Volume 89, Issue 9

Trehalose is a non-reducing sugar whose ability to stabilize biomolecules has brought about its widespread use in biological preservation applications. Trehalose is also an essential metabolite in a number of pathogens, most significantly the global pathogen Mycobacterium tuberculosis , though it is absent in humans and other mammals. Recently, there has been a surge of interest in modifying the structure of trehalose to generate analogs that have applications in biomedical research and biotechnology. Non-degradable trehalose analogs could have a number of advantages as bioprotectants and food additives. Trehalose-based imaging probes and inhibitors are already useful as research tools and may have future value in the diagnosis and treatment of tuberculosis, among other uses. Underlying the advancements made in these areas are novel synthetic methods that facilitate access to and evaluation of trehalose analogs. In this review, we focus on both aspects of the development of this class of molecules. First, we consider the chemical and chemoenzymatic methods that have been used to prepare trehalose analogs and discuss their prospects for synthesis on commercially relevant scales. Second, we describe ongoing efforts to develop and deploy detectable trehalose analogs, trehalose-based inhibitors, and non-digestible trehalose analogs. The current and potential future uses of these compounds are discussed, with an emphasis on their roles in understanding and combatting mycobacterial infection.

The N -acetylgalactosamine (GalNAc) residue is one of the units of chondroitin sulfate E (CS-E) which has been reported to have inhibitory activity against Japanese encephalitis virus (JEV). Herein, we describe the synthesis of a series of p -methoxyphenyl β-GalNAc derivatives with a sulfate group at 3-, 4-, and/or 6-positions using an efficient route through a common synthetic intermediate. By measuring the inhibition activity of these compounds that bear different numbers and positions of sulfate groups, the effect of position specificity for interaction with the virus was determined. From these results, GalNAc6S and GalNAc4S6S derivatives inhibited JEV infections well; we suggest the 6- O -sulfate group is necessary for selective recognition by the virus.

New xylofuranosyl and glucopyranosyl nucleoside phosphoramidates were synthesized as potential mimetics of nucleoside 5′-monophosphates. Their access involved N -glycosylation of uracil and 2-acetamido-6-chloropurine with 5′/6′-azido-1,2-di- O -acetyl glycosyl donors and subsequent Staudinger-phosphite reaction of the resulting azido nucleosides. The coupling of the purine derivative with the pyranosyl donor furnished N 9 - and N 7 -linked nucleosides in 1:1 ratio, whereas with the furanosyl donor, the N 9 -nucleoside was the major regioisomer formed. When using uracil, only 5′/6′-azido N 1 -linked nucleosides were obtained. The purine 5′/6′-azido nucleosides were converted into corresponding phosphoramidates in good yields. The antiproliferative effects of the nucleoside phosphoramidates and those of the azido counterparts on cancer cells were evaluated. While the nucleoside phosphoramidates did not show significant activities, the purine 5′/6′-azido nucleosides displayed potent effects against K562, MCF-7 and BT474 cell lines. The 5′-azidofuranosyl N 9 and N 7 -linked purine nucleosides exhibited highest activity towards the chronic myeloid leukemia cell line (K562) with GI 50 values of 13.6 and 9.7 μM, respectively. Among pyranosyl nucleosides, the N 7 -linked nucleoside was the most active compound with efficacy towards all cell lines assayed and a highest effect on K562 cells (GI 50 =6.8 μM). Cell cycle analysis of K562 and MCF-7 cells showed that the most active compounds cause G2/M arrest.

The four classical, biomolecular force fields designed to study hexopyranose-based carbohydrates (GROMOS 56a6 CARBO /56a6 CARBO_R , GROMOS 53a6 GLYC , CHARMM and GLYCAM06) have been tested in the context of ring-inversion properties. These properties were evaluated for both unfunctionalized monomers of all hexopyranoses of the d series and for residues in a chain composed of uniform units connected by α(1→4) and β(1→4) glycosidic linkages. The results indicate that the tested force fields differ in their predictions of the ring-inversion properties of both monomers and residues in a chain. The comparison with the available experimental data and with the semi-empirical Angyal scheme reveals that, at the level of monomers, GROMOS 56a6 CARBO , GROMOS 53a6 GLYC and CHARMM correctly reproduce the ring-inversion free energies. However, due to the lack of analogous reference data we cannot state which force field is more or less accurate in the context of ring distortion of residues in a chain. Therefore, the use of ab initio potentials is recommended in the prospective, quantitative studies on the related subject.

d -Glycopyranosyl glycerols are common natural products and exhibit strong biological properties, notably as moisturizing agents in cosmetics. Their chemical synthesis remains tedious thus decreasing their potential industrial and economic development, as well as the study of their structure-function relationships. In this work, the chemo-enzymatic synthesis of three enantiopure 3- O -(β- d -glycopyranosyl)- sn -glycerols was efficiently performed using an original glycosidase from Dictyoglomus thermophilum and their preservatives properties were assessed using a challenge test method. Amongst them, the 3- O -(β- d -glucopyranosyl)- sn -glycerol exhibited a specific anti-fungus activity.

Dietary flavonoids and synthetic derivatives have a well-known potential for biomedical applications. In this perspective, we report herein new methodologies to access chrysin and 5,7-dihydroxychromone, and these structures were combined with those of naturally occurring quercetin, luteolin, (+)-dihydroquercetin and apigenin to assemble a set of polyphenols with structure variations for in vitro testing over the aggregation of Alzheimer’s disease (AD) amyloid peptide Aβ 1−42 . Using thioflavin-T (ThT) monitored kinetics and subsequent mechanistic analysis by curve fitting, we show that catechol-type flavonoids reduce Aβ 1−42 fibril content by 30% at molar ratios over 10. Without affecting secondary nucleation, these compounds accelerate primary nucleation events responsible for early primary oligomer formation, putatively redirecting the latter into off-pathway aggregates. Atomic force microscopy (AFM) imaging of reaction end-points allowed a comprehensive topographical analysis of amyloid aggregate populations formed in the presence of each compound. Formation of Aβ 1−42 small oligomers, regarded as the most toxic amyloid structures, seems to be limited by flavonoids with a C2 phenyl group, while flavonol 3-OH is not a beneficial structural feature. Overall, the diversity of structural variations within flavonoids opens avenues for their development as chemical tools in the treatment of AD by tackling the formation and distribution of neurotoxic oligomers species.

This article describes the development of alkylated S -benzimidazolyl (SBiz) imidates as versatile building blocks for chemical glycosylation. The SBiz imidates have been originally developed as a new platform for active-latent glycosylations and its utility was further extended to other common strategies for oligosaccharide synthesis. This article expands upon the utility of these compounds. We developed a general protocol for the synthesis of a series of N -alkylated SBiz glycosides from N -protected SBiz aglycones by Lewis acid-mediated coupling with glucose pentaacetate. The N -alkylated SBiz moiety was found to be stable under strong basic conditions which allowed us to obtain both armed and disarmed N -alkylated SBiz donors. These donors showed good reactivity at a variety of activation conditions, and generally provided high yields in glycosylations.

Traditionally the perspective on reactive oxygen species (ROS) has centered on the role they play as carcinogenic or cancer-causing radicals. Over the years, characterization and functional studies have revealed the complexity of ROS as signaling molecules that regulate various physiological cellular responses or whose levels are altered in various diseases. Cancer cells often maintain high basal level of ROS and are vulnerable to any further increase in ROS levels beyond a certain protective threshold. Consequently, ROS-modulation has emerged as an anticancer strategy with synthesis of various ROS-inducing or responsive agents that target cancer cells. Of note, an increased carbohydrate uptake and/or induction of death receptors of cancer cells was exploited to develop glycoconjugates that potentially induce cellular stress, ROS and apoptosis. This mini review highlights the development of compounds that target cancer cells by taking advantage of redox or metabolic alteration in cancer cells.

We propose a novel, bi-dimensional analysis of partially N -acetylated chitosan oligosaccharides based on gas phase Infra-Red spectroscopy integrated to mass spectrometry (MS). By providing simultaneously MS and IR fingerprints, this approach combines the advantages of MS with the refined structural detail offered by gas phase spectroscopy and provides robust signatures for the rapid discrimination of the patterns of N -acetylation. Four mono- N -deacetylated and two doubly- N -deacetylated chitosan tetramer standards with well-defined patterns of acetylation were produced and analyzed by IR integrated to MS. We show that each sequence displays a unique combination of MS and IR fingerprints, thus offering a rapid diagnostic for the pattern of acetylation without the need for reducing end labeling.

The saponin natural product QS-21 is one of the most potent investigational adjuvants, which are substances added to vaccines to enhance the immunogenicity of the antigen and potentiate the immune response. While QS-21 has been coadministered with vaccines against cancers and infectious diseases in many clinical trials, its inherent liabilities (scarcity, heterogeneity, instability, and dose-limiting toxicity) have limited its widespread clinical use. Furthermore, its molecular mechanisms of action are poorly understood. Structural modification of the natural product using chemical synthesis has become an important strategy to overcome these limitations. This review focuses mainly on research efforts in the group of the late Professor David Y. Gin on the development of optimized synthetic saponin adjuvants derived from QS-21. A number of QS21 variants incorporating stable acyl chain amide linkages, truncated carbohydrate domains, and targeted modifications at the triterpene and central glycosyl ester linkage were designed, chemically synthesized, and immunologically evaluated. These studies delineated key minimal structural requirements for adjuvant activity, established correlations between saponin conformation and activity, and provided improved, synthetically accessible saponin adjuvants. Moreover, leveraging these structure–activity relationships, novel saponin probes with high potency and reduced toxicity were developed and used in biodistribution and fluorescence imaging studies, yielding early insights into their enigmatic mechanisms of action.