The enzyme‐resistant thioglycosides are highly valuable immunogens because of their enhanced metabolic stability. We report the first synthesis of a family of thiooligosaccharides related to the ...capsular polysaccharides (CPS) of Campylobacter jejuni HS:4 for potential use in conjugate vaccines. The native CPS structures of the pathogen consist of a challenging repeating disaccharide formed with β(1→4)‐linked 6‐deoxy‐β‐D‐ido‐heptopyranoside and N‐acetyl‐D‐glucosamine; the rare 6‐deoxy‐ido‐heptopyranosyl backbone and β‐anomeric configuration of the former monosaccharide makes the synthesis of this family of antigens very challenging. So far, no synthesis of the thioanalogs of the CPS antigens have been reported. The unprecedented synthesis presented in this work is built on an elegant approach by using β‐glycosylthiolate as a glycosyl donor to open the 2,3‐epoxide functionality of pre‐designed 6‐deoxy‐β‐D‐talo‐heptopyranosides. Our results illustrated that this key trans‐thioglycosylation can be designed in a modular and regio and stereo‐selective manner. Built on the success of this novel approach, we succeeded the synthesis of a family of thiooligosaccharides including a thiohexasaccharide which is considered to be the desired antigen length and complexity for immunizations. We also report the first direct conversion of base‐stable but acid‐labile 2‐trimethylsilylethyl glycosides to glycosyl‐1‐thioacetates in a one‐pot manner.
Enzyme‐resistant thioglycosides have the potential to be used as potent immunogens in vaccinations. The regio‐ and stereoselective opening of pyranosyl epoxides has been taken advantage of to obtain a family of very challenging thiooligosaccharide antigens related to Campylobacter jejuni HS:4 with unprecedented efficiency.
6‐Deoxy‐β‐ido‐heptopyranosides are challenging glycosides to synthesize due to their unusual 6‐deoxy‐heptose backbone, rare ido‐configuration and most importantly, the β‐1,2‐cis anomeric linkage. ...They are found in nature, such as being part of the repeating disaccharide of C. jejuni HS:4 capsular polysaccharides (CPs). Interestingly, the bacterial CPs is found to be partially modified with an O‐methyl phosphoramidate (MeOPN) functionality at the O‐2 or O‐7 position of the 6‐deoxy‐β‐d‐ido‐heptopyranosides. In this work, we report the first synthesis of three analogous of β‐d‐ido‐octopyranosides (1–3) that contain a 6,7‐dideoxy‐functionality and either a terminal methyl ester or carboxylic acid or amide. Since carboxylic acids have been reported as bioisosteres of phosphate group, compound 1–3 can be regarded as carbon‐based bioisosteres of 6‐Deoxy‐β‐ido‐heptopyranoside containing the MeOPN group without a chiral center. Compounds (1–3) were efficiently synthesized from a O‐2 activated β‐d‐galacto‐octopyranuronate (19) that was efficiently converted to the desired β‐d‐ido‐octopyranuronate configuration using an elegant one‐pot process.
Synthesis of the rare and challenging β‐d‐ido‐octopyranuronate configuration can be succeeded using a highly regio‐ and stereoselective one‐pot process from a 2‐O‐activated β‐d‐galacto‐octopyranuronate ester. The β‐d‐ido‐octopyranosyl ring was revealed to adopt predominantly a 4C1 chair conformation by NMR.
In this study, we report a novel per-6-substituted β-cyclodextrin (4) featuring seven phosphoramidate moieties as an innovative host for inclusion. This structurally well-defined host has remarkable ...water solubility and was isolated in pure form. Analytical techniques such as NMR and ITC were used to probe the molecular interactions with different drug molecules. Our investigations revealed that host 4 can form 2:1 inclusion complexes with various drugs. Further studies showed that the inclusions of drugs by β-CD host (4) are mostly enthalpy driven, highlighting the potential roles played by the phosphoramidate functionalities of the host. Comparatively, a per-O2, O3-acetylated analog (6) of compound 4 was also obtained, which also shows unusual water solubility but diminished inclusion capability.
is a bacterial pathogen that causes hundreds of millions of cases of food-borne gastroenteritis worldwide annually. The infection caused by this bacterium is also associated with several forms of ...post-infectious autoimmune sequelae that can be very serious, including the life-threatening Guillain-Barré syndrome. The capsular polysaccharides (CPS) of
HS:4 consist of a very unique repeating disaccharide unit that is characterized by a β-1,4-linked 6-deoxy-β-D-
-heptopyranose and an
-acetyl-β-D-glucosamine. Eliciting carbohydrate-specific antibodies against the CPS structures of
HS:4 is an attractive strategy. The 6-deoxy-
-configuration of the heptose combined with its β-anomeric configuration makes the chemical synthesis of the disaccharide very challenging. Here, we report an efficient synthesis to obtain the key repeating disaccharide and its analog in reverse order plus a trisaccharide. Our synthesis features a highly efficient, one-step stereo- and regioselective conversion of β-D-
-heptopyranosides to 6-deoxy-β-D-
-heptopyranosides
the intermediate 2,3-anhydro-β-D-
-heptopyranosides.
In the search for improved and safer gadolinium-based magnetic resonance imaging (MRI) contrast agents, macrocyclic cyclodextrins (CDs) attract great interest. Our group previously synthesized a ...cyclodextrin-based ligand with 1,2,3-triazolmethyl residues conjugated to β-CD, called β-CD(
A
), which efficiently chelates Gd(III) ions. To probe the local structure around the Gd(III) ion in the 1:1 Gd(III): β-CD(
A
) complex in aqueous solution (pH 5.5), we used extended X-ray absorption fine structure (EXAFS) spectroscopy. Least-squares curve fitting of the Gd L
3
-edge EXAFS spectrum revealed 5 Gd–O (4 COO
−
and 1 H
2
O) and 4 Gd–N (from two imino and two 1,2,3-triazole groups) bonds around the Gd(III) ion with average distances 2.36 and 2.56 ± 0.02 Å, respectively. A similar EXAFS spectrum was obtained from an aqueous solution of the clinically used MRI contrast agent NaGd(DOTA)(H
2
O), also 9-coordinated in its first shell. Careful analysis revealed that the mean Gd–N distance is shorter in the Gd(III): β-CD(
A
) (1:1) complex, indicating stronger Gd–N bonding and stronger Gd(III) complex formation than with the DOTA
4−
ligand. This is consistent with the lower free Gd
3+
concentration found previously for the Gd(III): β-CD(
A
) (1:1) complex than for the Gd(DOTA)(H
2
O)
−
complex, and shows its potential as an MRI probe.
Graphical abstract
EXAFS spectroscopy revealed a similar Gd(III) 9-coordination although slightly stronger for a modified β-cyclodextrin: Gd(III) 1:1 complex, Gd(LH
4
)
7−
, in aqueous solution than for the clinically used MRI contrast agent NaGd(DOTA)(H
2
O).
Bacterial nonulosonic acids such as pseudaminic acids and others constitute a family of 9-carbon monosaccharides that contain a common 3-deoxy-2-ketoacid fragment but differ in their ...stereochemistries at 5 stereogenic centers between C-4 to C-8. Their unique structures make them attractive targets for use as antigens in vaccinations to combat drug-resistant bacterial infections and their challenging stereochemistries have attracted considerable attention from chemists. In this work we report the development of an improved synthesis for 2,4-di-
-acetyl-l-altrose (l-2,4-Alt-diNAc), which is a key hexose required for the chemical and chemoenzymatic synthesis of pseudaminic acids. Using l-fucose as a starting material, our synthesis overcomes several pitfalls in previously reported syntheses.
Perivascular cuffs are portals for leucocyte entry into CNS parenchyma. Stephenson et al. report that in a rodent model of multiple sclerosis and brain tissue from patients, leucocytes could be ...enhanced within perivascular cuffs by elevated pro-inflammatory chondroitin sulfate proteoglycans. Targeting these proteoglycans reduced leucocyte trafficking and disease severity.
Abstract
Multiple sclerosis presents with profound changes in the network of molecules involved in maintaining central nervous system architecture, the extracellular matrix. The extracellular matrix components, particularly the chondroitin sulfate proteoglycans, have functions beyond structural support including their potential interaction with, and regulation of, inflammatory molecules. To investigate the roles of chondroitin sulfate proteoglycans in multiple sclerosis, we used the experimental autoimmune encephalomyelitis model in a time course study. We found that the 4-sulfated glycosaminoglycan side chains of chondroitin sulfate proteoglycans, and the core protein of a particular family member, versican V1, were upregulated in the spinal cord of mice at peak clinical severity, correspondent with areas of inflammation. Versican V1 expression in the spinal cord rose progressively over the course of experimental autoimmune encephalomyelitis. A particular structure in the spinal cord and cerebellum that presented with intense upregulation of chondroitin sulfate proteoglycans is the leucocyte-containing perivascular cuff, an important portal of entry of immune cells into the central nervous system parenchyma. In these inflammatory perivascular cuffs, versican V1 and the glycosaminoglycan side chains of chondroitin sulfate proteoglycans were observed by immunohistochemistry within and in proximity to lymphocytes and macrophages as they migrated across the basement membrane into the central nervous system. Expression of versican V1 transcript was also documented in infiltrating CD45+ leucocytes and F4/80+ macrophages by in situ hybridization. To test the hypothesis that the chondroitin sulfate proteoglycans regulate leucocyte mobility, we used macrophages in tissue culture studies. Chondroitin sulfate proteoglycans significantly upregulated pro-inflammatory cytokines and chemokines in macrophages. Strikingly, and more potently than the toll-like receptor-4 ligand lipopolysaccharide, chondroitin sulfate proteoglycans increased the levels of several members of the matrix metalloproteinase family, which are implicated in the capacity of leucocytes to cross barriers. In support, the migratory capacity of macrophages in vitro in a Boyden chamber transwell assay was enhanced by chondroitin sulfate proteoglycans. Finally, using brain specimens from four subjects with multiple sclerosis with active lesions, we found chondroitin sulfate proteoglycans to be associated with leucocytes in inflammatory perivascular cuffs in all four patients. We conclude that the accumulation of chondroitin sulfate proteoglycans in the perivascular cuff in multiple sclerosis and experimental autoimmune encephalomyelitis boosts the activity and migration of leucocytes across the glia limitans into the central nervous system parenchyma. Thus, chondroitin sulfate proteoglycans represent a new class of molecules to overcome in order to reduce the inflammatory cascades and clinical severity of multiple sclerosis.
Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in ...lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy to promote repair in multiple sclerosis and other neurological disorders.
Stroke is the second leading cause of death worldwide and has two major subtypes: ischemic stroke and hemorrhagic stroke. Neuroinflammation is a pathological hallmark of ischemic stroke and ...intracerebral hemorrhage (ICH), contributing to the extent of brain injury but also in its repair. Neuroinflammation is intricately linked to the extracellular matrix (ECM), which is profoundly altered after brain injury and in aging. In the early stages after ischemic stroke and ICH, immune cells are involved in the deposition and remodeling of the ECM thereby affecting processes such as blood-brain barrier and cellular integrity. ECM components regulate leukocyte infiltration into the central nervous system, activate a variety of immune cells, and induce the elevation of matrix metalloproteinases (MMPs) after stroke. In turn, excessive MMPs may degrade ECM into components that are pro-inflammatory and injurious. Conversely, in the later stages after stroke, several ECM molecules may contribute to tissue recovery. For example, thrombospondin-1 and biglycan may promote activity of regulatory T cells, inhibit the synthesis of proinflammatory cytokines, and aid regenerative processes. We highlight these roles of the ECM in ischemic stroke and ICH and discuss their potential cellular and molecular mechanisms. Finally, we discuss therapeutics that could be considered to normalize the ECM in stroke. Our goal is to spur research on the ECM in order to improve the prognosis of ischemic stroke and ICH.
Novel cyclodextrin (CD)-based amphiphilic poly(carboxylic acid)s that self-assemble into highly ordered smectic liquid crystalline mesophases were investigated as a novel class of protonic ...conductors. These structurally well-defined materials are synthesized from nontoxic and environment-friendly CDs, which possess a unique face-to-face pseudosymmetry. By taking advantage of such geometry, a series of flexible tetraethylene glycol groups terminated with a carboxylic acid functionality were introduced to the CD’s secondary face, resulting in the formation of long-range 2D hydrogen-bond networks in the smectic mesophases over a wide temperature window. This new material was found to exhibit impressive proton conductivities in solid states, up to 1.4 × 10–2 S cm–1 at 70 °C and 95% humidity. This constitutes the first report of amphiphilic CD-based liquid crystals applied as proton conductive materials.
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