RESUMEN
Conversions of diazocarbonyl carbohydrate compounds catalyzed by a series of rhodium and copper catalysts in conventional heating or microwave conditions were investigated. C-H insertion product was obtained in the presence of Rh(2)(OAc)(4). Intermolecular reactions rather than intramolecular reactions occurred in the presence of copper catalysts.
Asunto(s)
Cobre/química , Glucósidos/química , Cetonas/síntesis química , Compuestos Organometálicos/química , Rodio/química , Catálisis , Calor , Cetonas/química , MicroondasRESUMEN
An α-cyclodextrin-[60]fullerene conjugate with a flexible linker at the secondary face of α-cyclodextrin has been prepared, which displays significant water solubility and, more importantly, acts as a new class of HCV entry inhibitor with IC(50) at 0.17 µM level.
Asunto(s)
Antivirales/farmacología , Ciclodextrinas/farmacología , Fulerenos/química , Hepacivirus/efectos de los fármacos , Antivirales/síntesis química , Antivirales/química , Línea Celular Tumoral , Ciclodextrinas/síntesis química , Ciclodextrinas/química , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Solubilidad , Relación Estructura-ActividadRESUMEN
The search for new and potent cholinesterase inhibitors is an ongoing quest mobilizing many organic chemistry groups around the world as these molecules have been shown to treat the late symptoms of Alzheimer's disease as well as to act as neuroprotecting agents. In this work, we disclose the synthesis of novel 2-acetamidopurine nucleosides and, for the first time, regioselective N(7)-glycosylation with 2-acetamido-6-chloropurine, promoted by trimethylsilyl triflate, was accomplished by tuning the reaction conditions (acetonitrile as solvent, 65 degrees C, 5h) starting from 1-acetoxy bicyclic glycosyl donors, or by direct coupling of a methyl glucopyranoside with the nucleobase to obtain only N(7) nucleosides in reasonable yield (55-60%). The nucleosides as well as their sugar precursors were screened for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. While none of the compounds tested inhibited AChE, remarkably, some of the N(7) nucleosides and sugar bicyclic derivatives showed potent inhibition towards BChE. Nanomolar inhibition was obtained for one compound competing well with rivastigmine, a drug currently in use for the treatment of Alzheimer's disease. Experimental results showed that the presence of benzyl groups on the carbohydrate scaffold and the N(7)-linked purine nucleobase were necessary for strong BChE inactivation. A preliminary evaluation of the acute cytotoxicity of the elongated bicyclic sugar precursors and nucleosides was performed indicating low values, in the same order of magnitude as those of rivastigmine.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Nucleósidos de Purina/química , Nucleósidos de Purina/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/toxicidad , Fibroblastos/efectos de los fármacos , Glicosilación , Humanos , Nucleósidos de Purina/síntesis química , Nucleósidos de Purina/toxicidad , EstereoisomerismoRESUMEN
The relative configuration at C-6' of nucleoside antibiotic miharamycin A has been elucidated by NMR spectroscopy and proved to be S. The total synthesis of miharamycin B has also been investigated, which has led to the unprecedented construction of its core. The bicyclic sugar moiety has been elaborated by means of a SmI(2)-based keto-alkyne coupling. Elongation of its C-6 position towards a bicyclic sugar amino acid and conversion into a suitable glycosyl donor enabled efficient N-glycosylation with 2-aminopurine to take place to afford the nucleosidic part of miharamycin B. Final peptide coupling with arginine afforded the skeleton of miharamycin B. Unfortunately, attempts to deprotect this scaffold failed to afford the complex nucleoside antibiotic.
Asunto(s)
Antibacterianos/química , Nucleósidos/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Nucleósidos/síntesis química , EstereoisomerismoRESUMEN
Hemicarbasucrose, a close congener of sucrose in which the endocyclic oxygen atom of the glucose moiety is replaced by a methylene group was synthesized for the first time. The conformational behaviour of hemicarbasucrose was studied by a combination of molecular mechanics and NMR spectroscopy (J and NOE data). It was shown that the carbadisaccharide populates two distinct conformational families in solution, the normal syn-psi conformation, which is the predominating conformation of the parent natural O-glycoside, and the anti-psi conformation, which has not been detected for the O-disaccharide. Interestingly, the hemicarbasucrose is less flexible than its natural congener.
Asunto(s)
Sacarosa/análogos & derivados , Conformación de Carbohidratos , Secuencia de Carbohidratos , Espectroscopía de Resonancia Magnética , Datos de Secuencia Molecular , Oxígeno/química , Sacarosa/químicaRESUMEN
The selective and efficient functionalisation of large concave molecules is a chemical challenge opening the door to various applications, such as artificial enzymes. We propose here a method, based on deprotection of benzylated cyclodextrins, to selectively access a variety of complex structures with two or three new different functionalities on the primary platform. Our strategy is based on a mechanistic hypothesis involving the approach of an aluminium reagent between the primary oxygen atom and the endocyclic one of the same sugar unit. Due to its cyclic directionality, a change in steric hindrance on a given position of the cyclodextrin has a different effect on the clockwise or the counterclockwise directions. This concept is illustrated and exploited in two complementary ways: deoxygenation of the primary position of two diametrically opposed sugars induces a debenzylation reaction on the neighbouring clockwise sugars of alpha- and beta-cyclodextrins. Reversible capping, or bascule-bridging, of the same pair of sugars has the same effect on the debenzylation of alpha-cyclodextrin, but induces an important change of the geometry of beta-cyclodextrin, hence allowing the selective access to yet another functionalisation pattern. A combined use of deoxygenation and bascule-bridging allows the access to an alpha-cyclodextrin with its three pairs of primary functions differentiated and ready for further modifications. Bascule-bridge or deoxy-sugars are two complementary means to operate steric decompression and induce selective reactions to efficiently access a number of new patterns of functionalities on concave molecules.
Asunto(s)
Reactivos de Enlaces Cruzados/química , Desoxiazúcares/química , alfa-Ciclodextrinas/química , beta-Ciclodextrinas/química , Benceno/química , Hidrógeno/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oxígeno/química , EstereoisomerismoRESUMEN
A short and convenient strategy was developed for the first stereoselective chemical synthesis of aminobacteriohopanetetrol (= (1R,2R,3S,4S)-5-amino-1-[(22R)-hopan-30-yl]pentane-1,2,3,4-tetrol; 1), a typical biomarker for methanotrophic bacteria. Comparison of the NMR spectra of the synthetic and natural (peracetylated) product enabled us to unambiguously corroborate the absolute configuration of the functionalized pentyl side chain of 1.
Asunto(s)
Methylococcaceae/metabolismo , Triterpenos/síntesis química , Biomarcadores/química , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estereoisomerismo , Triterpenos/químicaRESUMEN
5a-Difluoro-5a-carbamannopyranose (gem-difluoro-carbamannopyranose) and 5a-difluoro-5a-carbagalactopyranose (gem-difluoro-carbagalactopyranose), close congeners of their respective natural sugars, in which the endocyclic oxygen atom has been replaced by a gem-difluoromethylene group, were synthesized from D-mannose and D-galactose, using a rearrangement strategy.
Asunto(s)
Flúor/química , Galactosa/química , Manosa/química , Conformación de Carbohidratos , Galactosa/análogos & derivados , Indicadores y Reactivos , Manosa/análogos & derivados , Modelos MolecularesRESUMEN
The conformational behaviour of the C-glycoside beta-C-Gal-(1-->3)-beta-Glc-OMe (1) has been studied using a combination of molecular mechanics and NMR spectroscopy (proton-proton coupling constants and nuclear Overhauser effects). It is shown that the C-disaccharide populates two distinctive conformational families in solution, the normal syn-psi conformation, which is the predominating conformation of parent O-glycoside 2, and the anti-psi conformation, which has not been detected for the O-disaccharide.
Asunto(s)
Disacáridos/química , Glicósidos/química , Biomimética , Conformación de Carbohidratos , Disacáridos/síntesis química , Galactosa , Glucosa , Espectroscopía de Resonancia Magnética , Modelos MolecularesRESUMEN
The conformational behavior of the C-glycoside analogue of N-acetyl-lactosamine, beta-C-Gal-(1-->4)-beta-GlcNAc-OMe, 1, has been studied using a combination of molecular mechanics calculations and NMR spectroscopy (J and NOE data). It is shown that the C-disaccharide populates three distinctive conformational families in solution, the major one being the anti-psi conformation. Of note, this conformation is only marginally populated for the O-disaccharide. Due to its conspicuous role in the regulation of adhesion, growth and tissue invasion of tumors and its avid binding to N-acetyl-lactosamine human, galectin-1 was tested as a receptor. This endogenous lectin recognizes a local minimum of 1, the syn-PhiPsi conformer, and thus a conformational selection process is correlated with the molecular recognition event.
Asunto(s)
Amino Azúcares/química , Galectina 1/química , Glicósidos/química , Lectinas de Plantas/toxicidad , Acetilglucosamina/química , Conformación de Carbohidratos , Adhesión Celular , División Celular , Disacáridos/química , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Lectinas de Plantas/químicaRESUMEN
The synthesis of a bicyclic analogue of the naturally occurring alpha-L-iduronic acid locked in a biologically active (2)S0 skewboat conformation is disclosed. The desired (2)S0 conformation has been obtained by tethering the C-2 and C-5 carbon atoms of the sugar ring with a dimethyloxy bridge and confirmed by NMR and molecular modeling. The new mimic displays the exact hydroxyl pattern of alpha-L-iduronic acid, a major monosaccharide component of glycosaminoglycans and thus represents a closer mimic of the latter, compared to previously reported bicyclic analogs.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Ácido Idurónico/análogos & derivados , Ácido Idurónico/química , Oligosacáridos/química , Conformación de Carbohidratos , Glicosaminoglicanos/química , Heparina/química , Ácido Idurónico/síntesis química , Indicadores y Reactivos , Modelos Moleculares , Conformación Molecular , Oligosacáridos/síntesis químicaRESUMEN
Bacteriohopanoids represent a particularly important series of triterpenoids, widely distributed in bacteria. One of the common features of these pentacyclic hopanepolyols is the presence of an extended non-terpenoid and polyhydroxylated side chain attached to the triterpenic moiety through a C--C bond. The biological function of biohopanoids also has to be addressed when one considers the broad diversity in both structures and functionalities found in the side chain. Moreover, the stereochemistries of some biohopanoids are still unconfirmed, due to the lack of synthetic methods to prepare them. In this study we describe an efficient methodology for the formation of the C--C bond between the C(30)-hopane component and C(5)-polyhydroxylated carbohydrates through the use of a hopanyllithium intermediate, which has enabled us to synthesize several biohopanoid derivatives. We also report the first synthesis of hopanepentol bearing an additional hydroxy group at position C31.
Asunto(s)
Bacterias/química , Ribosa/química , Triterpenos/química , Glicósidos/química , Hidroxilación , Litio/química , Modelos Químicos , Compuestos Organometálicos/química , Terpenos/químicaRESUMEN
New seven-membered iminosugars with potent and selective inhibition towards glycosidases have been prepared as 1-N-iminosugar homologues via a tandem Staudinger-azaWittig mediated ring expansion.
Asunto(s)
Azepinas/química , Iminoazúcares/síntesis química , Piperidinas/química , Celulasas/antagonistas & inhibidores , Celulasas/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Glucano 1,4-alfa-Glucosidasa/antagonistas & inhibidores , Glucano 1,4-alfa-Glucosidasa/química , Glicósido Hidrolasas/antagonistas & inhibidores , Glicósido Hidrolasas/química , Iminopiranosas/química , Iminoazúcares/química , Estructura Molecular , alfa-Manosidasa/antagonistas & inhibidores , alfa-Manosidasa/químicaRESUMEN
Perbenzylated methyl pentofuranosides were submitted to the action of three alkylalanes and regioselective debenzylation at O-2 of the four pentoses was observed when choosing the right match between anomeric configuration and aluminium reagent. Diisobutylalane (DIBAL-H) allowed an easy access to reduced open-chain compounds, whereas trimethylalane (TMAL) stereoselectively produced methylated open chain derivatives.
Asunto(s)
Acetales/química , Compuestos de Bencilo/química , Metilglicósidos/química , Conformación de Carbohidratos , Secuencia de Carbohidratos , Espectroscopía de Resonancia Magnética , Estructura Molecular , EstereoisomerismoRESUMEN
A range of new tetra- and pentahydroxylated seven-membered iminoalditols has been efficiently synthesized from epoxyazepane precursors via nucleophilic opening with hydride or oxygenated species and subsequent hydrogenolysis. One tetrahydroxylated azepane, a ring homologue of deoxymannojirimycin, displays a selective and fairly good inhibition of alpha-L-fucosidase.
Asunto(s)
Azepinas/química , Inhibidores Enzimáticos/síntesis química , Compuestos Epoxi/química , Glicósido Hidrolasas/antagonistas & inhibidores , alfa-L-Fucosidasa/antagonistas & inhibidores , 1-Desoxinojirimicina , Alcoholes del Azúcar/síntesis químicaRESUMEN
Metathesis versatility has been exploited to reveal the cyclic directionality of cyclodextrins and to selectively synthesise a unique cyclodextrin bearing three pairs of orthogonal protecting groups on its primary rim.
Asunto(s)
alfa-Ciclodextrinas/química , alfa-Ciclodextrinas/síntesis química , Estructura Molecular , Sensibilidad y EspecificidadRESUMEN
Fluorinated carbohydrates constitute a very important class of mechanistic probes for glycosyl-processing enzymes. In this study, we describe the first synthesis of fluorinated and phosphonylated exo-glycals and their corresponding nucleotide sugars in the galactofuranose series. The synthetic protocol that we have developed is a Selectfluor-mediated fluorination/elimination sequence on phosphonylated exo-glycals, and it offers a new entry into fluorinated carbohydrate chemistry. The challenging E/Z stereochemical assignment of the resulting tetrasubstituted alkenes, which bear an alkoxy, an alkyl, a fluoro, and a phosphonyl group, has been achieved through NMR experiments. The corresponding (E)- and (Z)-nucleotide fluorosugars have been prepared and tested as inhibitors of UDP-galactopyranose mutase (UGM). UGM is a flavoenzyme that catalyzes the isomerization of uridine diphosphate(UDP)-galactopyranose into UDP-galactofuranose, a key step of the biosynthesis of important mycobacterial cell-wall glycoconjugates. The two diastereomeric molecules were found to display time-dependent inactivation of UGM, as expected from preliminary results using non-fluorinated exo-glycal nucleotides. The inhibitory properties of the two fluorinated molecules led us to suggest that the inactivation mechanism proceeds through two-electron processes, despite the presence of the flavin cofactor within the UGM catalytic site.
Asunto(s)
Flúor/química , Galactosa/química , Transferasas Intramoleculares/antagonistas & inhibidores , Nucleótidos/síntesis química , Nucleótidos/farmacologíaRESUMEN
UDP-galactopyranose mutase (UGM) catalyzes the isomerization of UDP-galactopyranose (UDP-Galp) into UDP-galactofuranose (UDP-Galf), an essential step of the mycobacterial cell wall biosynthesis. The first mechanistic assumption proposed in the literature was the involvement of 1,4-anhydrogalactose 1 as intermediate of this ring contraction. To confirm or rule out this hypothesis, we synthesized 1 and engaged it in reactions with UGM. The expected formations of UDP-Galf and UDP-Galp were never observed, thus showing that 1 is not, in fact, a low energy intermediate of this enzymatic contraction.
Asunto(s)
Galactosa/análogos & derivados , Transferasas Intramoleculares/metabolismo , Uridina Difosfato/análogos & derivados , Catálisis , Combinación de Medicamentos , Galactosa/química , Galactosa/metabolismo , Estructura Molecular , Aceites , Fenoles , Temperatura , Uridina Difosfato/metabolismoRESUMEN
This study describes the syntheses of bacteriohopanetetrol and its glucosamine derivative through a key direct coupling of a ribose derivative to the hopane skeleton.