Carbohydrate Analogues Research Articles

Synthesis of 1,2-Disubstituted C-Aryl Glycosides via Palladium/Norbornene Cooperative Catalysis.

The Catellani reaction offers an opportunity to address multiple chemical bonds in a single pot. However, it is still quite a challenge to construct fully substituted olefins via this strategy, especially in electron-rich, unstable, and highly functionalized glycals. Herein we report the first palladium-catalyzed Catellani reaction for the direct preparation of 1,2-disubstituted C-aryl glycosides from easily available 2-iodoglycals, bromoaryl, and alkene/alkyne substrates. This transformation exhibits a wide substrate scope, accommodating diverse functional groups and intricate molecular frameworks. This innovative reactivity offers an efficient pathway to valuable 1,2-disubstituted carbohydrate analogues and molecular building blocks, facilitating novel strategic bond disconnections and broadening the reactivity landscape of palladium catalysis.

In vitro antimicrobial, anticancer evaluation, and in silico studies of mannopyranoside analogs against bacterial and fungal proteins: Acylation leads to improved antimicrobial activity

Carbohydrate analogs are an important, well-established class of clinically useful medicinal agents that exhibit potent antimicrobial activity. Thus, we explored the various therapeutic potential of methyl α-D-mannopyranoside (MαDM) analogs, including their ability to synthesize and assess their antibacterial, antifungal, and anticancer properties; additionally, molecular docking, molecular dynamics simulation, and ADMET analysis were performed. The structure of the synthesized MαDM analogs was ascertained by spectroscopic techniques and physicochemical and elemental analysis. In vitro antimicrobial activity was assessed and revealed significant inhibitory effects, particularly against gram-negative bacteria along with the prediction of activity spectra for substances (PASS). Concurrently, MαDM analogs showed good results against antifungal pathogens and exhibited promising anticancer effects in vitro, demonstrating dose-dependent cytotoxicity against Ehrlich ascites carcinoma (EAC) cancer cells while sparing normal cells from compound 5, with an IC50 of 4511.65 µg/mL according to the MTT colorimetric assay. A structure–activity relationship (SAR) study revealed that hexose combined with the acyl chains of decanoyl (C-10) and benzenesulfonyl (C6H5SO2-) had synergistic effects on the bacteria and fungi that were examined. Molecular docking was performed against the Escherichia coli (6KZV) and Candida albicans (1EAG) proteins to acquire insights into the molecular interactions underlying the observed biological activities. The docking results were further supported by 100 ns molecular dynamics simulations, which provided a dynamic view of the stability and flexibility of complexes involving MαDM and its targets. In addition, ADMET analysis was used to evaluate the toxicological and pharmacokinetic profiles. Owing to their promising drug-like properties, these MαDM analogs exhibit potential as prospective therapeutic candidates for future development.

Unlocking the power of sugar: carbohydrate ligands as key players in nanotherapeutic-assisted targeted cancer therapy.

Cancer cells need as much as 40-times more sugar than their normal cell counterparts. This sugar demand is attained by the excessive expression of inimitable transporters on the surface of cancer cells, driven by their voracious appetite for carbohydrates. Nanotechnological advances drive research utilizing ligand-directed therapeutics and diverse carbohydrate analogs. The precise delivery of these therapeutic cargos not only mitigates toxicity associated with chemotherapy but also reduces the grim toll of mortality and morbidity among patients. This in-depth review explores the potential of these ligands in advanced cancer treatment using nanoparticles. It offers a broader perspective beyond the usual ways we deliver drugs, potentially changing the way we fight cancer.

Targeting Carbohydrate Mimetics of Tetrahydrofuran-Containing Acetogenins to Prostate Cancer.

The high potency of the tetrahydrofuran-containing acetogenins (THF-ACGs) against a broad range of human cancer cell lines has stimulated interest in structurally simpler mimetics. In this context, we have previously reported THF-ACG mimetics in which the THF and butenolide moieties of a mono-THF-ACG were replaced with carbohydrate and thiophene residues, respectively. In the present study, towards the targeting of these carbohydrate analogues to prostate cancer (PCa), we synthesized prodrugs in which a parent thiophene or butenolide congener was conjugated through a self-immolative linker to 2-[3-(1,3-dicarboxypropyl)ureido] pentanedioic acid (DUPA), a highly specific ligand for prostate-specific membrane antigen (PSMA), which is overexpressed on prostate tumors. Both prodrugs were found to be more active against receptor positive LNCaP than receptor-negative PC-3 cells, with 2.5 and 12 times greater selectivity for the more potent thiophene analog and the less active butenolide congener, respectively. This selectivity for LNCaP over PC-3 contrasted with the behavior of the parent drugs, which showed similar or significantly higher activity for PC-3 compared to LNCaP. These data support the notion that higher activity of these DUPA-derived prodrugs against LNCaP cells is connected to their binding to PSMA and suggest that the conjugation of PSMA ligands to this family of cytotoxic agents may be effective for targeting them to PCa.

Utilizing Reusable Catalyst Phosphotungstic Acid for the Synthesis of Thioglycoside from Per-O-acetyl Saccharides with Microwave-Assisted and De-O-acetylation with Methanol.

Traditional methods for synthesizing complex oligosaccharides currently developed are not efficient, requiring a new glycosylation methodology. Herein, using phosphotungstic acid (PTA) as a catalyst has demonstrated to be a simple possibility for carbohydrate synthesis. The methodology is engineered into a PTA-catalyzed thioglycoside preparation under microwave conditions and de-O-acetylation of carbohydrates. These easier operations and convenient protocols display a wide substrate scope. Moreover, both methods can be developed into a one-pot reaction for the efficient synthesis of carbohydrate analogues.

Synthesis of carbohydrate analogues of the THF-acetogenin 4-deoxyannomontacin and their cytotoxicity against human prostate cancer cell lines

The THF containing acetogenin 4-deoxyannonmontacin (4-DAN) has attracted interest for its potent cytotoxicity against a broad range of human tumor cell lines, and relatively simple structure. Herein is described the synthesis and cytotoxicity of C-10 epimers of 4-DAN and analogues thereof comprising carbohydrate and thiophene substitutes for the THF and butenolide moieties respectively. The key synthetic ploy was the union of THF and butenolide segments or their substitutes, via an alkene cross metathesis. The different analogues showed cytotoxicity in the low micromolar to nanomolar range against the human prostate cancer cell lines LNCaP and PC3. A relatively simple mannose-linked thiophene analog was found to be similar in activity to 4-DAN.

Synthesis and Structural Characteristics of all Mono- and Difluorinated 4,6-Dideoxy-d-xylo-hexopyranoses

Protein-carbohydrate interactions are implicated in many biochemical/biological processes that are fundamental to life and to human health. Fluorinated carbohydrate analogues play an important role in the study of these interactions and find application as probes in chemical biology and as drugs/diagnostics in medicine. The availability and/or efficient synthesis of a wide variety of fluorinated carbohydrates is thus of great interest. Here, we report a detailed study on the synthesis of monosaccharides in which the hydroxy groups at their 4- and 6-positions are replaced by all possible mono- and difluorinated motifs. Minimization of protecting group use was a key aim. It was found that introducing electronegative substituents, either as protecting groups or as deoxygenation intermediates, was generally beneficial for increasing deoxyfluorination yields. A detailed structural study of this set of analogues demonstrated that dideoxygenation/fluorination at the 4,6-positions caused very little distortion both in the solid state and in aqueous solution. Unexpected trends in α/β anomeric ratios were identified. Increasing fluorine content always increased the α/β ratio, with very little difference between regio- or stereoisomers, except when 4,6-difluorinated.

Iminosugars as glycosyltransferase inhibitors.

Iminosugars are naturally occurring carbohydrate analogues known since 1967. These natural compounds and hundreds of their synthetic derivatives prepared over five decades have been mainly exploited to inhibit the glycosidases, the enzymes catalysing the glycosidic bond cleavage, in order to find new drugs for the treatment of type 2 diabetes and other diseases. However, iminosugars are also inhibitors of glycosyltransferases, the enzymes responsible for the synthesis of oligosaccharides and glycoconjugates. The selective inhibition of specific glycosyltransferases involved in cancer or bacterial infections could lead to innovative therapeutic agents. The synthesis and biological properties of all the iminosugars assayed to date as glycosyltransferase inhibitors are reviewed in the present article.

A light- and heat-driven glycal diazidation approach to nitrogenous carbohydrate derivatives with antiviral activity.

The aminated mimetics of 2-keto-3-deoxy-sugar acids such as the anti-influenza clinical drugs oseltamivir (Tamiflu) and zanamivir (Relenza) are important bioactive molecules. Development of synthetic methodologies for accessing such compound collections is highly desirable. Herein, we describe a simple, catalyst-free glycal diazidation protocol enabled by visible light-driven conditions. This new method requires neither acid promoters nor transition-metal catalysts and takes place at ambient temperature within 1-2 hours. Notably, the desired transformations could be promoted by thermal conditions as well, albeit with lower efficacy compared to the light-induced conditions. Different sugar acid-derived glycal templates have been converted into a range of 2,3-diazido carbohydrate analogs by harnessing this mild and scalable approach, leading to the discovery of new antiviral agents.

The buckwheat iminosugar D-fagomine attenuates sucrose-induced steatosis and hypertension in rats

AbstractD-Fagomine (1,2 dideoxynojirimycin) is an iminosugar, a carbohydrate analogue that includes an endocyclic nitrogen instead of oxygen, that is naturally present in buckwheat and buckwheat-based foodstuffs. This study examines the long-term functional effect of d-fagomine on sucrose-induced factors of metabolic syndrome and explores possible molecular mechanisms behind its action. We evaluated Wistar Kyoto rats fed a standard diet were given a 35% sucrose (glucose/fructose) solution with d-fagomine (or not, for comparison) or mineral water (controls) for 24 weeks. The variables measured were body weight and energy intake; glucose tolerance (oral glucose tolerance test); plasma leptin concentration; plasma lipid profile; the populations of Bacteroidetes, Firmicutes, bacteroidales, clostridiales, enterobacteriales, and Escherichia coli in feces; blood pressure; urine uric acid and F2t isoprostanes (F2-IsoPs); perigonadal fat deposition and hepatic histology and diacylglycerols (DAGs) in liver and adipose tissue. We found that d-Fagomine reduced sucrose induced hypertension, urine uric acid, F2-IsoPs as markers of oxidative stress (OS), steatosis and liver DAGs (32:1, 32:2, 34:1 and 36:2) without affecting perigonadal (visceral) fat deposition or DAG levels in visceral adipose tissue. It showed a slight tendency to reduce sugar induced impaired glucose tolerance. d-Fagomine also promoted excretion of enterobacteriales generated by the dietary intervention. We postulate that fructose increases visceral fat deposition independently of liver de novo liposynthesis and that d-fagomine attenuates steatosis and blood pressure mainly by reducing liver fructose levels. The reduction of blood pressure may be associated with an effect on uric acid synthesis while the reduced levels of selected active liver DAGs may explain the weak effect on sucrose-induced impaired glucose tolerance, which may be primarily induced by visceral fat deposition. In conclusion, the increased populations of excreted enterobacteriales may be connected to the levels of excreted uric acid. d-Fagomine counteracts sucrose-induced steatosis and hypertension presumably by reducing the postprandial levels of fructose in the liver as a consequence of intestinal sucrase inhibition.

Exploring the Chemistry of Non-sticky Sugars: Synthesis of Polyfluorinated Carbohydrate Analogues of d-Allopyranose.

There is a growing interest in the preparation of polyfluorinated carbohydrates. A limited number of fluorohexopyranosides have been used in biological investigations because of the synthetic challenge they present. Hence, we report the synthesis of fluorinated homodimer, fluorodisaccharides, C-terminal fluoroglycopeptides, lipoic acid fluoroglycoconjugate and trifluoroallopyranoside derivatives functionalized at C-6. Our strategy uses levoglucosan as inexpensive starting material and facilitates an approach to complex carbohydrate analogues with multiple C-F bonds. The challenge of our synthetic route centered around an efficient preparation of crucial 1,6-anhydro-2,4-dideoxy-difluoroglucopyranose and focused on achieving a difficult glycosylation of the trifluoroallopyranose donor. The results clearly highlight challenges related to the preparation of polyhalogenated complex organic molecules and pave the way to access novel medically relevant tools.

Bacterial sialoglycosidases in Virulence and Pathogenesis.

Human oral microbiome and dysbiotic infections have been recently evidently identified. One of the major reasons for such dysbiosis is impairment of the immune system. Periodontitis is a chronic inflammatory disease affecting the tissues that surround and support the teeth. In the United States., approximately 65 million people are affected by this condition. Its occurrence is also associated with many important systemic diseases such as cardiovascular disease, rheumatoid arthritis, and Alzheimer’s disease. Among the most important etiologies of periodontitis is Porphyromonas gingivalis, a keystone bacterial pathogen. Keystone pathogens can orchestrate inflammatory disease by remodeling a normally benign microbiota causing imbalance between normal and pathogenic microbiota (dysbiosis). The important characteristics of P. gingivalis causing dysbiosis are its virulence factors which cause effective subversion of host defenses to its advantage allowing other pathogens to grow. Some of the mechanisms involved in these processes are still not well-understood. However, various microbial strategies target host sialoglycoproteins for immune dysregulation. In addition, the enzymes that break down sialoglycoproteins and sialoglycans are the “sialoglycoproteases”, resulting in exposed terminal sialic acid. This process could lead to pathogen-toll like receptor (TLR) interactions mediated through sialic acid receptor ligand mechanisms. Assessing the function of P. gingivalis sialoglycoproteases, could pave the way to designing carbohydrate analogues and sialic acid mimetics to serve as drug targets.

Development of antibodies for N-(1-deoxy-D-fructos-1-yl) fumonisin B1 and cross-reaction with modified fumonisins

Fumonisins are a group of mycotoxins that are routinely found worldwide in commodities such as maize. The group, which has many members, is generally characterised by the presence of one or more tricarballylic acid groups esterified to a long carbon backbone. The diversity of this group of toxins is further augmented by their ability to interact with matrix components non-covalently and to form covalent products with matrix constituents, such as carbohydrates and proteins. Covalent modifications to the toxins make it more difficult to assess the total amounts that may be present in a commodity. We developed monoclonal antibodies (Mabs) against a known product of the reaction of fumonisin B1 (FB1) with glucose: N-(1-deoxy-D-fructos-1-yl) fumonisin B1 (NDFrc-FB1). Similar reactions were used to produce fructosyl-analogs of fumonisins B2 and B3, as well as galactose, maltose, and rhamnose analogs of FB1. These analogs were tested in a competitive indirect ELISA for cross-reactivity towards one of the developed antibodies (Mab 213221). All of the carbohydrate analogs cross-reacted with the Mab, at levels ranging from 75% (the FB3 analog derived from D-glucose) to 181% (the FB1 analog derived from maltose). These results suggested the assay was capable of binding to a wide variety of fumonisin-carbohydrate derivatives. The same antibody was incorporated into an immunoaffinity column that was used to isolate modified fumonisins from a sample of naturally contaminated maize. These results demonstrate the potential to isolate and detect modified fumonisins and will facilitate efforts to determine the frequency of the occurrence of these compounds in maize.

A Chiron approach towards the stereoselective synthesis of polyfluorinated carbohydrates

The replacement of hydroxyl groups by fluorine atoms on hexopyranose scaffolds may allow access to the discovery of new chemical entities possessing unique physical, chemical and ultimately even biological properties. The prospect of significant effects generated by such multiple and controlled substitutions encouraged us to develop diverse synthetic routes towards the stereoselective synthesis of polyfluorinated hexopyranoses, six of which are unprecedented. Hence, we report the synthesis of heavily fluorinated galactose, glucose, mannose, talose, allose, fucose, and galacturonic acid methyl ester using a Chiron approach from inexpensive levoglucosan. Structural analysis of single-crystal X-ray diffractions and NMR studies confirm the conservation of favored 4C1 conformation for fluorinated carbohydrate analogs, while a slightly distorted conformation due to repulsive 1,3-diaxial F···F interaction is observed for the trifluorinated talose derivative. Finally, the relative stereochemistry of multi-vicinal fluorine atoms has a strong effect on the lipophilicities (logP).

Revealing the mechanism for covalent inhibition of glycoside hydrolases by carbasugars at an atomic level

Mechanism-based glycoside hydrolase inhibitors are carbohydrate analogs that mimic the natural substrate’s structure. Their covalent bond formation with the glycoside hydrolase makes these compounds excellent tools for chemical biology and potential drug candidates. Here we report the synthesis of cyclohexene-based α-galactopyranoside mimics and the kinetic and structural characterization of their inhibitory activity toward an α-galactosidase from Thermotoga maritima (TmGalA). By solving the structures of several enzyme-bound species during mechanism-based covalent inhibition of TmGalA, we show that the Michaelis complexes for intact inhibitor and product have half-chair (2H3) conformations for the cyclohexene fragment, while the covalently linked intermediate adopts a flattened half-chair (2H3) conformation. Hybrid QM/MM calculations confirm the structural and electronic properties of the enzyme-bound species and provide insight into key interactions in the enzyme-active site. These insights should stimulate the design of mechanism-based glycoside hydrolase inhibitors with tailored chemical properties.

Copper(II)nitrate catalyzed regioselective protection of primary alcohols with 4,4′-dimethoxytrityl and 2,7-dimethyl-9-phenyl xanthen-9-yl groups in nucleosides and carbohydrates

ABSTRACTRegioselective protection of primary hydroxyl group in nucleoside and carbohydrate analogs was accomplished using dimethoxytrityl alcohol (DMTr-OH) or dimethylpixyl alcohol (DMPx-OH) in presence of copper(II)nitrate as a Lewis acid catalyst. Excellent selectivity was observed for the protection of primary hydroxyl group over secondary while glycosidic bond remain unaffected. Utility of this methodology was further exemplified via DMTr- and DMPx-protection of alipahtic acyclic and cyclic diols.

A Diazido Mannose Analogue as a Chemoenzymatic Synthon for Synthesizing Di-N-acetyllegionaminic Acid-Containing Glycosides.

A chemoenzymatic synthon was designed to expand the scope of the chemoenzymatic synthesis of carbohydrates. The synthon was enzymatically converted into carbohydrate analogues, which were readily derivatized chemically to produce the desired targets. The strategy is demonstrated for the synthesis of glycosides containing 7,9-di-N-acetyllegionaminic acid (Leg5,7Ac2 ), a bacterial nonulosonic acid (NulO) analogue of sialic acid. A versatile library of α2-3/6-linked Leg5,7Ac2 -glycosides was built by using chemically synthesized 2,4-diazido-2,4,6-trideoxymannose as a chemoenzymatic synthon for highly efficient one-pot multienzyme (OPME) sialylation followed by downstream chemical conversion of the azido groups into acetamido groups. The syntheses required 10 steps from commercially available d-fucose and had an overall yield of 34-52 %, thus representing a significant improvement over previous methods. Free Leg5,7Ac2 monosaccharide was also synthesized by a sialic acid aldolase-catalyzed reaction.

A Diazido Mannose Analogue as a Chemoenzymatic Synthon for Synthesizing Di‐N‐acetyllegionaminic Acid‐Containing Glycosides

AbstractA chemoenzymatic synthon was designed to expand the scope of the chemoenzymatic synthesis of carbohydrates. The synthon was enzymatically converted into carbohydrate analogues, which were readily derivatized chemically to produce the desired targets. The strategy is demonstrated for the synthesis of glycosides containing 7,9‐di‐N‐acetyllegionaminic acid (Leg5,7Ac2), a bacterial nonulosonic acid (NulO) analogue of sialic acid. A versatile library of α2‐3/6‐linked Leg5,7Ac2‐glycosides was built by using chemically synthesized 2,4‐diazido‐2,4,6‐trideoxymannose as a chemoenzymatic synthon for highly efficient one‐pot multienzyme (OPME) sialylation followed by downstream chemical conversion of the azido groups into acetamido groups. The syntheses required 10 steps from commercially available d‐fucose and had an overall yield of 34–52 %, thus representing a significant improvement over previous methods. Free Leg5,7Ac2 monosaccharide was also synthesized by a sialic acid aldolase‐catalyzed reaction.

Colorimetric Detection of Acetyl Xylan Esterase Activities.

Colorimetric detection of reaction products is typically preferred for initial surveys of acetyl xylan esterase (AcXE) activity. This chapter will describe common colorimetric methods, and variations thereof, for measuring AcXE activities on commercial, synthesized, and natural substrates. Whereas assays using pNP-acetate, α-naphthyl acetate, and 4-methylumbelliferyl acetate (4MUA) are emphasized, common methods used to measure AcXE activity towards carbohydrate analogs (e.g., acetylated p-nitrophenyl β-D-xylopyranosides) and various acetylated xylans are also described. Strengths and limitations of the colorimetric assays are highlighted.

ChemInform Abstract: Asymmetric Cycloaddition: An Efficient Synthesis of Enantiopure Isoxazolines Substituted with Carbohydrate Analogues.

A simple and convenient method for the synthesis of heterocycles substituted with carbohydrate analogs is described. The chiral optically pure five-membered glycoconjugates containing the isoxazoline unit were obtained by an aromatic nitrile oxides cycloaddition with 1-phenyl-1,2-dihydro-pyridazine-3,6-dionyl N-glycoside derivatives.