RESUMEN
A strategy towards the synthesis of three different target molecules, namely 1,4-dideoxy-1,4-imino-l-xylitol, deacetyl (+)-anisomycin and amino-substituted piperidine iminosugars, molecules of potential biological and medicinal significance, is reported from a common amino-vicinal diol intermediate derived from tri-O-benzyl-d-glucal. Construction of the key pyrrolidine ring present in 1,4-dideoxy-1,4-imino-l-xylitol and (+)-anisomycin was a consequence of thermodynamically driven concomitant intramolecular nucleophilic addition reaction of the amino group to the resultant aldehyde obtained by oxidative cleavage of the amino-vicinal diol. Alternatively, double nucleophilic substitution on an amino-diol, after mesylation, with various amines delivered amino-substituted piperidine iminosugars in good yields.
Asunto(s)
Anisomicina/síntesis química , Iminoazúcares/síntesis química , Piperidinas/síntesis química , Xilitol/análogos & derivados , Anisomicina/química , Iminofuranosas/síntesis química , Iminofuranosas/química , Iminoazúcares/química , Conformación Molecular , Piperidinas/química , Estereoisomerismo , Xilitol/síntesis química , Xilitol/químicaRESUMEN
N-Substituted derivatives of 1,4-dideoxy-1,4-imino-d-mannitol (DIM), the pyrrolidine core of swainsonine, have been synthesized efficiently and stereoselectively from d-mannose with 2,3:5,6-di-O-isopropylidene DIM (10) as a key intermediate. These N-substituted derivatives include N-alkylated, N-alkenylated, N-hydroxyalkylated and N-aralkylated DIMs with the carbon number of the alkyl chain ranging from one to nine. The obtained 33 N-substituted DIM derivatives were assayed against various glycosidases, which allowed a systematic evaluation of their glycosidase inhibition profiles. Though N-substitution of DIM decreased their α-mannosidase inhibitory activities, some of the derivatives showed significant inhibition of other glycosidases.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glicósido Hidrolasas/antagonistas & inhibidores , Manitol/análogos & derivados , Animales , Inhibidores Enzimáticos/química , Glicósido Hidrolasas/metabolismo , Humanos , Iminofuranosas/síntesis química , Iminofuranosas/química , Iminofuranosas/farmacología , Concentración 50 Inhibidora , Manitol/síntesis química , Manitol/química , Manitol/farmacología , Ratas , Swainsonina/químicaRESUMEN
A P(V)-N activation method based on nucleoside phosphoropiperidate/DCI system has been developed for improved synthesis of diverse UDP-furanoses. The reaction conditions including temperature, amount of activator, and reaction time were optimized to alleviate the degradation of UDP-furanoses to cyclic phosphates. In addition, an efficient and facile phosphoramidite route was employed for the preparation of furanosyl-1-phosphates.
Asunto(s)
Arabinosa/análogos & derivados , Imidazoles/química , Iminofuranosas/síntesis química , Arabinosa/síntesis química , Arabinosa/química , Iminofuranosas/química , Nucleósidos/química , Fosfatos/química , Piperidinas/química , Uridina/químicaRESUMEN
A formal enantioselective synthesis of nectrisine, a potent α-glucosidase inhibitor, was carried out starting from butadiene monoepoxide through a synthetic sequence involving enantioselective allylic substitution, cross-metathesis, dihydroxylation, and cyclization.
Asunto(s)
Inhibidores de Glicósido Hidrolasas/síntesis química , Iminofuranosas/síntesis química , Paladio/química , Aminación , Aminas/síntesis química , Butadienos , Catálisis , Ciclización , Hidroxilación , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , EstereoisomerismoRESUMEN
Gem-difluoromethylated and trifluoromethylated derivatives of DMDP-related iminosugars have been synthesized from cyclic nitrones 12, 13, 18, ent-18 or 23 and nitrone-derived aldehydes 20 or ent-20. The fluorinated iminosugars were assayed against various glycosidases, and ent-8 showed moderate but selective α-l-rhamnosidase inhibition. Difluoro or trifluoro units influenced the inhibitory activities of iminosugars in a more complex manner than single fluoro substitution. This may be correlated with their highly hydrophobic character and strong electron-withdrawing effect.
Asunto(s)
Clorofluorocarburos de Metano/química , Glicósido Hidrolasas/antagonistas & inhibidores , Hidrocarburos Fluorados/química , Iminofuranosas/química , Óxidos de Nitrógeno/química , Clorofluorocarburos de Metano/síntesis química , Ciclización , Hidrocarburos Fluorados/síntesis química , Iminofuranosas/síntesis química , Estructura MolecularRESUMEN
Ring closure of a 3,5-di-O-triflate derived from D-altrose with benzylamine allowed the formation of both monocyclic and bicyclic azetidine analogues of swainsonine.
Asunto(s)
Azetidinas/síntesis química , Hexosas/química , Manitol/análogos & derivados , Polímeros/síntesis química , Swainsonina/análogos & derivados , Swainsonina/síntesis química , Azetidinas/química , Ciclización , Iminofuranosas/síntesis química , Iminofuranosas/química , Manitol/síntesis química , Manitol/química , Manosidasas/antagonistas & inhibidores , Estructura Molecular , Polímeros/química , Sorbitol/análogos & derivados , Relación Estructura-Actividad , Swainsonina/químicaRESUMEN
A review dealing with 1,4-iminoalditol (hydroxylated pyrrolidine) derivatives as inhibitors of alpha-L-fucosidases including the different synthetic approaches for their preparation as well as their inhibitory properties is presented.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Iminofuranosas/síntesis química , Iminofuranosas/farmacología , alfa-L-Fucosidasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Iminofuranosas/química , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A versatile and concise synthesis of N-alkylated 1,4-dideoxy-1,4-imino-D-arabinitol and 1,4-dideoxy-1,4-imino-L-xylitol derivatives is described. These were prepared using pseudohemiketal lactams as key intermediates, which in turn were obtained from sucrose. The key intermediates were prepared by a diastereospecific tandem reaction which facilitated the introduction of various substituents on the nitrogen atom of the iminosugars.
Asunto(s)
Lactamas/química , Alcoholes del Azúcar/síntesis química , Xilitol/análogos & derivados , Alquilación , Arabinosa , Iminofuranosas/síntesis química , Iminofuranosas/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Estereoisomerismo , Alcoholes del Azúcar/química , Xilitol/síntesis química , Xilitol/químicaRESUMEN
The asymmetric synthesis of 1-C-alkyl-l-arabinoiminofuranoses 1 was achieved by asymmetric allylic alkylation (AAA), ring closing metathesis (RCM), and Negishi cross coupling as key reactions. Some of the prepared compounds showed potent inhibitory activities towards intestinal maltase, with IC(50) values comparable to those of commercial drugs such as acarbose, voglibose, and miglitol, which are used in the treatment of type 2 diabetes. Among them, the inhibitory activity (IC(50)=0.032µM) towards intestinal sucrase of 1c was quite strong compared to the above commercial drugs.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores de Glicósido Hidrolasas , Iminofuranosas/química , Iminofuranosas/farmacología , alfa-Glucosidasas/metabolismo , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/enzimología , Inhibidores Enzimáticos/síntesis química , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Iminofuranosas/síntesis química , RatasRESUMEN
Carbohydrates in the thermodynamically disfavored furanose ring conformation are not present in mammalian glycoconjugates, but are widespread in the glycans produced by many bacterial pathogens. In bacteria, these furanose sugars are often found in cell surface glycoconjugates, and are essential for the viability or virulence of the organisms. As a result, the enzymes involved in the biosynthesis of bacterial furanosides are attractive targets as potential selective antimicrobial chemotherapeutics. However, before such chemotherapeutics can be designed, synthesized, and evaluated, more information about the activity and specificity of these enzymes is required. This chapter describes assays that have been used to study enzymes involved in the biosynthesis of one of the most abundant naturally occurring furanose residues, galactofuranose (Galf). In particular, the focus is on UDP-galactopyranose mutase and galactofuranosyltransferases. The assays described in this chapter require UDP-galactofuranose (UDP-Galf); therefore, a procedure for the preparation of UDP-Galf, as well as various UDP-Galf derivatives, using a three-enzyme chemoenzymatic procedure, is also described.
Asunto(s)
Bacterias , Bioensayo/métodos , Galactosa/análogos & derivados , Iminofuranosas/química , Uridina Difosfato/análogos & derivados , Bacterias/metabolismo , Secuencia de Carbohidratos , Cromatografía Líquida de Alta Presión , Fructanos/química , Galactosa/química , Iminofuranosas/síntesis química , Datos de Secuencia Molecular , Uridina Difosfato/químicaRESUMEN
A highly regioselective reductive cleavage of the bis-benzylidene acetal of D-mannitol was performed using a BF(3) x Et(2)O/Et(3)SiH reagent system. A chiral intermediate 6 thus obtained was efficiently utilized in the stereoselective synthesis of the anticancer agent OGT2378 (3) and glycosidase inhibitor derivative N-tosyl 1,4-dideoxy-1,4-imino-L-xylitol (22). Chemoselective reduction of azido epoxide 10 followed by regioselective intramolecular cyclization of amino epoxide 11 resulted in the exclusive formation of deoxyidonojirimycin derivative 12. By changing the order of deprotection, the chiral intermediate 6 was readily transformed to glycosidase inhibitor derivative 22.
Asunto(s)
Acetales/química , Antineoplásicos/síntesis química , Compuestos de Bencilideno/química , Inhibidores Enzimáticos/síntesis química , Glicósido Hidrolasas/antagonistas & inhibidores , Iminoazúcares/síntesis química , Piperidinas/síntesis química , Xilitol/análogos & derivados , Antineoplásicos/química , Inhibidores Enzimáticos/química , Glicósido Hidrolasas/metabolismo , Iminofuranosas/síntesis química , Iminofuranosas/química , Iminoazúcares/química , Manitol/química , Modelos Moleculares , Estructura Molecular , Piperidinas/química , Estereoisomerismo , Xilitol/síntesis química , Xilitol/químicaRESUMEN
A short, stereoselective synthesis of the naturally occurring pyrrolidine radicamine B is reported. Garner's (R)-aldehyde, prepared from D-serine, was the chiral starting material. The pyrrolidine ring was stereoselectively created in a very efficient way through a five-step, one-pot transformation. In addition, an intermediate of this synthesis was transformed into an intermediate of a previously published synthesis of the potent alpha-glucosidase inhibitor nectrisine.
Asunto(s)
Iminofuranosas/síntesis química , Pirrolidinas/síntesis química , Aldehídos/química , Serina/química , EstereoisomerismoRESUMEN
A highly stereoselective synthesis of C-vinyl furanosides through the S(N)2 inversion at the C-3 position of the 1,2-dideoxy-hept-1-enitols is disclosed. Treatment of the 1,2-dideoxy-hept-1-enitols with diphenylammonium trifluoromethanesulfonate as the acid catalyst produced the C-vinyl furanosides (3,6-anhydro-1,2-dideoxy-hept-1-enitol derivatives) via a subsequent S(N)2 intramolecular debenzyloxyation-cycloetherification reaction at the C-3 position.
Asunto(s)
Iminofuranosas/síntesis química , Alcoholes del Azúcar/química , Compuestos de Vinilo/síntesis química , Conformación de Carbohidratos , Catálisis , Iminofuranosas/química , Indicadores y Reactivos , Modelos Moleculares , Estereoisomerismo , Termodinámica , Compuestos de Vinilo/químicaRESUMEN
A stereoselective approach for synthesizing (2R,5S)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine 1 (2,5-dideoxy-2,5-imino-d-glucitol, DGDP) was achieved using a seven-step approach starting from 2,3,4,6-tetra-O-benzyl-d-mannose (7). Key steps for the preparation of the title compound 1 involved the regioselective and diastereoselective amination of the cinnamyl anti-1,2-polybenzyl ethers 5 and 6 using chlorosulfonyl isocyanate (CSI) and ring cyclization to form the pyrrolidine ring. The reaction between anti-1,2-polybenzyl ether 5 and CSI in toluene at 0 degrees C afforded the corresponding anti-1,2-amino alcohol 4 as a major product with a diastereoselectivity of 16:1 in 76% yield. The mechanism underlying these reactions may be explained by the neighboring-group effect leading to the retention of stereochemistry.
Asunto(s)
Alcaloides/síntesis química , Isocianatos/química , Manitol/análogos & derivados , Pirrolidinas/síntesis química , Aminación , Derris/química , Iminofuranosas/síntesis química , Manitol/síntesis química , EstereoisomerismoRESUMEN
A facile synthesis is reported for five-membered iminocyclitols which allows for variation in stereochemistry at all the chiral centers, diverse C1- and N-substitution, and the potential for a three-component combinatorial process. The key step is inversion at the C4 stereocenter (L-lyxo sugar --> D-ribono azasugar). The exo-imino to endo-iminocyclitol process was extended to the D-lyxo and the D- and L-hexose series. Some analogues were found to be more potent than N-butyl DNJ and N-nonyl DNJ in antiviral activity.
Asunto(s)
1-Desoxinojirimicina/farmacología , Antivirales/síntesis química , Compuestos Aza/síntesis química , Iminofuranosas/síntesis química , 1-Desoxinojirimicina/química , Antivirales/química , Compuestos Aza/química , Iminofuranosas/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
The synthesis of new analogues of the naturally occurring glycosidase inhibitor, salacinol, and its ammonium analogue, ghavamiol is described. These analogues contain an additional hydroxymethyl group at C-1, which was intended to form additional polar contacts within the active site of glycosidase enzymes. The target zwitterionic compounds were synthesized by means of nucleophilic attack at the least hindered carbon atom of 2,4-O-benzylidene-l (or d)-erythritol 1,3-cyclic sulfate by 2,5-anhydro-1,3:4,6-di-O-benzylidene-2,5-dideoxy-5-thio (or 1,5-imino)-l-iditol.
Asunto(s)
Glicósido Hidrolasas/antagonistas & inhibidores , Compuestos de Amonio Cuaternario/síntesis química , Alcoholes del Azúcar/síntesis química , Sulfatos/síntesis química , Arabinosa/síntesis química , Secuencia de Carbohidratos , Inhibidores Enzimáticos , Eritritol/síntesis química , Iminofuranosas/síntesis química , Estructura MolecularRESUMEN
The total syntheses of tetrahydroxy-LCB 1, alpha-galactosyl ceramide 2, and 1,4-dideoxy-1,4-imino-L-ribitol 3 via D-allosamine derivatives as common synthons are described here.
Asunto(s)
Arabinosa/síntesis química , Galactosilceramidas/síntesis química , Glucosamina/análogos & derivados , Alcoholes del Azúcar/síntesis química , Aminación , Arabinosa/química , Galactosilceramidas/química , Glucosamina/síntesis química , Glucosamina/química , Hidroxilación , Iminofuranosas/síntesis química , Iminofuranosas/química , Estructura Molecular , Estereoisomerismo , Alcoholes del Azúcar/químicaRESUMEN
Two new 1-N-iminosugars have been prepared as hexofuranose analogues in an efficient manner by an RCM-based route. Both 3,4-disubstituted pyrrolidines display moderate inhibitory activity against Mycobacterium smegmatis galactan biosynthesis. [structure: see text]