Synthesis Of Glycosides Research Articles

Additive-assisted synthesis of α-Kdo glycosides with peracetylated glycosyl ynenoate as a donor.

A DMF-modulated glycosylation approach for the stereoselective synthesis of α-Kdo glycosides with readily accessible peracetylated Kdo ynenoate as a donor was described. By utilizing this approach, we completed the synthesis of various linkage types of Kdo-Kdo disaccharides and the α-Kdo-containing protected trisaccharide variant relevant to the lipopolysaccharide of Coxiella burnetii strain Nine Mile.

Bio-inspired Synthesis and Bioactivities of Phenylethanoid Glycosides Crenatosides

Here, we report an effective approach to the synthesis of phenylethanoid glycosides bearing a fused 1,4-dioxane motif, employing a bio-inspired oxidative cyclization of the glucose 2-OH and the benzylic carbon...

Synthesis of sulfated lactosyl glycosides for evaluation in vaccine adjuvant formulations

Adjuvants are essential components of vaccines as they enable protection against multiple pathogens by enhancing the duration, magnitude and or quality of immune responses.

Design and synthesis of oxytocin glycosides for the treatment of pain and substance use disorder.

Peptide drugs are a promising alternative to classical small molecule therapeutics with diverse applications, ranging from antibiotic resistant infection to prostate cancer. Oxytocin (OT) is a highly evolutionarily conserved peptide neurohormone and has been of interest for pharmaceutical use since 1909. Despite their increased safety profile relative to most small molecule drugs, peptides are poor candidates based on the pharmacokinetic (PK) properties from their peptide nature. Broad application of OT as a drug has been limited by these same PK issues. Several strategies have been proposed to overcome these limitations, among them glycosylation, which was used in combination with other sequence modifications to produce robust antinociception in mouse models, increased selectivity and potency at the OT receptor, and improved stability in rats.

Stereocontrolled Synthesis of α-3-Deoxy-d-manno-oct-2-ulosonic Acid (α-Kdo) Glycosides Using C3-p-Tolylthio-Substituted Kdo Donors: Access to Highly Branched Kdo Oligosaccharides.

3-Deoxy-d-manno-oct-2-ulosonic acid (Kdo) is an eight-carbon monosaccharide found widely in bacterial lipopolysaccharides (LPSs) and capsule polysaccharides (CPSs). We developed an indirect method for the stereoselective synthesis of α-Kdo glycosides with a C3-p-tolylthio-substituted Kdo phosphite donor. The presence of the p-tolylthio group enhanced the reactivity, suppressed the formation of elimination by-products (2,3-enes), and provided complete α-stereocontrol. A variety of Kdo α-glycosides were synthesized by our method in excellent yields (up to 98 %). After glycosylation, the p-tolylthio group can be efficiently removed by free-radical reduction. Subsequently, the orthogonality of the phosphite donor and thioglycoside donor was demonstrated by the one-pot synthesis of a trisaccharide in Helicobacter pylori and Neisseria meningitidis LPS. Moreover, an efficient total synthesis route to the challenging 4,5-branched Kdo trisaccharide in LPSs from several A. baumannii strains was highlighted. To demonstrate the high reactivity of our approach further, the highly crowded 4,5,7,8-branched Kdo pentasaccharide was synthesized as a model molecule for the first time. Additionally, the reaction mechanism was investigated by DFT calculations.

β-Glucosidase on clay minerals: Structure and function in the synthesis of octyl glucoside

β-Glucosidase is a biological macromolecule that catalyzes the hydrolysis of various glycosides and oligosaccharides. It may also be used to catalyze the synthesis of glycosides under suitable conditions. Carrier-bound β-glucosidase can enhance the enzymatic activity in the synthesis of glycosides in organic solvent solutions, although the molecular mechanism regulating activity is yet unknown. This study investigated the impact of utilizing montmorillonite (Mmt), attapulgite (Attp), and kaolinite (Kao) as carriers on the activity of β-glucosidase from Prunus dulcis (PdBg). When Attp was used as carriers, the molecular dynamic (MD) simulations found the distance between pNPG and the active site residues E183 and E387 was minimally impacted by the adsorptions, hence PdBg maintained about 81.3 ± 0.89 % of its native activity. Out of the three clay minerals, the relative activity of PdBg loaded on Mmt was the lowest because of the highest electrostatic energy. The substrate channel of PdBg on Kao is directed towards the surface, limiting the accessibility of substrates. Secondary structure and conformation studies revealed that the conformational stability of PdBg in solvent solutions was enhanced by coupling to Attp. Unlike dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF) and 1,2-dimethoxyethane (DME), tert-butanol (t-BA) did not penetrate into the active site of PdBg interfering with its binding to the substrate. The maximum yield of n-octyl-β-glucoside (OGP) synthesis catalyzed by Attp-immobilized PdBg reached 48.3 %.

Syntheses of propargyl glycosides of disaccharides of the capsular polysaccharides from serotypes 4, 7F, and 9V Streptococcus pneumoniae for glycoconjugate vaccines

We have developed a means of presenting relatively small glycans in a context to make them T cell-dependent antigens. This approach requires synthesis of glycans that remain close to carrier proteins upon conjugation, allowing T cell recognition and generation of B cells that produce high-affinity antibodies and memory toward target pathogens. In this work, we describe the syntheses of three disaccharides of the capsular polysaccharides from serotypes 4, 7F and 9V Streptococcus pneumoniae (Sp) as propargyl glycosides for use in this vaccine strategy. While variations of these disaccharides have previously been synthesized, none have been synthesized with an alkyne as the linker. Incorporation of the alkyne led to redesign of the synthesis of each disaccharide. All three disaccharides were synthesized without use of benzyl protective groups, one of the most used carbohydrate protective groups due to its stability and ease of removal via hydrogenation. We report challenges that arose while synthesizing the targets with less common protective groups, such as naphthyl ethers, and the methods used to successfully overcome these challenges.

Tris(pentafluorophenyl)borane-Catalyzed Stereoselective C-Glycosylation of Glycals: A Facile Synthesis of Allyl and Alkynyl Glycosides

AbstractIn modern advances, tris(pentafluorophenyl)borane (commonly known as BCF) catalyst has risen to prominence owing to its extensive versatility in the use of myriad of organic reactions. An efficient and highly stereoselective α-C-glycosylation strategy is presented by employing a catalytic amount of B(C6F5)3 under mild reaction conditions en route to 2,3-unsaturated C-glycosides. The reaction features a broad functional group tolerance including a variety of glycals coupled with allyltrimethylsilane and trimethylsilylphenylacetylene to access the corresponding 2,3-unsaturated allyl- and alkynyl-C-glycosides with excellent α-selectivity. The reaction proceeds in good to excellent yields via concomitant borane activation of glycal donor under mild conditions.

Curcuminoid Nanovesicles as Advanced Therapeutics

AbstractTurmeric (Curcuma longa rhizome) is well‐known for its therapeutic properties in traditional Indian and Chinese medicines. It has preventive and therapeutic activity against diseases that target human body systems as well as various cancer types. This review focuses on the mechanism of action of curcumin against various factors involved in the metastatic process. The antimicrobial, antidiabetic, anti‐oxidant, and anti‐HIV activities and mechanism of curcumin‐functionalized nanovesicles are also reviewed. Despite the biocompatibility of curcumins, its medical applications are limited due to its low bioavailability, insolubility in water, and degradation at certain pH levels. Moreover, the low stability and rapid metabolism of curcumin limits its clinical applications. Therefore, it is imperative to design strategies to mitigate this shortfall which include the synthesis of curcumin glycosides or the development of curcumin delivery systems to improve the bioavailability and therapeutic efficacy of curcumin. This review provides insight into the different chemical methods for the synthesis and modification adopted to achieve these compounds.

Enzymatic Glycosylation Strategies in the Production of Bioactive Compounds

Enzymatic glycosylation is a versatile and sustainable biotechnological approach that plays a pivotal role in the production of bioactive compounds. This process involves the enzymatic transfer of sugar moieties onto various acceptor molecules, such as small molecules, peptides, or proteins, resulting in the synthesis of glycosides. These glycosides often exhibit enhanced bioactivity, improved solubility, and enhanced stability, making them valuable in pharmaceuticals, nutraceuticals, and the food industry. This review explores the diverse enzymatic glycosylation strategies employed in the synthesis of bioactive compounds. It highlights the enzymatic catalysts involved, including glycosyltransferases, glycosidases, glycophosphorylases, and glycosynthases. It considers the advantages and disadvantages of these biocatalysts in the stereoselective and regioselective synthesis of different types of glycosylated molecules, phenolic and aliphatic alcohols, oligosaccharides, polysaccharides, glycoderivatives, glycopeptides, and glycoproteins with a clear focus on food and pharmaceutical chemistry. Furthermore, the review outlines various sources of sugar donors, activated glycosides, and sugar nucleotides, as well as the utilization of engineered enzymes and microorganisms for glycosylation reactions. The advantages of enzymatic glycosylation, including its high regioselectivity, stereoselectivity, and sustainability, are emphasized. Therefore, these approaches combining the use of different catalytic systems, the improvement of tools such as immobilization technology or chemical or genetic modification to improve the glycosylation process, could be useful tools in continuous biotechnological advancements.

Genome-Wide Identification and Expression Analysis of bZIP Family Genes in Stevia rebaudiana.

The basic (region) leucine zippers (bZIPs) are evolutionarily conserved transcription factors widely distributed in eukaryotic organisms. In plants, they are not only involved in growth and development, defense and stress responses and regulation of physiological processes but also play a pivotal role in regulating secondary metabolism. To explore the function related to the bZIP gene family in Stevia rebaudiana Bertoni, we identified 105 SrbZIP genes at the genome-wide level and classified them into 12 subfamilies using bioinformation methods. Three main classes of cis-acting elements were found in the SrbZIP promoter regions, including development-related elements, defense and stress-responsive elements and phytohormone-responsive elements. Through protein-protein interaction network of 105 SrbZIP proteins, SrbZIP proteins were mainly classified into four major categories: ABF2/ABF4/ABI5 (SrbZIP51/SrbZIP38/SrbZIP7), involved in phytohormone signaling, GBF1/GBF3/GBF4 (SrbZIP29/SrbZIP63/SrbZIP60) involved in environmental signaling, AREB3 (SrbZIP88), PAN (SrbZIP12), TGA1 (SrbZIP69), TGA4 (SrbZIP82), TGA7 (SrbZIP31), TGA9 (SrbZIP95), TGA10 (SrbZIP79) and HY5 (SrbZIP96) involved in cryptochrome signaling, and FD (SrbZIP72) promoted flowering. The transcriptomic data showed that SrbZIP genes were differentially expressed in six S. rebaudiana cultivars ('023', '110', 'B1188', '11-14', 'GP' and 'GX'). Moreover, the expression levels of selected 15 SrbZIP genes in response to light, abiotic stress (low temperature, salt and drought), phytohormones (methyl jasmonate, gibberellic acid and salicylic acid) treatment and in different tissues were analyzed utilizing qRT-PCR. Some SrbZIP genes were further identified to be highly induced by factors affecting glycoside synthesis. Among them, three SrbZIP genes (SrbZIP54, SrbZIP63 and SrbZIP32) were predicted to be related to stress-responsive terpenoid synthesis in S. rebaudiana. The protein-protein interaction network expanded the potential functions of SrbZIP genes. This study firstly provided the comprehensive genome-wide report of the SrbZIP gene family, laying a foundation for further research on the evolution, function and regulatory role of the bZIP gene family in terpenoid synthesis in S. rebaudiana.

Flavonoids as Aglycones in Retaining Glycosidase-Catalyzed Reactions: Prospects for Green Chemistry.

Flavonoids and their glycosides are abundant in many plant-based foods. The (de)glycosylation of flavonoids by retaining glycoside hydrolases has recently attracted much interest in basic and applied research, including the possibility of altering the glycosylation pattern of flavonoids. Research in this area is driven by significant differences in physicochemical, organoleptic, and bioactive properties between flavonoid aglycones and their glycosylated counterparts. While many flavonoid glycosides are present in nature at low levels, some occur in substantial quantities, making them readily available low-cost glycosyl donors for transglycosylations. Retaining glycosidases can be used to synthesize natural and novel glycosides, which serve as standards for bioactivity experiments and analyses, using flavonoid glycosides as glycosyl donors. Engineered glycosidases also prove valuable for the synthesis of flavonoid glycosides using chemically synthesized activated glycosyl donors. This review outlines the bioactivities of flavonoids and their glycosides and highlights the applications of retaining glycosidases in the context of flavonoid glycosides, acting as substrates, products, or glycosyl donors in deglycosylation or transglycosylation reactions.

Solvent Engineering for Nonpolar Substrate Glycosylation Catalyzed by the UDP-Glucose-Dependent Glycosyltransferase UGT71E5: Intensification of the Synthesis of 15-Hydroxy Cinmethylin β-d-Glucoside.

Sugar nucleotide-dependent glycosyltransferases are powerful catalysts of the glycosylation of natural products and xenobiotics. The low solubility of the aglycone substrate often limits the synthetic efficiency of the transformation catalyzed. Here, we explored different approaches of solvent engineering for reaction intensification of β-glycosylation of 15HCM (a C15-hydroxylated, plant detoxification metabolite of the herbicide cinmethylin) catalyzed by safflower UGT71E5 using UDP-glucose as the donor substrate. Use of a cosolvent (DMSO, ethanol, and acetonitrile; ≤50 vol %) or a water-immiscible solvent (n-dodecane, n-heptane, n-hexane, and 1-hexene) was ineffective due to enzyme activity and stability, both impaired ≥10-fold compared to a pure aqueous solvent. Complexation in 2-hydroxypropyl-β-cyclodextrin enabled dissolution of 50 mM 15HCM while retaining the UGT71E5 activity (∼0.32 U/mg) and stability. Using UDP-glucose recycling, 15HCM was converted completely, and 15HCM β-d-glucoside was isolated in 90% yield (∼150 mg). Collectively, this study highlights the requirement for a mild, enzyme-compatible strategy for aglycone solubility enhancement in glycosyltransferase catalysis applied to glycoside synthesis.

Dihydrochalcone glycoside biosynthesis in Malus is regulated by two MYB-like transcription factors and is required for seed development.

Dihydrochalcones (DHCs) including phlorizin (phloretin 2'-O-glucoside) and its positional isomer trilobatin (phloretin 4'-O-glucoside) are the most abundant phenylpropanoids in apple (Malus spp.). Transcriptional regulation of DHC production is poorly understood despite their importance in insect- and pathogen-plant interactions in human physiology research and in pharmaceuticals. In this study, segregation in hybrid populations and bulked segregant analysis showed that the synthesis of phlorizin and trilobatin in Malus leaves are both single-gene-controlled traits. Promoter sequences of PGT1 and PGT2, two glycosyltransferase genes involved in DHC glycoside synthesis, were shown to discriminate Malus with different DHC glycoside patterns. Differential PGT1 and PGT2 promoter activities determined DHC glycoside accumulation patterns between genotypes. Two transcription factors containing MYB-like DNA-binding domains were then shown to control DHC glycoside patterns in different tissues, with PRR2L mainly expressed in leaf, fruit, flower, stem, and seed while MYB8L mainly expressed in stem and root. Further hybridizations between specific genotypes demonstrated an absolute requirement for DHC glycoside production in Malus during seed development which explains why no Malus spp. with a null DHC chemotype have been reported.

Radical Pathway Glycosylation Empowered by Bench-Stable Glycosyl Donors.

ConspectusThe study of carbohydrates has emerged as a crucial research area in various disciplines due to their pivotal roles in cellular processes. To facilitate in-depth exploration of their biological functions, chemical glycosylation reactions that allow facile access of glycoconjugates to a broad research community are highly needed. In classical glycosylation reactions, a glycosyl donor is activated by an acid to generate a reactive electrophilic intermediate, which subsequently forms a glycosidic bond upon reaction with a nucleophilic acceptor. Such an ionic pathway glycosylation has been the mainstay technique for glycoconjugate synthesis and allowed the synthesis of numerous intricate structures. Nevertheless, limitations still exist. For instance, when labile glycosyl donors or harsh activating conditions are required, these methods show limited tolerance to hydroxyl groups that are abundant on sugar rings. In addition, achieving good stereocontrol represents another longstanding obstacle. In recent years, new modes of donor activation have been sought to tackle the above challenges.We noted that glycosylation methods passing through the intermediacy of glycosyl radicals via a cascade of single-electron transfer steps possess significant but underexplored potential. Progress in this area has been slow due in large part to a dearth of handy methods to generate and maneuver glycosyl radicals. Most existing methods call for either forcing conditions or unstable/inconvenient starting materials. In order to better exploit the power of the radical pathway glycosylation, we have developed a range of glycosyl donors─namely, glycosyl sulfoxides, glycosyl sulfones, and glycosyl sulfinates─that are bench stable and can be readily prepared from simple starting materials. These donors can be activated to form glycosyl radicals under mild conditions. Enabled by the use of these donors, we have developed a series of glycosylation methods that could be used for making O-, S-, or C-glycosides, some of which were previously difficult to access. In many cases, no protecting group on glycosyl donors is required. As an illustration of their potential utility, our methods have been adopted in the preparation of sugar-drug conjugates, sugar-DNA conjugates, glycopeptides, and even glycoproteins. While in most cases the intrinsic reactivity of glycosyl radical intermediates can be explored to access axially configured products, some of the methods also allow the utilization of external, delicate reagents, or catalysts to override such innate preference and achieve catalyst-controlled stereoselectivity.We believe that radical pathway glycosylation has enormous potential and can inspire the development of novel methods for glycoside synthesis. In this Account, we highlight the design principles for the development of our glycosyl donors, summarize our recent advancements in radical pathway glycosylation enabled by their use, and provide an outlook on the future directions of this field.

Development of silver nanoparticles based on the method using quince seed mucilage for ascorbic acid determination.

Nanoparticles are used in various fields such as chemistry, pharmacy, biotechnology, and food science since they provide higher sensitivity than traditional optical detection methods. Recently, synthesis of nanomaterials using green chemistry has become popular. Many phytochemical components are used in the synthesis of nanoparticles, including vitamins, proteins, polysaccharides, glycosides, essential oils and phenolic compounds. A novel green nanotechnology-based method using quince seed mucilage (QSM) was designed for the determination of ascorbic acid in pharmaceutical preparations. QSM, a natural polysaccharide, was used as a bioreducing and stabilizing reagent in the proposed silver nanoparticle (SNP)-based method. In the first stage of the developed method, silver(I) is reduced to silver(0) via QSM and spherical, homogeneous SNPs were prepared (QSM-SNPs). In the second stage of the developed method, SNPs nuclei were enlarged with the addition of ascorbic acid. The developed method was validated by performance parameters (linearity, recovery, and precision). Ascorbic acid determination was performed by measuring increase in absorbance at 420 nm. The limit of detection and limit of quantification for ascorbic acid were, respectively, found to be at 0.27 and 0.90 μM. The QSM-SNP-based method was successfully applied to effervescent tablets containing ascorbic acid. The standards of the excipients frequently used in pharmaceutical preparations did not interfere with the developed method. The developed QSM-SNP-based method satisfies the requirements of green nanotechnology. The developed QSM-SNP-based method is simple, fast, eco-friendly and low-cost.

Visible-Light-Mediated Synthesis of C-Alkyl Glycosides via Glycosyl Radical Addition and Aryl Migration.

A visible-light-induced glycoarylation of activated olefins has been accomplished. Glycosyl radicals are generated via radical transfer strategies between (TMS)3SiOH and glycosyl bromides. Subsequent radical translocation and rapid 1,4-aryl migration form β-sugar amide derivatives, and eight types of sugars are compatible with this reaction. Further, the cascade reaction produced a quaternary carbon center with good functional group adaptability and high regioselectivity in mild conditions.

Synthesis of phenylethanoid glycosides from acrylic esters of glucose and aryldiazonium salts via palladium-catalyzed cross-coupling reactions and evaluation of their anti-Alzheimer activity

Cinnamic acid-containing sugar compounds such as phenylethanoid glycosides are widely present in nature and display various biological activities. In this work, the synthesis of trans-cinnamic acid containing phenylethanoid glycosides was achieved via palladium-catalyzed cross-coupling reactions between glycosyl acrylic esters and aryldiazonium salts. A wide range of functionalized aryldiazonium salts were successfully coupled with 6-O- and 4-O-acrylic esters of glucose under optimized conditions. The reactions proceeded at room temperature in the absence of additives and base. The desired products were obtained in good to excellent yields. Selected compounds from the library were screened for anti-Alzheimer activity, while compound 16 displayed significant inhibitory activities against butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) enzymes.

Stereoselective Aromatic O-Glycosylation of Glycosyl Chloride with Arylboronic Acid under an Air Atmosphere.

A novel exclusive β-selective O-aryl glycosylation was developed using glycosyl chloride and arylboronic acid with a palladium catalyst under an air atmosphere. The reaction was insensitive to moisture and characterized using readily available and bench-stable glycosyl chloride and arylboronic acid as substrates. A diverse range of substrate scopes, including various arylboronic acids and glycosyl chloride donors, was well-tolerated in this method. Arylboronic acid was oxidized by O2 in air to produce phenol as the aromatic source. This new strategy provides an alternative route and may find broad applications in efficient synthesis of bioactive O-aryl glycosides in the future.

Identification, Chemical Synthesis, and Sweetness Evaluation of Rhamnose or Xylose Containing Steviol Glycosides of Stevia (Stevia rebaudiana) Leaves.

Steviol glycosides obtained from Stevia rebaudiana leaves are increasingly used in the food industry as natural low-calorie sweeteners. Among them, the sweetness of major glycosides composed of glucose residues (e.g., stevioside and rebaudioside A) has been widely studied. However, the properties of minor natural products containing rhamnose or xylose residues are poorly investigated. In this study, five unreported steviol glycosides containing rhamnose or xylose were extracted from our developing stevia leaves, and their sweetness was evaluated. The highly glycosylated steviol glycosides were identified, and their structures were examined by fragmentation analysis using mass spectrometry. Chemical synthesis of these glycosides confirmed their structures and allowed sensory evaluation of minor steviol glycosides. Our study revealed that a xylose-containing glycoside, rebaudioside FX1, exhibits a well-balanced sweetness, and thus, it is a promising candidate for natural sweeteners used in the food industry.