RESUMO
2A-F,3B,C,E,F,6B,C,E,F-Tetradeca-O-benzyl-α-cyclodextrin or Ling's tetrol is a unique α-cyclodextrin derivative that is partially protected with specific access points on both rims of the cyclodextrin structure. Ling's tetrol is therefore potentially useful for the synthesis of more complex and sophisticated enzyme models and supramolecular structures. However, the original synthesis gave only 10% yield after a reaction time of 4 days, and a recent improvement that gave 52% yield required two steps and a reaction time in one step of 6 days. Here, a single-step synthesis is reported where Ling's tetrol is obtained in a yield of 59% with a reaction time of 40 hours. 2A-F,3B,C,E,F,6B,C,E,F-Tetradeca-O-benzyl-α-cyclodextrin was subsequently converted into 6A,D-dicarboxy-3A,D-diepi-α-cyclodextrin, 3A,D-dioxo-α-cyclodextrin and 3A,D-diamino-3A,D-dideoxy-3A,D-diepi-α-cyclodextrin. The binding of these compounds to CH4 and CO2 was determined.
RESUMO
Carbon dioxide (CO2) emissions from industrial processes, power generation, and transportation contribute significantly to global warming and climate change. Carbon capture and storage (CCS) technologies are essential to reduce these emissions and mitigate the effects of climate change. Cyclodextrins (CDs), cyclic oligosaccharides, are studied as potential CO2 capture agents due to their unique molecular structures and high selectivity towards CO2. In this paper we have investigated binding efficiency of a number of cyclodextrins towards CO2. It is found that the crystal structure of α-cyclodextrin with CO2 has a 1:1 stoichioimetry and that a number of simple and modified cyclodextrins bind CO2 in water with a Kg of 0.18-1.2 bar-1 (7-35 M-1) with per-O-methyl α-cyclodextrin having the highest CO2 affinity.
RESUMO
An α-cyclodextrin protected with 2,4-dichlorobenzyl groups on the primary alcohols and ordinary benzyl groups on the secondary alcohols was prepared and subjected to DIBAL (diisobutylaluminum hydride)-promoted selective debenzylation. Debenzylation proceeded by first removing two dichlorobenzyl groups from the 6A,D positions and then removing one or two benzyl groups from the 3A,D positions.
RESUMO
The kinetics of the reaction of perbenzyl α-cyclodextrin was studied varying the concentration of DIBAL and substrate, and the temperature. The initial debenzylation was found to be 1st order in substrate and follow the relationship 0.0675+0.179[DIBAL]2 with respect to the concentration of DIBAL. The second and the third debenzylation which led to the 3A ,6A ,6D -triol (Lings triol) were both found to be 1st order in substrate concentration and zero order in DIBAL concentration. Longer reaction times with DIBAL in high concentration gave further debenzylation to comparatively complex mixtures containing the 2B,3A ,6A ,6D -tetrol and the 3A ,6A ,6C ,6D -tetrol. In contrast reaction at 0.1â M DIBAL gave the symmetrical 3A ,6A ,3D,6D-tetrol (Lings tetrol) in 60 % yield. The effect of chlorine or methyl substitution of the phenyl groups of perbenzyl α-cyclodextrin was also investigated. Per 4-chlorobenzyl slowed down the reaction with DIBAL, while 4-methylbenzyl increased the reaction rate, but still gave the corresponding 6â A-monool or 6A ,6D -diol products. A Hammett reaction constant of -4.9 was found for the first debenzylation showing a high degree of positive charge in the transition state. The per(2,4-dichlorobenzyl)-α-cyclodextrin-derivative was completely resistant to DIBAL, however upon addition of trimethyl aluminium this derivative also reacted to give the 6A ,6D -diol product.
Assuntos
alfa-Ciclodextrinas , CinéticaRESUMO
Three different cyclodextrin acids, 6A,6D-di-O-(prop-2-carboxy-1,3-dienyl)-α-cyclodextrin (1), 6-deoxy-ß-cyclodextrin-6-carboxylic acid (2), 6-deoxy-ß-cyclodextrin-6-ethylenecarboxylic acid (3), were prepared and attached to amino PEGA resin as amides using coupling conditions with COMU and NEM. Host-guest binding to the resins was studied by fluorescence microscopy using 8-anilinoaphtalene-1-sulfonic acid (ANS) as guest, and was found to follow the equation IF = IFmax*[ANS]/([ANS] + Kd) where F, Fmax and Kd are the fluorescence, maximum fluorescence and Kd the dissociation constant for the ANS-cyclodextrin complex, respectively. Kd was 4.4, 2.4 and 4.9 × 10-4 M for the three resins. Competitive inhibition of ANS binding was performed with 1-adamantanylamine and octyl ß-d-glucoside with the latter being selective for the α-cyclodextrin as expected.
Assuntos
Resinas Acrílicas/química , Ciclodextrinas/química , Polietilenoglicóis/química , Microscopia de Fluorescência , Estrutura MolecularRESUMO
Gaucher disease is caused by mutations in human acid ß-glucosidase or glucocerebrosidase (GCase), the enzyme responsible for hydrolysis of glucosyl ceramide in the lysosomes. Imino- and azasugars such as 1-deoxynojirimycin and isofagomine are strong inhibitors of the enzyme and are of interest in pharmacological chaperone therapy of the disease. Despite several crystal structures of the enzyme with the imino- and azasugars bound in the active site having been resolved, the actual acid-base chemistry of the binding is not known. In this study we show, using photoinduced electron transfer (PET), that 1-deoxynojirimycin and isofagomine derivatives are protonated by human acid ß-glucosidase when bound, even if they are completely unprotonated outside the enzyme. While isofagomine derivative protonation to some degree was foreshadowed by earlier crystal structures, 1-deoxynojirimycin derivatives were not believed to act as basic amines in the enzyme.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Inibidores Enzimáticos/química , Glucosilceramidase/química , Imino Piranoses/química , Prótons , Ensaios Enzimáticos , Corantes Fluorescentes/química , Glucosilceramidase/antagonistas & inibidores , Humanos , Fenantrenos/químicaRESUMO
On the basis of computational design, a focused one-bead one-compound library has been prepared on microparticle-encoded PEGA1900 beads consisting of small tripeptides with a triazole-capped N-terminal. The library was screened towards a double point-mutated version of the human FKBP12 protein, known as the destabilizing domain (DD). Inspired by the decoded library hits, unnatural peptide structures were screened in a novel on-bead assay, which was useful for a rapid structure evaluation prior to off-bead resynthesis. Subsequently, a series of 19 compounds were prepared and tested using a competitive fluorescence polarization assay, which led to the discovery of peptide ligands with low micromolar binding affinity towards the DD. The methodology represents a rapid approach for identification of a novel structure scaffold, where the screening and initial structure refinement was accomplished using small quantities of library building blocks.
Assuntos
Técnicas de Química Combinatória , Peptídeos/química , Proteína 1A de Ligação a Tacrolimo/química , Sítios de Ligação , Humanos , Modelos Moleculares , Estrutura MolecularRESUMO
A series of 35 analogues of Shld with modifications in the A-residue and the C-residues were prepared and investigated for binding to FKBP and GFP accumulation in transgenic plants. The modifications investigated explored variations that were supposedly inside or outside the receptor binding site with the latter being important by influencing the overall polarity of the compounds in order to improve the absorption in plants. The binding of the new compounds to the destabilizing domain was determined using a fluorescence polarization competition assay, and the GFP expression in engineered Arabidopsis thaliana was studied. The results showed that modifications of the C-building block phenol with acidic, basic, and neutral groups led to better ligands with some being better than Shld in the plant. Generally small, polar substituents showed the best GFP accumulation.
Assuntos
Morfolinas/síntese química , Morfolinas/farmacologia , Proteínas de Plantas/biossíntese , Plantas Geneticamente Modificadas/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/química , Proteínas de Fluorescência Verde , Ligantes , Modelos Moleculares , Proteínas de Plantas/genética , Ligação ProteicaRESUMO
A synthesis of the important FKBP ligand Shld is reported. The synthesis avoids stoichiometric use of expensive and chiral reagents, maintains enantioselectivity and provides a high overall yield (39%). The main features in the method are enantioselective alkylation for preparation of the phenyl acetic acid moiety (building block A), catalytic enantioselective reduction for obtaining the chiral diaryl-1-propanol (building block C), and direct acylation of S-pipecolic tartrate rather than use of expensive Fmoc-pipecolic acid. The assembly of the building blocks A-C is reversed in comparison to previous synthesis, which also eliminates the need for protective groups.
RESUMO
A series of N-alkylated analogues of 1-deoxynojirimycin containing a fluorescent 10-chloro-9-anthracene group in the N-alkyl substituent were prepared. The anthracene group acted as a reporting group for protonation at the nitrogen in the iminosugar because an unprotonated amine was found to quench fluorescence by photoinduced electron transfer. The new compounds were found to inhibit ß-glucosidase from Phanerochaete chrysosporium and α-glucosidase from Aspergillus niger, with Ki values in the low micro- to nanomolar range. Fluorescence and inhibition versus pH studies of the ß-glucosidase-iminosugar complexes revealed that the amino group in the inhibitor is unprotonated when bound, while one of the active site carboxylates is protonated.
RESUMO
Unprecedented simple artificial metalloenzymes were made from cyclodextrin diacids. Six α- and ß-cyclodextrin diacids were prepared and their metal-binding and acid properties were investigated. The diacids formed fairly stable complexes with copper, zinc, and iron, with dissociation constants of 0.4-8×10-4 â m. The iron complexes were found to catalyse a Fenton-like oxidation reaction of benzylic alcohols, which displayed Michaelis-Menten catalysis and rate accelerations up to 2700.
Assuntos
Complexos de Coordenação/metabolismo , Ciclodextrinas/química , Álcoois Benzílicos/química , Calorimetria , Catálise , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cobre/química , Ferro/química , Cinética , Conformação Molecular , Oxirredução , Oxirredutases/química , Oxirredutases/metabolismo , Zinco/químicaRESUMO
Silyl groups such as TBDPS, TBDMS, TIPS or TMS are well-known and widely used alcohol protective groups in organic chemistry. Cyclic silylene protective groups are also becoming increasingly popular. In carbohydrate chemistry silyl protective groups have frequently been used primarily as an orthogonal protective group to the more commonly used acyl and benzyl protective groups. However, silyl protective groups have significantly different electronic and steric requirements than acyl and alkyl protective groups, which particularly becomes important when two or more neighboring alcohols are silyl protected. Within the last decade polysilylated glycosyl donors have been found to have unusual properties such as high (or low) reactivity or high stereoselectivity. This mini review will summarize these findings.
RESUMO
Research during the last two decades has shown a remarkable directional component of the substituent effects of hydroxy groups, which has a profound effect on the properties of hydroxylated compounds such as carbohydrates. While the epimerisation of a single hydroxyl function is well studied the consequence of multiple epimerisations is more speculative. In this work the effect of three epimerisations was investigated. To this end epimeric 2-phenyl iminoxylitols that have a phenyl group as a conformational anchor and thus hydroxyl groups in the axial or equatorial position, respectively, were synthesized and their pKa and conformation were studied. The results show that the large difference in the electronic effect between the axial and equatorial hydroxyls is partially cancelled by counteracting steric hindrance from 1,3-diaxial interactions. Hydrogen bonding does not appear to play any role in the electronic influence of the hydroxyl groups.
RESUMO
A new series of superarmed glycosyl donors has been investigated. It was demonstrated that the S-ethyl leaving group allows for high reactivity, which is much higher than that of equally equipped S-phenyl glycosyl donors that were previously investigated by our groups. The superarmed S-ethyl glycosyl donors equipped with a 2-O-benzoyl group gave complete ß-stereoselectivity. Utility of the new glycosyl donors has been demonstrated in a one-pot one-addition oligosaccharide synthesis with all of the reaction components present from the beginning.
Assuntos
Glicosídeos/química , Oligossacarídeos/síntese química , Configuração de Carboidratos , Glicosilação , Oligossacarídeos/química , EstereoisomerismoRESUMO
Herein we report the synthesis of N-alkylated deoxynojirimycin derivatives decorated with a selenoureido motif at the hydrocarbon tether as an example of unprecedented multitarget agents. Title compounds were designed as dual drugs for tackling simultaneously the Gaucher disease (by selective inhibition of ß-glucosidase, Ki = 1.6-5.5 µM, with improved potency and selectivity compared to deoxynojirimycin) and its neurological complications (by inhibiting AChE, Ki up to 5.8 µM). Moreover, an excellent mimicry of the selenoenzyme glutathione peroxidase was also found for the catalytic scavenging of H2O2 (Kcat/Kuncat up to 640) using PhSH as a cofactor, with improved activity compared to known positive controls, like (PhSe)2 and ebselen; therefore, such compounds are also excellent scavengers of peroxides, an example of reactive oxygen species present at high concentrations in patients of Gaucher disease and neurological disorders.
Assuntos
Desenho de Fármacos , Doença de Gaucher/tratamento farmacológico , Imino Açúcares/química , Compostos Organosselênicos/química , 1-Desoxinojirimicina/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Alquilação , Celulases/antagonistas & inibidores , Glucosamina/análogos & derivados , Glucosamina/farmacologia , Glutationa Peroxidase/antagonistas & inibidores , Humanos , Imino Açúcares/farmacologia , Compostos Organosselênicos/farmacologiaRESUMO
Mannosylations with benzylidene protected mannosyl donors were found to be ß-selective even when no preactivation was performed. It was also found that the kinetic ß-product in some cases anomerizes fast to the thermodynamically favored α-anomer under typical reaction conditions.
RESUMO
N-(10-Chloro-9-anthracenemethyl)isofagomine 5 and N-(10-chloro-9-anthracenemethyl)-1-deoxynojirimycin 6 were prepared, and their inhibition of almond ß-glucosidase was measured. The isofagomine derivative 5 was found to be a potent inhibitor, while the 1-deoxynojirimycin derivative 6 displayed no inhibition at the concentrations investigated. Fluorescence spectroscopy of 5 with almond ß-glucosidase at different pH values showed that the inhibitor nitrogen is not protonated when bound to the enzyme. Analysis of pH inhibition data confirmed that 5 binds as the amine to the enzyme's unprotonated dicarboxylate form. This is a radically different binding mode than has been observed with isofagomine and other iminosugars in the literature.