New Set of Orthogonal Protecting Groups for the Modular Synthesis of Heparan Sulfate Fragments

Prabhu, A. Antony Muthu; Venot, and Andre P.; Boons, Geert‐Jan

doi:10.1021/ol0359261

Cited by 66 publications

(47 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The anomeric center of the disaccharides will be protected as thexyldimethyl silyl (TDS) glycosides and this functionality can easily be removed by treatment with HF in pyridine without affecting the other protecting groups. The resulting lactol can then be converted into a trichloroacetimidate by employing K 2 CO 3 and trichloroacetonitrile in DCM 20. Finally, benzyl ethers are used as permanent protecting groups for the other hydroxyls.…”

Section: Resultsmentioning

confidence: 99%

Modular Synthesis of Heparan Sulfate Oligosaccharides for Structure−Activity Relationship Studies

et al. 2009

Self Cite

View full text Add to dashboard Cite

Although hundreds of heparan sulfate binding proteins have been identified, and implicated in a myriad of physiological and pathological processes, very little information is known about ligand requirements for binding and mediating biological activities by these proteins. This difficulty results from a lack of technology for establishing structure-activity-relationships, which in turn is due to the structural complexity of natural heparan sulfate (HS) and difficulties of preparing well-defined HSoligosaccharides. To address this deficiency, we have developed a modular approach for the parallel combinatorial synthesis of HS oligosaccharides that utilizes a relatively small number of selectively protected disaccharide building blocks, which can easily be converted into glycosyl donors and acceptors. The utility of the modular building blocks has been demonstrated by the preparation of a library of twelve oligosaccharides, which has been employed to probe structural features of HS for inhibiting the protease, BACE-1. The complex variations in activity with structural changes support the view that important functional information is embedded in HS sequences. Furthermore, the most active derivative provides an attractive lead compound for the preparation of more potent compounds, which may find use as a therapeutic agent for Alzheimer's disease.

show abstract

Section: Resultsmentioning

confidence: 99%

Modular Synthesis of Heparan Sulfate Oligosaccharides for Structure−Activity Relationship Studies

et al. 2009

Self Cite

View full text Add to dashboard Cite

show abstract

“…Based on the analysis of the structural motifs of heparan sulfate, it has been proposed that only six strategically selected monosaccharides are required to prepare eight disaccharide motifs, which in principle should give access to all possible HS structures 68. In this strategy, the Lev esters are employed for those hydroxyls that need sulfation.…”

Section: Monosaccharide Synthesismentioning

confidence: 99%

Opportunities and challenges in synthetic oligosaccharide and glycoconjugate research

2009

Self Cite

View full text Add to dashboard Cite

Synthetic oligosaccharides and glycoconjugates are increasingly used as probes for biological research and as lead compounds for drug and vaccine discovery. These endeavors are, however, complicated by a lack of general methods for the routine preparation of this important class of compounds. Recent development such as one-pot multi-step protecting group manipulations, the use of unified monosaccharide building blocks, the introduction of stereoselective glycosylation protocols, and convergent strategies for oligosaccharide assembly, are beginning to address these problems. Furthermore, oligosaccharide synthesis can be facilitated by chemo-enzymatic methods, which employ a range of glycosyl transferases to modify a synthetic oligosaccharide precursor. Glycosynthases, which are mutant glycosidases, that can readily form glycosidic linkages are addressing a lack of a wide range glycosyltransferases. The power of carbohydrate chemistry is highlighted by an ability to synthesize glycoproteins.There is a growing appreciation that posttranslational modifications, such as glycosylation, dramatically increase protein complexity and function. [1][2][3][4][5][6] For example, almost all cell surface and secreted proteins are modified by covalently-linked carbohydrate moieties and the glycan structures on these glycoproteins have been implicated as essential mediators in processes such as protein folding, cell signaling, fertilization, embryogenesis, neuronal development, hormone activity, and the proliferation of cells and their organization into specific tissues. In addition, overwhelming data supports the relevance of glycans in pathogen recognition, inflammation, innate immune responses, and the development of autoimmune diseases and cancer. [7][8][9][10] The importance of protein glycosylation is also underscored by the developmental abnormalities observed in a growing number of human disorders known as Congenital Disorders of Glycosylation caused by defects in the glycosylation machinery. 11Polysaccharides are major constituents of the microbial cell surfaces and, for example, the bacterial cell wall can contain relatively large amounts of capsular polysaccharides (CPS) or lipopolysaccharides (LPS). 12 These components are important virulence factors by promoting bacterial colonization, blocking phagocytosis, and interfering with leukocyte migration and adhesion. CPS and LPS can be recognized by receptors of the innate immune system leading to the production of cytokines, chemokines, and cellular adhesion molecules.13 -16 With a few exceptions, bacterial polysaccharides can induce an adaptive immune response and, not surprisingly, bacterial saccharides have been employed for the development of vaccines for several pathogens.17 -20

show abstract

“…[9] The usage of orthogonal protecting groups affords a solution for regioselective masking and unmasking of hydroxyl groups. [10] This synthetic approach apparently has two advantages. One is to effectively reduce the number of synthetic steps and the time required, and the other one allows the possibility of incorporating functional groups into specific position(s).…”

Section: Introductionmentioning

confidence: 99%

Expeditious Synthesis of Orthogonally Protected Saccharides through Consecutive Protection/Glycosylation Steps

Liu

et al. 2015

Israel Journal of Chemistry

View full text Add to dashboard Cite

We recently developed a facile synthesis to yield orthogonally protected mannose‐ and Gal‐β1,3/4‐GlcNAc‐containing oligosaccharides. With optimized reaction conditions, the protection/glycosylation steps were carried out in a successive manner, without purification of intermediate products. The entire development sequence is herein described in detail, including each installation and removal of protecting groups, the optimization of glycosylation reactions, the successive operation of reaction steps, and further applications for glycan synthesis. We also discuss the unsolved problems and current challenges.

show abstract

New Set of Orthogonal Protecting Groups for the Modular Synthesis of Heparan Sulfate Fragments

Cited by 66 publications

References 28 publications

Modular Synthesis of Heparan Sulfate Oligosaccharides for Structure−Activity Relationship Studies

Modular Synthesis of Heparan Sulfate Oligosaccharides for Structure−Activity Relationship Studies

Opportunities and challenges in synthetic oligosaccharide and glycoconjugate research

Expeditious Synthesis of Orthogonally Protected Saccharides through Consecutive Protection/Glycosylation Steps

Contact Info

Product

Resources

About