RESUMO
Atopic dermatitis is a chronic, inflammatory skin disease. A variety of systemic treatments are available for patients with moderate-to-severe atopic dermatitis. The efficacy, safety and administration profile of these treatments vary, and determining the optimal treatment strategy may require weighing the benefits and drawbacks of therapies with diverse characteristics. This study used an online discrete choice experiment survey to investigate treatment preferences among adults with atopic dermatitis from Denmark, France, the UK, or Canada. Participants were identified through existing online panels. The survey included questions regarding different treatment attributes, defined based on currently approved treatments for moderate to severe atopic dermatitis. Treatment preferences were measured as the relative importance of different treatment attributes. A total of 713 respondents met the inclusion criteria and completed the survey. The discrete choice experiment identified a significant preference for avoiding the risk of severe adverse events, and for oral pill every day compared with biweekly injections. The time to full effect was not rated as being important. These findings suggest that patients with moderate-to-severe atopic dermatitis prioritize safety as most important, followed by ease of administration in their treatment preferences, while time to full effect and monitoring requirements were the least important attributes.
Assuntos
Dermatite Atópica , Adulto , Humanos , Dermatite Atópica/diagnóstico , Dermatite Atópica/tratamento farmacológico , Preferência do Paciente , Resultado do Tratamento , Administração Cutânea , Inquéritos e QuestionáriosRESUMO
We report on the stereoselective multigram scale preparation of cyclohexyl- and phenyl thioglycosides of 2-azido-2-deoxy-ß-d-gluco- and galactopyranosides from d-N-acetylglucosamine using a catalytic and solvent-free method. Two of the prepared building blocks were used as key intermediates for the synthesis of human milk oligosaccharides LNT and LNnT in their protected form.
Assuntos
Tioglicosídeos , Humanos , Glucosamina , Galactosamina , Leite Humano , OligossacarídeosRESUMO
We demonstrate a new and high-yielding method for removal of benzylidene acetals and para-methoxybenzyl ethers under catalytic conditions (BF3:OEt2 orFeCl3, 10 mol%) with mercaptoacetic acid as a scavenger. The reaction coproducts are converted to water-soluble molecules, which can be removed by aqueous extraction, thereby bypassing the need for chromatographic purification. The reaction was demonstrated on both multimilligram and multigram scale.
RESUMO
A systematic study of the effect of various 6-O-acyl groups on anomeric selectivity in glucosylations with thioglycoside donors was conducted. All eight different esters were found to induce moderate-to-high α-selectivity in glucosylation with l-menthol with the best being 6-O-p-nitrobenzoyl. The effect appears to be general across various glucosyl acceptors, glucosyl donor types, and modes of activation. No evidence was found in favor of distal participation.
Assuntos
Ésteres , GlicosilaçãoRESUMO
A new and environmentally friendly protocol for the conversion of sugar per-acetates into thioglycosides under solvent free and catalytic conditions is presented. The procedure involves heating in the presence of InCl3 and various aryl thiols. For alkyl thioglycoside synthesis, cyclohexane thiol was found to give good results and yield a glycosyl donor with reactivity similar to a thioethyl congener. The established optimum reaction conditions were found to provide the desired thioglycoside products in an easy and highly diastereoselective manner even when conducted on a multigram scale.
Assuntos
Tioglicosídeos , Catálise , Glicosilação , Oligossacarídeos , Solventes , Compostos de SulfidrilaRESUMO
The reaction of a series of anomeric thioglycosides with various glycosyl acceptors and N-iodosuccinimide/catalytic triflic acid was investigated with respect to reactivity and anomeric selectivity. In general, ß-configured donors were found to give a more ß-selective reaction outcome compared to their α-configured counterparts. The relative reactivity of various thioglycosides was measured through competition experiments, and the following order was established: phenyl, tolyl, methyl, ethyl, isopropyl, and 1-adamantyl.
Assuntos
Tioglicosídeos , Catálise , GlicosilaçãoRESUMO
Competitive inhibitors of galactocerebrosidase (GALC) could be candidates for pharmacological chaperone therapy of patients with Krabbe disease. The known and selective nortropane-type iminosugar galacto-noeurostegine has been found to competitively inhibit GALC with K i = 7 µM at pH 4.6, which is 330-fold more potent than the analogous deoxynoeurostegine. It was shown through X-ray protein crystallography that galacto-noeurostegine binds to the active site of GALC in its bicyclic form.
RESUMO
A high-yielding palladium-catalyzed C-S cross-coupling is presented for utilization in carbohydrate chemistry as a key transformation for attachment of a second chelating sulfur atom that allows the exploitation of a latent-active glycosylation strategy with Cu(OTf)2 as the promoter. The novel approach employs o-Br-benzyl thioglycosides as latent glycosyl donors and o-SMe-benzyl thioglycosides as the active counterparts.
RESUMO
Gaseous fluorescein monoanions are weakly fluorescent; they display a broad fluorescence spectrum and a large Stokes shift. This contrasts with the situation in aqueous solution. One explanation of the intriguing behavior in vacuo is based on internal proton transfer from the pendant carboxyphenyl group to one of the xanthene oxygens in the excited state; another that rotation of the carboxyphenyl group relative to the xanthene leads to a partial charge transfer from one chromophore (xanthene) to the other (carboxyphenyl) when the π orbitals start to overlap. To shed light on the mechanism at play, we synthesized two fluorescein derivatives where the carboxylic acid group is replaced with either an ester or a tertiary amide functionality and explored their gas-phase ion fluorescence using the home-built LUminescence iNstrument in Aarhus (LUNA) setup. Results on the fluorescein methyl ester that has no acidic proton clearly disprove the former explanation: The spectrum remains broad, and the band center (at 605 nm) is shifted even more to the red than that of fluorescein (590 nm). Experiments on the other variant that contains a piperidino amide are also in favor of the second explanation as here the piperidino already causes the dihedral angle between the planes defining the xanthene and the benzene ring to be less than 90° in the ground state (i.e., 63°), according to density functional theory calculations. As a result of the closer similarity between the ground-state and excited-state structures, the fluorescence spectrum is narrower than those of the other two ions, and the band maximum is further to the blue (575 nm). In accordance with a more delocalized ground state of the amide derivative, action spectra associated with photoinduced dissociation recorded at another setup show that the absorption-band maximum for the amide derivative is redshifted compared to that of fluorescein (538 nm vs. 525 nm).
RESUMO
The present paper is a commentary on the electronic effects that protecting groups exert on glycosylation chemistry. Specifically, its purpose is to rectify the misguided use of the term electron donating benzyl groups, which hardly makes sense in the context of protecting groups on alcohols in saturated systems such as carbohydrates. It is argued that benzyl ethers (OBn) should rightfully be referred to as being inductively electron withdrawing, even if they are less so than benzoyl esters (OBz).
Assuntos
Produtos Biológicos/química , Elétrons , Éteres/química , Configuração de Carboidratos , GlicosilaçãoRESUMO
Here, we report on the first combined one-pot use of the two so-called "click reactions": the thiol-ene coupling and the copper-catalyzed alkyne-azide cycloaddition. These reactions were employed in an alternating and one-pot fashion to combine appropriately functionalized monomeric carbohydrate building blocks to create mimics of trisaccharides and tetrasaccharides as single anomers, with only minimal purification necessary. The deprotected oligosaccharide mimics were found to bind both plant lectins and human galectin-3.
RESUMO
A new synthetic route for formation of a central cycloheptanone intermediate leading to the nortropane alkaloid calystegine B2 is described. The approach installs the desired ketone functionality directly in a ring-closing metathesis step. The target compound was prepared over 10 steps from commercially available methyl α-d-xylopyranoside.
Assuntos
Metilglicosídeos/química , Nortropanos/síntese química , Alcaloides de Solanáceas/síntese química , Cicloeptanos/química , Estrutura Molecular , Nortropanos/química , Alcaloides de Solanáceas/química , Estereoisomerismo , Xilose/análogos & derivados , Xilose/químicaRESUMO
Four new α-glucosidase inhibitors have been synthesised through 5-8 synthetic steps from a common synthetic intermediate obtained through a recently developed carbocyclisation. The compounds were designed as hybrids of the known glucosidase inhibitors valienamine, voglibose and miglitol. All four compounds showed activity against rat intestinal sucrase with the most potent inhibitor acting at low micromolar concentration. The newly synthesised compounds were not as potent as miglitol against sucrase but showed greater selectivity towards the tested glycosidases. The most potent inhibitors were docked into a homology model built for this study of rat intestinal sucrase explaining the difference in potency between two diastereoisomers with varying orientation of a secondary amine.
Assuntos
Etilenos/química , Etilenos/farmacologia , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/farmacologia , alfa-Glucosidases/metabolismo , Técnicas de Química Sintética , Ciclização , Etilenos/síntese química , Etilenos/metabolismo , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/metabolismo , Simulação de Acoplamento Molecular , Conformação Proteica , alfa-Glucosidases/químicaRESUMO
Neighboring group effects were investigated in gluco- and manno-configured thioglycosides under NIS/TfOH activation. Donors possessing a 2-O-benzoyl group that are capable (1,2-trans) and incapable (1,2-cis) of exerting nucleophilic push were compared with donors possessing a participatory neutral 2-O-benzyl group. By using competition experiments between sets of glycosyl donors the direct effect of neighboring group participation and the electron withdrawing effect of the 2-O-benzoyl group could be separated. The study brings insight into how the stereochemistry of the 1 and 2 position and how the nature of the aglycon (Ph or Et) have a pronounced effect on glycosyl donor reactivity.
RESUMO
It was established that 2-O-benzoyl-3,4,6-tri-O-benzyl protected ß-SEt, ß-SPh and ß-SBox glucosyl donors are not superarmed when using the NIS/TfOH promoter system, but instead have a similar reactivity as their classically armed tetra-O-benzyl protected glucosyl counterparts. The ß-SBox 2-O-benzoyl-3,4,6-tri-O-benzyl glucosyl donor, however, was found to be superarmed under DMTST activation. Our studies have shown that the increased reactivity of the ß-SBox 2-O-benzoyl-3,4,6-tri-O-benzyl glucosyl donor with DMTST activation could be a unique case, and that the high reactivity of glucosyl donors with the 2-O-benzoyl-3,4,6-tri-O-benzyl protection pattern is not general as earlier suggested.
RESUMO
A novel Ferrier-type carbocyclization is reported. It involves a carbohydrate-derived lactone acetal synthesized from methyl α-d-glucopyranoside, which upon treatment with excess vinylmagnesium bromide provides a highly substituted carbocyclic product as a single stereoisomer. The yield is greatly increased when N,N,N',N'-tetramethylethylenediamine is added to the reaction mixture. Optimized reaction conditions have been applied to lactone acetals derived from other carbohydrates. Based on the obtained results, a possible reaction mechanism has been proposed. Furthermore, scalability of the reaction up to 15 g scale and derivatization of the carbocyclic product has been demonstrated, including the formation of a rare trans-bicyclo[4.3.0]nonene scaffold via a ring-closing metathesis. The structure of this and all carbocyclic products were confirmed by X-ray crystallographic analysis.
RESUMO
We have explored the possibility of using 1,3-diiodo-5,5-dimethylhydantoin (DIDMH) as an alternative to N-iodosuccinimide (NIS) for activation of glycosyl donors of the thioglycoside type in various glycosylation reactions. DIDMH was found to match NIS when it comes to the capability to activate thioglycosides and provide glycosylation products in good yields. Notably, with the two equivalents of reactive iodonium ions per molecule of DIDMH less mass needs to be added making this activator a more atom economically alternative to NIS. Furthermore, DIDMH was found to be stable upon storage for weeks and comparably priced to NIS. With this knowledge in hand we therefore encourage the carbohydrate community to consider using DIDMH for activation of thioglycosides in glycosylation reactions.
Assuntos
Succinimidas/química , Tioglicosídeos/química , Glicosilação , Mesilatos/químicaRESUMO
From a series of competition experiments, we have explored the degree to which various para-substituents (CN, Br, H, OMe, pyrrolidino) of a 2-O-benzoyl functionalized glucosyl donor of the thioglycoside type affect the rate of glycosylation under N-iodosuccinimide/triflic acid activation. As expected, electron-withdrawing groups were found to decrease the rate of glycosylation, whereas electron-donating groups resulted in the opposite outcome, underscoring the influence on the reaction rate exerted by a participating group. On this basis, a Hammett linear free-energy relationship was established (R 2 = 0.979, ρ = 0.6), offering fundamental insight into the magnitude of anchimeric assistance in glycosylation chemistry.
RESUMO
With the aim of improving the general glycosylation protocol to facilitate easy product isolation it was shown that amide by-products from glycosylation with trichloroacetimidate and N-phenyl trifluoroacetimidate donors could be removed during reaction work-up by washing with a basic aqueous solution. Excess glycosyl acceptor or lactol originating from glycosyl donor hydrolysis could equally be removed from the reaction mixture by derivatization with a basic tag and washing with an acidic solution during reaction work-up.
Assuntos
Acetamidas/isolamento & purificação , Cloroacetatos/química , Tioglicosídeos/química , Técnicas de Química Sintética , Cloroacetatos/isolamento & purificação , Diaminas/química , Glicosilação , HidróliseRESUMO
The monosaccharide N-acetyl-d-glucosamine (GlcNAc) is an abundant building block in naturally occurring oligosaccharides, but its incorporation by chemical glycosylation is challenging since direct reactions are low yielding. This issue, generally agreed upon to be caused by an intermediate 1,2-oxazoline, is often bypassed by introducing extra synthetic steps to avoid the presence of the NHAc functional group during glycosylation. The present paper describes new fundamental mechanistic insights into the inherent challenges of performing direct glycosylation with GlcNAc. These results show that controlling the balance of oxazoline formation and glycosylation is key to achieving acceptable chemical yields. By applying this line of reasoning to direct glycosylation with a traditional thioglycoside donor of GlcNAc, which otherwise affords poor glycosylation yields, one may obtain useful glycosylation results.