RESUMEN
A series of DAB-peptide and DAB-dipeptide derivatives were synthesized from D-tartrate-derived nitrone 18. The DAB peptides 16 are derivatives of trans,trans-3,4-dihydroxy-L-proline. Glycosidase inhibition assay found four of them to be weak and selective bovine liver ß-galactosidase inhibitors, and the C-2' methyl substituted compound 23b showed the most potent ß-galactosidase inhibition (IC50 = 0.66 µM). Molecular docking studies revealed different docking modes of compound 23b compared to those of other DAB-peptides, and partial similarity of compound 23b to DGJ.
Asunto(s)
Dipéptidos , Glicósido Hidrolasas , Animales , Bovinos , Simulación del Acoplamiento Molecular , Péptido C , beta-Galactosidasa , Relación Estructura-Actividad , Estructura MolecularRESUMEN
A series of iso-allo-DNJ and L-isoDALDP derivatives were synthesized from dithioacetal 16 with sequential and highly diastereoselective Ho and Henry reactions, and aziridinium intermediate-mediated ring rearrangement as key steps. Glycosidase inhibition assay found four of them as selective α-glucosidase inhibitors, and the less substituted compound 30 showed more potent α-glucosidase inhibition (IC50 = 9.3 µM) than the others. Molecular docking study revealed different docking modes of the iso-allo-DNJ and L-isoDALDP derivatives from their parent compounds, and also the similarity of compound 30 to isofagomine.
Asunto(s)
Inhibidores de Glicósido Hidrolasas , alfa-Glucosidasas , alfa-Glucosidasas/metabolismo , Relación Estructura-Actividad , Simulación del Acoplamiento Molecular , Inhibidores de Glicósido Hidrolasas/farmacología , Glicósido Hidrolasas , Estructura MolecularRESUMEN
C-7-fluorinated derivatives of two important polyhydroxylated pyrrolizidines, casuarine and australine, were synthesized with organocatalytic stereoselective α-fluorination of aldehydes as the key step. The strategy is extensively applicable to some synthetically challenging fluorinated iminosugars and carbohydrates. The docking studies indicated that the potent inhibitions of trehalase and amyloglucosidase by the fluorinated polyhydroxylated pyrrolizidines are due to the interaction modes dominated by fluorine atoms in these iminosugars with the amino acids' residues of the corresponding enzymes. Steady interactions were established between the C-7 fluoride and a hydrophobic pocket in amyloglucosidase by untypical anion-π interactions. These unexpected docking modes and related structure-activity relationship studies emphasize the value of fluorination in the design of polyhydroxylated pyrrolizidine glycosidase inhibitors.
Asunto(s)
Glucano 1,4-alfa-Glucosidasa , Glicósido Hidrolasas , Alcaloides , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Pirroles , Alcaloides de PirrolicidinaRESUMEN
Four diastereomers belonging to the family of casuarines, including casuarine (1), 6-epi-casuarine (2), 7-epi-casuarine (13) and 6,7-diepi-casuarine (14), have been synthesized from D-arabinose-derived cyclic nitrone 7 and nitrone-derived aldehyde 4 by a stereocomplementary strategy. Glycosidase inhibition comparison showed that 6-epi-casuarine (2) exhibits enhanced inhibition of trehalase (IC50 = 9.7 µM) and 6,7-diepi-casuarine (14) leads to specific inhibition of trehalase.
RESUMEN
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
Ten pairs of pyrrolidine analogues of pochonicine and its stereoisomers have been synthesized from four enantiomeric pairs of polyhydroxylated cyclic nitrones. Among the ten N-acetylamino pyrrolidine analogues, only compounds with 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and pochonicine (1) configurations showed potent inhibition of ß-N-acetylhexosaminidases (ß-HexNAcases); while 1-amino analogues lost almost all their inhibitions towards the tested enzymes. The assay results reveal the importance of the N-acetylamino group and the possible right configurations of pyrrolidine ring required for this type of inhibitors.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Pirrolidinas/química , Alcaloides de Pirrolicidina/química , Alcaloides de Pirrolicidina/síntesis química , beta-N-Acetilhexosaminidasas/antagonistas & inhibidores , Animales , Ciclización , Glicósido Hidrolasas/antagonistas & inhibidores , Glicósido Hidrolasas/metabolismo , Ratas , Estereoisomerismo , beta-N-Acetilhexosaminidasas/metabolismoRESUMEN
Cross-metathesis (CM) and Keck asymmetric allylation, which allows access to defined stereochemistry of a remote side chain hydroxyl group, are the key steps in a versatile synthesis of broussonetine M (3) from the d-arabinose-derived cyclic nitrone 14. By a similar strategy, ent-broussonetine M (ent-3) and six other stereoisomers have been synthesized, respectively, starting from l-arabino-nitrone (ent-14), l-lyxo-nitrone (ent-3-epi-14), and l-xylo-nitrone (2-epi-14) in five steps, in 26%-31% overall yield. The natural product broussonetine M (3) and 10'-epi-3 were potent inhibitors of ß-glucosidase (IC50 = 6.3 µM and 0.8 µM, respectively) and ß-galactosidase (IC50 = 2.3 µM and 0.2 µM, respectively); while their enantiomers, ent-3 and ent-10'-epi-3, were selective and potent inhibitors of rice α-glucosidase (IC50 = 1.2 µM and 1.3 µM, respectively) and rat intestinal maltase (IC50 = 0.29 µM and 18 µM, respectively). Both the configuration of the polyhydroxylated pyrrolidine ring and C-10' hydroxyl on the alkyl side chain affect the specificity and potency of glycosidase inhibition.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glicósido Hidrolasas/antagonistas & inhibidores , Glicósido Hidrolasas/química , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Inhibidores Enzimáticos/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , Pirrolidinas/química , Relación Estructura-ActividadRESUMEN
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
The first total synthesis of (+)-broussonetine W (4), a naturally-occurring pyrrolidine iminosugar isolated from the traditional Chinese medical plant Broussonetia kazinoki SIEB (Moraceae), has been completed through a concise synthetic route starting from the readily available d-arabinose derived cyclic nitrone 10 in 11 steps and 31% overall yield, with regioselective installation of the α,ß-unsaturated ketone functional group by the elimination of HBr from α-bromoketone as the key step. A number of analogs of (+)-broussonetine W (4) with variable side chain length, different polyhydroxylated pyrrolidine core configurations or saturated cyclohexanones have also been prepared to explore the glycosidase inhibition and the preliminary structure-activity relationship of this intriguing class of compounds. Glycosidase inhibition studies identified the natural product (+)-broussonetine W (4) as a selective and potent inhibitor of ß-galactosidase (IC50 = 0.03 µM), while its enantiomer was a selective and potent inhibitor of α-glucosidase (IC50 = 0.047 µM). It was found that the configuration of the polyhydroxylated pyrrolidine ring played a key role on their glycosidase inhibitory activities. The length of side chain and α,ß-unsaturated ketone functional group also exhibited some effect on their glycosidase inhibition.
Asunto(s)
Productos Biológicos/síntesis química , Productos Biológicos/farmacología , Iminoazúcares/síntesis química , Iminoazúcares/farmacología , beta-Galactosidasa/antagonistas & inhibidores , Animales , Productos Biológicos/química , Bovinos , Técnicas de Química Sintética , Iminoazúcares/química , Concentración 50 Inhibidora , EstereoisomerismoRESUMEN
Fluorinated and conformationally fixed derivatives of L-homoDMDP, i.e., 2,5-dideoxy-2,5-imino-DL-glycero-L-manno-heptitol, have been synthesized from d-xylose-derived cyclic nitrone 10 with oxazolidinone 19 or 28 and oxazinanone 22 or 32 as key intermediates. An evaluation of glycosidase inhibition showed replacement of the C-6 hydroxyl groups with fluoride in L-homoDMDP and its C-6 epimer did not have a significant influence on α-glucosidase inhibition by these iminosugars, while replacement of an amino group with a cyclic carbamate group in most conformationally fixed derivatives led to a sharp decrease in the level of glycosidase inhibition, revealing the importance of the free amino group in interaction of enzymes with these molecules.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Iminoazúcares/química , Oxazolidinonas/síntesis química , alfa-Glucosidasas/química , Halogenación , Iminoazúcares/síntesis química , Conformación Molecular , Estructura Molecular , Oxazolidinonas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
This paper identifies the required configuration and orientation of α-glucosidase inhibitors, miglitol, α-1-C-butyl-DNJ, and α-1-C-butyl-LAB for binding to ntSI (isomaltase). Molecular dynamics (MD) calculations suggested that the flexibility around the keyhole of ntSI is lower than that of ctSI (sucrase). Furthermore, a molecular-docking study revealed that a specific binding orientation with a CH-π interaction (Trp370 and Phe648) is a requirement for achieving a strong affinity with ntSI. On the basis of these results, a new class of nortropane-type iminosugars, labystegines, hybrid iminosugars of LAB and calystegine, have been designed and synthesized efficiently from sugar-derived cyclic nitrones with intramolecular 1,3-dipolar cycloaddition or samarium iodide catalyzed reductive coupling reaction as the key step. Biological evaluation showed that our newly designed 3(S)-hydroxy labystegine (6a) inherited the selectivity against intestinal α-glucosidases from LAB, and its inhibition potency was 10 times better than that of miglitol. Labystegine, therefore, represents a promising new class of nortropane-type iminosugar for improving postprandial hyperglycemia.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Iminoazúcares/farmacología , Nortropanos/farmacología , Sacarasa/antagonistas & inhibidores , alfa-Glucosidasas/metabolismo , Arabinosa/química , Sitios de Unión/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Iminofuranosas/química , Iminoazúcares/síntesis química , Iminoazúcares/química , Intestinos/enzimología , Conformación Molecular , Simulación de Dinámica Molecular , Nortropanos/síntesis química , Nortropanos/química , Sacarasa/metabolismo , Alcoholes del Azúcar/química , Tropanos/químicaRESUMEN
A new eremophilane derivative, (3aR,4R,5S,7S,7aS)-2-acetyl-7,7a-dihydroxy-3a,4-dimethyl-3a,4,5,6,7,7a-hexahydro-3H-inden-5-yl acetate (1) and three known compounds, 10beta-hydroxy-eremophil-7 (11)-en-12,8alpha-olide(2), beta-sitosterol (3) and beta-daucosterol(4) have been isolated from Ligularia intermedia. The compounds were isolated by column chromatography on silica gel and Sephadex LH-20,and identified on the basis of spectral analyses (MS, 1H-NMR, 13C-NMR).
Asunto(s)
Asteraceae/química , Medicamentos Herbarios Chinos/química , Naftalenos/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Estructura Molecular , Naftalenos/aislamiento & purificación , Sesquiterpenos Policíclicos , SesquiterpenosRESUMEN
Broussonetine S (9), its C-1' and C-10' stereoisomers, and their corresponding enantiomers have been synthesized from enantiomeric arabinose-derived cyclic nitrones, with cross metathesis (CM), epoxidation and Keck asymmetric allylation as key steps. Glycosidase inhibition assays showed that broussonetine S (9) and its C-10' epimer (10'-epi-9) were nanomolar inhibitors of bovine liver ß-galactosidase and ß-glucosidase; while their C-1' stereoisomers were 10-fold less potent towards these enzymes. The glycosidase inhibition results and molecular docking calculations revealed the importance of the configurations of pyrrolidine core and C-1' hydroxyl for inhibition potency and spectra. Together with the docking calculations we previously reported for α-1-C-alkyl-DAB derivatives, we designed and synthesized a series of 6-C-alkyl-DMDP derivatives with very simple alkyl chains. The inhibition potency of these derivatives was enhanced by increasing the length of the side chain, and maintained at nanomolar scale inhibitions of bovine liver ß-glucosidase and ß-galactosidase after the alkyl groups are longer than eight or ten carbons for the (6R)-C-alkyl-DMDP derivatives and their 6S epimers, respectively. Molecular docking calculations indicated that each series of 6-C-alkyl-DMDP derivatives resides in the same active site of ß-glucosidase or ß-galactosidase with basically similar binding conformations, and their C-6 long alkyl chains extend outwards along the hydrophobic groove with similar orientations. The increasing inhibitions of ß-glucosidase and ß-galactosidase with the number of carbon atoms in the side chains may be explained by improved adaptability of longer alkyl chains in the hydrophobic grooves. In addition, the lower ß-glucosidase and ß-galactosidase inhibitions of (6S)-C-alkyl-DMDP derivatives than their C-6 R stereoisomers can be attributed to the misfolding of their alkyl chains and resulted decreased adaptability in the hydrophobic groove. The work reported herein is valuable for design and development of more potent and selective inhibitors of ß-galactosidase and ß-glucosidase, which have potential in treatment of lysosomal storage diseases. Furthermore, part of the 6-C-alkyl-DMDP derivatives and their enantiomers were also tested as potential anti-cancer agents; all the compounds tested were found with moderate cytotoxic effects on MKN45 cells, which would indicate potential applications of these iminosugars in development of novel anticancer agents.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos , Simulación del Acoplamiento Molecular , beta-Galactosidasa , beta-Glucosidasa , beta-Galactosidasa/antagonistas & inhibidores , beta-Galactosidasa/metabolismo , Bovinos , Animales , Relación Estructura-Actividad , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , beta-Glucosidasa/antagonistas & inhibidores , beta-Glucosidasa/metabolismo , Estructura Molecular , Relación Dosis-Respuesta a Droga , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/químicaRESUMEN
The first total synthesis of both broussonetine I and J2 together with their enantiomers have been accomplished via the same synthetic route through 18 and 16 steps in excellent overall yields (18% and 19%, respectively), starting from R-glyceraldehyde. Broussonetine I was found to be a potent inhibitor of ß-glucosidase (IC50 = 2.9 µM), while ent-broussonetine I and ent-broussonetine J2 were found to be potent inhibitors of α-glucosidase (IC50 = 0.33 and 0.53 µM, respectively).
Asunto(s)
Inhibidores Enzimáticos/farmacología , Glicósido Hidrolasas/antagonistas & inhibidores , Iminoazúcares/farmacología , Animales , Aspergillus niger/enzimología , Bovinos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Glicósido Hidrolasas/metabolismo , Caracoles Helix/enzimología , Iminoazúcares/síntesis química , Iminoazúcares/química , Conformación Molecular , Plantas/enzimología , Ratas , Saccharomyces cerevisiae/enzimología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Pochonicine, the first naturally occurring polyhydroxylated pyrrolizidine containing an acetamidomethyl group, which was isolated from Pochonia suchlasporia var. suchlasporia TAMA 87, together with its enantiomer and their C-1 and/or C-3 epimers, have been synthesized from the sugar-derived cyclic nitrones 9D and 9L, respectively. An in-depth NMR study showed that both the (1)H and (13)C NMR spectra of the synthetic pochonicines (1D and 1L) matched very well with those of natural pochonicine in D2O, which unequivocally determined the relative configuration of the natural product as 1D or 1L. In addition, comparison of the optical rotations of the synthetic pochonicines and that of the natural product, but more convincingly their glycosidase inhibition profiles, confirmed the absolute configuration of natural pochonicine as 1R,3S,5R,6R,7S,7aR. Thereby, the structure of natural pochonicine was unequivocally determined as (+)-(1R,3S,5R,6R,7S,7aR)-pochonicine (1D). Glycosidase inhibition experiments showed that natural pochonicine 1D and its epimers 2D, 3D, and 4D all are powerful inhibitors of hexosaminidases (five ß-N-acetylglucosaminidases and two ß-N-acetylgalactosaminidases) while their enantiomers 1L, 2L, 3L, and 4L are much weaker inhibitors of the same enzymes. (-)-3-epi-Pochonicine (2L) was found to be a potent and selective inhibitor of α-l-rhamnosidase. None of the compounds showed any inhibition of α-GalNAcase.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Alcaloides de Pirrolicidina/síntesis química , beta-N-Acetilhexosaminidasas/antagonistas & inhibidores , beta-N-Acetilhexosaminidasas/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Espectroscopía de Resonancia Magnética , Estructura Molecular , Alcaloides de Pirrolicidina/química , Alcaloides de Pirrolicidina/aislamiento & purificación , Alcaloides de Pirrolicidina/farmacología , EstereoisomerismoRESUMEN
A general and efficient method has been developed for the synthesis of sugar-derived azepane nitrones starting from aldohexoses, with an intramolecular condensation of aldehyde and hydroxylamine as the key step. Through this strategy, each aldohexose produced a pair of azepane nitrones, which are precursors of various azepane iminosugars.
Asunto(s)
Carbohidratos/química , Óxidos de Nitrógeno/síntesis química , Estructura Molecular , Óxidos de Nitrógeno/químicaRESUMEN
A general and efficient method for the synthesis of polyhydroxylated pyrrolizidines and indolizidines has been developed based on the NHC-catalyzed cross-coupling of sugar-derived cyclic nitrones with enals, which afforded the key intermediates, γ-hydroxyl amino esters, in good to excellent yields. Thus, a variety of polyhydroxylated pyrrolizidines and indolizidines have been synthesized and assayed against various glycosidases, which showed that aryl or alkyl substituents at C-7 of pyrrolizidines or at C-8 of indolizidines reduced the potency of the glycosidase inhibition of these bicyclic iminosugars.
Asunto(s)
Carbohidratos/química , Compuestos Heterocíclicos/química , Indolicidinas/síntesis química , Cetonas/química , Metano/análogos & derivados , Óxidos de Nitrógeno/química , Alcaloides de Pirrolicidina/síntesis química , Catálisis , Técnicas de Química Sintética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glicósido Hidrolasas/antagonistas & inhibidores , Indolicidinas/química , Indolicidinas/farmacología , Metano/química , Alcaloides de Pirrolicidina/química , Alcaloides de Pirrolicidina/farmacologíaRESUMEN
Protected L-homoDMDP en-8 and its C-6 epimer en-7 were prepared through two different pathways starting from the vinylpyrrolidine en-9. Based on the NMR and X-ray analysis, the stereochemistry of homoDMDP at C-6 was confirmed to be consistent with reported data. Compounds en-7 and en-8 are general intermediates for the synthesis of a series of 6-C-alkylated DMDP-related natural products, such as broussonetine G, homoDMDP-7-O-apioside, homoDMDP-7-O-b-D-xyloside and so on.
Asunto(s)
Productos Biológicos/química , Piperazinas/química , Piridazinas/química , Productos Biológicos/síntesis química , Estructura Molecular , Piperazinas/síntesis química , Piridazinas/síntesis química , EstereoisomerismoRESUMEN
D-glucopyranose-derived and L-idopyranose-derived piperidine nitrones were synthesized in good overall yields through six-step reaction sequence starting from readily available 2,3,4,6-tetra-O-benzyl-D-glucopyranose. The method is efficient and could be general for the synthesis of aldohexose-derived piperidine nitrones which are precursors of piperidine iminosugars.
Asunto(s)
Iminoazúcares , Óxidos de Nitrógeno , Piperidinas , Iminoazúcares/síntesis química , Iminoazúcares/química , Óxidos de Nitrógeno/síntesis química , Óxidos de Nitrógeno/química , Piperidinas/síntesis química , Piperidinas/químicaRESUMEN
A series of α-1-C-alkyl DAB (1,4-dideoxy-1,4-imino-d-arabinitol) and LAB (1,4-dideoxy-1,4-imino-l-arabinitol) derivatives with aryl substituents have been designed as analogues of broussonetine W (12), and assayed as glycosidase inhibitors. While the inhibition spectrum of α-1-C-alkyl DAB derivative 16 showed a good correlation to that of broussonetine W (12), introduction of substituents on the terminal aryl (17a-f) or hydroxyl groups at C-1' position of the alkyl chains (18a-e) decreased their α-glucosidase inhibitions but greatly improved their inhibitions of bovine liver ß-glucosidase and ß-galactosidase. Furthermore, epimerization of C-1' configurations of compounds 18a-e clearly lowered their inhibition potency of bovine liver ß-glucosidase and ß-galactosidase. Notably, some of the α-1-C-alkyl DAB derivatives were also found to have potent human lysosome ß-glucosidase inhibitions. In contrast, enantiomers of compounds 18a-e and 1'-epi-18a-e generally showed increased α-glucosidase inhibitions, but sharply decreased bovine liver ß-glucosidase and ß-galactosidase inhibitions. Molecular docking calculations unveiled the novel two set of binding modes for each series of compounds; introduction of C-1' hydroxyl altered the conformations of the pyrrolidine rings and orientation of their long chains, resulting in improved accommodation in the hydrophobic grooves. The compounds reported herein are very potent ß-glucosidase and ß-galactosidase inhibitions with novel binding mode; and the structure-activity relationship provides guidance for design and development of more pyrrolidine pharmacological chaperones for lysosomal storage diseases.