Nuno M. Xavier

Sugars containing α,β-unsaturated carbonyl systems: synthesis and their usefulness as scaffolds in carbohydrate chemistry

The alpha,beta-unsaturated carbonyl function occurs in a wide variety of bioactive natural products. It is usually associated with the bioactivities of these compounds and acts as Michael acceptors for the addition of protein nucleophilic groups. The design and synthesis of sugars containing this functionality has provided a wide range of compounds, which can serve as building blocks of high synthetic versatility. This review deals with the chemistry of sugar-based molecules bearing singly linked or fused unsaturated lactones and ketones along with that of pyranoid enones and enonolactones. Examples are given of their syntheses and transformations into a variety of complex sugar derivatives such as branched-chain sugars, C-nucleosides, C-glycosyl derivatives, and various natural products, including selected analogues.

Carbohydrate-Based Lactones: Synthesis and Applications

The synthesis and uses of different kinds of carbohydrate-based lactones are described. This group of compounds includes aldonolactones, other related monocyclic lactones and bicyclic systems. The latter can arise from uronic acids, carboxymethyl ethers or glycosides, or from C-branched sugars.

A "natural" approach: synthesis and cytoxicity of monodesmosidic glycyrrhetinic acid glycosides.

Several pentacyclic triterpenoic acids have shown noteworthy antitumor activity, among them betulinic acid as well as oleanolic acid and derivatives thereof. Glycyrrhetinic acid (GA) exhibits some cytotoxic activity albeit this compound is not as active as betulinic acid, but GA came in the focus of scientific interest since it triggers apoptosis in tumor cells. In addition, it can be extracted from the roots of liquorice in high yields. Previous studies revealed that the introduction of an extra hydrophilic moiety increases the cytotoxicity of these compounds. Thus, a series of GA glycosides was prepared utilizing hexoses as well as pentoses (in D- and L-configuration) by using glycosyl trichloroacetimidates and TMSOTf as catalyst. The compounds were screened for cytotoxic activity against seven human cancer cell lines and the not malignant murine cell line NIH 3T3using a photometric SRB assay. The compounds trigger apoptosis as shown from extra trypan blue and acridine orange/ethidium bromide staining.

Zeolites and other silicon-based promoters in carbohydrate chemistry.

Silicon-based materials, namely zeolites, clays, and silica gel have been widely used in organic synthesis, allowing mild reaction conditions and environmentally friendly methodologies. These heterogeneous catalysts are easy to handle, possess nontoxic and noncorrosive character and offer the possibility of recovery and reuse, thus contributing to clean and sustainable organic transformations. Moreover, they present shape-selective properties and provide stereo- and regiocontrol in chemical reactions. Herein, we survey the most significant applications of silicon-based materials as catalysts in carbohydrate chemistry, to mediate important transformations such as glycosylation, sugar protection and deprotection, and hydrolysis and dehydration. Emphasis is placed on their promising synthetic potential in comparison with conventional catalysts.

Electrospray ionization mass spectrometric analysis of newly synthesized α,β-unsaturated γ-lactones fused to sugars

Knowledge of the fragmentation mechanisms of lactones and their behaviour under electrospray ionization (ESI) conditions can be extended to larger and more complex natural products that contain an alpha,beta-unsaturated gamma-lactone moiety in their structure. Moreover, little is known about the gas-phase behaviour of alpha,beta-unsaturated gamma-lactones linked or fused to sugars. Therefore, five alpha,beta-unsaturated gamma-lactones (butenolides) fused to a pyranose ring, recently synthesized compounds with potential relevance regarding their biological properties, were investigated using ESI-MS and ESI-MS/MS in both positive and negative ion modes. Their fragmentation mechanisms and product ion structures were compared. It was observed that two isomers could be unambiguously distinguished in the negative ion mode by the fragmentation pathways of their deprotonated molecules as well as in the positive ion mode by the fragmentation pathways of either the protonated or the sodiated molecule. Fragmentation mechanisms are proposed taking into account the MS/MS data and semi-empirical calculations using the PM6 Hamiltonean. The semi-empirical calculations were also very useful in determining the most probable protonation and cationization sites.

Self-organizing behaviour of glycosteroidal bolaphiles: insights into lipidic microsegregation

In this article we describe work on the synthesis of bolaphile biomimics composed of glucose head groups and steroidal units linked together by a methylene chain of varying length. The condensed phases formed by self-organization of the products as a function of temperature were characterized by differential scanning calorimetry and thermal polarized light microscopy. The results of these studies show that the thermal stabilities of the lamellar mesophases formed vary linearly as a function of increasing aliphatic composition, which reflects a linear hydrophobic-hydrophilic balance with respect to transition temperatures.

Synthesis of glucopyranos-6′-yl purine and pyrimidine isonucleosides as potential cholinesterase inhibitors. Access to pyrimidine-linked pseudodisaccharides through Mitsunobu reaction

Abstract The synthesis of new isonucleosides comprising purine and pyrimidine-derived systems linked to methyl glucopyranosidyl units at C-6 and evaluation of their cholinesterase inhibitory profiles is reported. Their access was based on the Mitsunobu coupling of partially acetylated and benzylated methyl glucopyranosides with purine and pyrimidine derivatives. While the reactions with purines and theobromine proceeded with complete regioselectivity, affording exclusively N9- or N1-linked 6′-isonucleosides, respectively, the use of pyrimidine nucleobases led to N1 and/or N3-glucopyranosid-6′-yl pyrimidines and/or to N1,N3/2-O,4-O-pyrimidine-linked pseudodisaccharides through bis-coupling, depending on the substitution pattern of the sugar precursor and on the nature of the nucleobase. From this series of compounds, four were shown to be effective and selective inhibitors of acetylcholinesterase with inhibition constants in the micromolar concentration range. A tri-O-acetylated N1-glucopyranosid-6′-yl theobromine and a benzylated N1,N3-bis-glucopyranosid-6-yl thymine were the most active molecules with Ki values of 4 μM. A tri-O-benzylated glucopyranosid-6′-yl uracil displayed good and selective inhibition of butyrylcholinesterase (Ki=8.4±1.0 μM), similar to that exhibited by the standard galantamine. Molecular docking simulations, performed with the two most effective acetylcholinesterase inhibitors, showed interactions with key amino acid residues located at the enzyme’s active site gorge, which explain the competitive component of their inhibitory activities.

Enantioselective synthesis in carbohydrate-based drug discovery: imino sugars, alkaloids and macrolide antibiotics.

This review is dedicated to enantioselective methods for the generation of carbohydrate-based lead compounds for drug research. Selected examples encompassing imino sugars, bicyclic imino sugar-type alkaloids such as castanospermine, swainsonine, or alexine, as well as macrolide glycosides are covered and discussed.

Environmentally friendly approaches to the synthesis of new antibiotics from sugars

In light of the biological importance of carbohydrates and their role when present in antibiotic agents, the design and synthesis of carbohydrate-based antibiotics has occupied a prominent place in drug discovery. This review focuses on synthetic carbohydrate antimicrobial agents, giving special emphasis to novel structures easily accessible from readily available carbohydrate precursors.

Furanose C-C-linked γ-lactones: a combined ESI FTICR MS and semi-empirical calculations study.

Sugars that incorporate the unsaturated carbonyl motif have become important synthetic targets not only as a result of their potential biological properties but also as precursors in the synthesis of many bioactive products. Moreover, little is known about the influence of the γ-lactone moiety in the fragmentation pattern of furanose rings. Therefore, two α,β-unsaturated γ-lactones (butenolides) and two β-hydroxy γ-lactones, C-C linked to a furanose ring were studied using electrospray ionization FTICR mass spectrometry. The behaviour of the protonated and sodiated forms of the compounds under study has been compared considering their structural features. Fragmentation mechanisms were established and ion structures were proposed taking into account the MS(2) and MS(3) experiments, accurate mass measurements and semi-empirical calculations. These inexpensive methods proved to be a valuable resource for proposing protonation sites and for the establishment of fragmentation pathways.