented by deprotonating the hydroxyl group in position 2 of the glyconitriles during the process.
RESUMEN
We propose here the synthesis and biological evaluation of 3,4-dideoxy-GalCer derivatives. The absence of the 3- and 4-hydroxyls on the sphingoid base is combined with the introduction of mono or difluoro substituent at C3 (analogues 8 and 9, respectively) to evaluate their effect on the stability of the ternary CD1d/GalCer/TCR complex which strongly modulate the immune responses. Biological evaluations were performed in vitro on human cells and in vivo in mice and results discussed with support of modeling studies. The fluoro 3,4-dideoxy-GalCer analogues appears as partial agonists compared to KRN7000 for iNKT cell activation, inducing T(H)1 or T(H)2 biases that strongly depend of the mode of antigen presentation, including human vs mouse differences. We evidenced that if a sole fluorine atom is not able to balance the loss of the 3-OH, the presence of a difluorine group at C3 of the sphingosine can significantly restore human iNKT activation.
Asunto(s)
Adyuvantes Inmunológicos/síntesis química , Galactosilceramidas/síntesis química , Células T Asesinas Naturales/efectos de los fármacos , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/farmacología , Animales , Células Presentadoras de Antígenos/efectos de los fármacos , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Antígenos CD1d/inmunología , Antígenos CD1d/metabolismo , Línea Celular , Femenino , Galactosilceramidas/química , Galactosilceramidas/inmunología , Galactosilceramidas/metabolismo , Galactosilceramidas/farmacología , Humanos , Enlace de Hidrógeno , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Células T Asesinas Naturales/inmunología , Células T Asesinas Naturales/metabolismo , Estabilidad Proteica , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-Actividad , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/metabolismo , Células Th2/efectos de los fármacos , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
Our goal in the search for potentially bioactive analogues of KRN 7000 was to design an easy synthetic approach to a library of analogues using a strategy recently developed in our laboratory based on a Nucleophilic addition followed by an Epoxide Opening (the NEO strategy). Through the use of a common pivotal structure, a new C-galactoside ester analogue (23) was synthesized which showed an encouraging T(H)2 biased response during preliminary biological tests.
Asunto(s)
Galactósidos/química , Galactósidos/síntesis química , Galactosilceramidas/química , Glucolípidos/síntesis química , Animales , Proliferación Celular , Células Cultivadas , Ésteres , Galactósidos/farmacología , Glucolípidos/química , Glucolípidos/farmacología , Interferón gamma/metabolismo , Interleucina-4/metabolismo , RatonesRESUMEN
3,6-Anhydro-1-(aryl or alkylamino)-1-deoxy-D-sorbitol derivatives have been prepared in four steps from isosorbide, a by-product from the starch industry. The inhibitory activities of these new compounds have been evaluated towards 13 glycosidases. A first lead-compound was identified, which inhibited beta-N-acetylglucosaminidase from bovine kidney (82% inhibition at 1mM).
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Glicósido Hidrolasas/antagonistas & inhibidores , Sorbitol/síntesis química , Animales , Bovinos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glicósido Hidrolasas/metabolismo , Isosorbida/química , Riñón/enzimología , Sorbitol/análogos & derivados , Sorbitol/farmacologíaRESUMEN
Preparation of several acyclonucleosides containing both a difluoromethylphosphonate group and a triazole moiety is described starting from a difluorophosphonosulfide. The key step of the synthesis involves a copper(I)-catalyzed Huisgen 1-3 dipolar cycloaddition between difluorophosphonylated azides and propargylated nucleobases derived from thymine and 2-amino-6-chloropurine.
Asunto(s)
Cobre/química , Nucleótidos/química , Nucleótidos/síntesis química , Organofosfonatos/química , Alquinos/química , CatálisisRESUMEN
Several alpha-C-(alkynyl)-galactosides were synthesized using a tandem reaction involving the addition of a metal alkynylide to a chiral acyclic epoxyaldehyde, followed by an in situ closure of the generated alkoxide on the epoxide function.
Asunto(s)
Galactósidos/química , Aldehídos/síntesis química , Aldehídos/química , Galactósidos/síntesis química , Estructura Molecular , Zinc/químicaRESUMEN
N-phosphorylimines undergo Lewis acid-catalyzed Diels-Alder reactions with Danishefsky's diene. Application of the chiral catalyst zinc(II)-(S)-BINOL results in good-to-low asymmetric induction but poor chemical conversion. However, the absolute stereochemistry of novel aza-Diels-Alder cycloadducts, such as diethyl 4-oxo-2-phenyl-3,4-dihydropyridin-1(2H)-ylphosphonate, can be determined using circular dichroism (CD). Comparison between experimental and TDDFT-calculated CD spectrum shows that use of the (S)-catalyst results in predominant formation of the (6R) cycloadducts.