Alberto Marra

Calixarene and Calixresorcarene Glycosides: Their Synthesis and Biological Applications

It is firmly established that cell surface carbohydrate-protein interactions are at the forefront of a myriad of vital cellular events.1 Such interactions, however, are usually weak, with KD values of the order of mM for monosaccharides. However, when a set of multivalent saccharides is clustered together with the right structure and spatial disposition, the interaction becomes strong and specific. This augmented association is more than what would be expected on the basis of the increased carbohydrate local concentration, and it has been termed glycoside cluster effect.2 It is quite obvious that in order to intervene efficiently on these interactions, multivalent external agents have to be employed. In this context, one can envisage the use of glycoclusters firmly anchored to a conformationally rigidified calixarene or calixresorcarene scaffold as suitable systems for protein recognition and consequently protein activity inhibition. This is especially important in those cases in which carbohydrateprotein interactions are detrimental such as viral and bacterial infections, inflammations, and cancer metastasis. The aim of this review is to present the various approaches that have been carried out for the synthesis of multivalent calixarene and calixresorcarene glycosides (calixsugars) displaying different anomeric linkages and carbohydrate-macrocycle tethers. The validation of the biological activity of suitably designed calixsugars as well as of complex molecular systems in which they were introduced will be also reported. The synthesis and biological applications of calixarene glycoconjugates represented a new way of considering * To whom correspondence should be addressed. E-mail: adn@unife.it (A.D.); mra@unife.it (A.M.). Alessandro Dondoni has been Professor of Organic Chemistry at the University of Ferrara from 1975 to 2008. At present he is Senior Scientist at the same University. He has been the recipient of several awards, including A. Mangini Gold Medal from the Italian Chemical Society (1996), Avogadro-Minakata Lectureship Award of the Chemical Society of Japan (1999), Ziegler-Natta Lectureship Award of the German Chemical Society (1999), Lincei National Academy Prize in Chemistry (1999), and G. Berti Gold Medal from the Italian Chemical Society (2010). His present research interests are in new synthetic methods, organocatalysis, and carbohydrate chemistry. He recently started a new program dealing with the use of free-radical thiol-ene coupling as a click ligation tool for peptide and protein modification. A large part, if not all, of his chemistry is being developed with the aim of providing new products for biochemical studies and pharmaceutical and biomedical applications. Chem. Rev. 2010, 110, 4949–4977 4949

Stereoselective synthesis of 2-thioglycosides of N-acetylneuraminic acid

Treatment of methyl 5-acetamido-2,4,7,8,9-penta-O-acetyl-3,5-dideoxy-β-d-glycero-d-galacto-2-nonulopyranosonate (1) severally with thiophenol, phenylmethanethiol, and ethanethiol in the presence of boron trifluoride etherate gave the corresponding 2-thio-β-glycosides 3–5. Treatment of methyl (5-acetamido-4,7,8,9-tetra-O-acetyl-3,5-dideoxy-β-d-glycero- d-galacto-2-nonulopyranosyl chloride)onate (2) severally with thiophenol in the presence of N,N-di-isopropylethylamine, O-ethyl S-potassium dithiocarbonate, and O-ethyl S-potassium thiocarbonate gave the corresponding 2-thio-α-glycosides 7, 10, and 11, of which 10 was converted into the ethyl 2-thio-α-glycoside 9 on heating with N,N-dimethylformamide-sodium iodide. The phenyl 2-thioglycosides 3 and 7 were converted into the corresponding sulfones.

Oxime ligation: a chemoselective click-type reaction for accessing multifunctional biomolecular constructs.

There is a growing need for biocompatible click reactions in order to prepare multifunctional conjugates, which are valuable molecules for innovative biomedical applications. In this context, we review the recent advances in the implementation of oxime ligation for the synthesis of multivalent or multicomponent systems. The value of these products is emphasized by their use in cell targeting, imaging, synthetic vaccines, and surface modifications.

Validation of the copper(i)-catalyzed azide-alkyne coupling in ionic liquids. Synthesis of a triazole-linked C-disaccharide as a case study.

The first study of a copper(I)-catalyzed azide-alkyne click reaction in ionic liquids (ILs) is reported. The cycloaddition of a sugar azide with a sugar acetylene (CuI, i-Pr2EtN, 80 degrees C) was carried out in 10 ILs as well as in standard molecular solvents (toluene and DMF) to give the 1,4-disubstituted triazole-linked C-disaccharide. The highest yields (84 and 95%) were registered in Ammoeng 110 and [C(8)dabco][N(CN)(2)]. The latter solvent was recycled in four subsequent reactions without loss of the reaction efficiency. Reactions carried out in the absence of the Hünigs base afforded mixtures of 1,4- and 1,5-disubstituted triazole regioisomers.

Photoinduced Thiol-Ene Coupling as a Click Ligation Tool for Thiodisaccharide Synthesis

The high efficiency and selectivity of the thiol-ene radical reaction has been validated by the photoinduced coupling of anomeric sugar thiols with sugar alkenes to give 1,6-linked S-disaccharides in good to excellent yields (76-92%) and high diastereoselectivities (up to 99%). The reaction appears to be well-qualified as an exemplar click process.

Photoinduced Addition of Glycosyl Thiols to Alkynyl Peptides: Use of Free-Radical Thiol−Yne Coupling for Post-Translational Double-Glycosylation of Peptides

Double glycosylation of cysteine-containing peptides has been carried out by a one-pot two-step sequence comprising selective S-propargylation followed by photoinduced (lambda (max) 365 nm) free-radical hydrothiolation with glycosyl thiols. Conditions were established for the sequential introduction of two different thiol residues such as a glycosyl and a biotinyl derivative.

Preparation of pyranoid glycal derivatives from phenyl thioglycosides and glycosyl phenyl sulphones

Abstract Phenyl thioglycopyranosides with various protecting groups (acetal, ether, ester) underwent reductive lithiation at C-1, followed by rapid elimination of the 2-substituent, when treated with lithium naphthalenide in tetrahydrofuran at low temperature. Thus, pyranoid glycal derivatives with acid-labile protecting groups were obtained in excellent yields. Glycopyranosyl phenyl sulphones were prepared quantitatively by oxidation of the corresponding phenyl thioglycosides with catalytic amounts of ruthenium trichloride in the presence of sodium periodate in a biphasic solvent system. These compounds also gave rise to pyranoid glycal derivatives in excellent yields when treated with lithium naphthalenide in tetrahydrofuran at low temperature. A β-linked 2′-deoxydisaccharide glycal derivative was also prepared from the corresponding disaccharide phenyl thioglycoside. Phenyl thioglycopyranosides carrying a 2-xanthate group underwent a radical reductive elimination when treated with tributyltin hydride, to afford glycal derivatives in good yields under neutral conditions.

Design of Triazole‐Tethered Glycoclusters Exhibiting Three Different Spatial Arrangements and Comparative Study of their Affinities towards PA‐IL and RCA 120 by Using a DNA‐Based Glycoarray

Sugar‐coated chips: Glycoside clusters are valuable tools for carbohydrate–lectin recognition studies. However, the spatial arrangement of the sugar residues is a key issue in the design of high‐affinity glycoclusters. Here the affinities of linear and antenna‐ and calixarene‐based galactoside clusters towards two lectins derived from Pseudomonas aeruginosa and Ricinus communis were compared by means of glycoarrays.

A novel class of glycosyl donors: Anomeric S-xanthates of 2-azido-2-deoxy-D-galactopyranosyl derivatives☆

Abstract Variously substituted O-ethyl S-(2-azido-2-deoxy-D-galactopyranosyl) dithiocarbonates have been easily prepared via a two-step azidoxanthation reaction of the corresponding galactals (1,5-anhydro-2-deoxy-D-lyxo-hex-1-enitols).They are efficient glycosyl donors for the stereoselective synthesis of protected precursors of biologically important galactosamine-containing oligosaccharides.

Synthesis of sugar-based silica gels by copper-catalysed azide-alkyne cycloaddition via a single-step azido-activated silica intermediate and the use of the gels in hydrophilic interaction chromatography

Novel sugar-based silica gels were prepared by exploiting the copper-catalysed azide-alkyne cycloaddition (CuAAC) of two different sugar alkynes, namely, ethynyl C-galactoside 1 and propargyl O-lactoside 2, with new single-step azido-activated silica gels. The fully characterised stationary phases were generally used for hydrophilic interaction chromatography (HILIC), with particular application in the stereoselective separation of monosaccharides. Dynamic HILIC (DHILIC) experiments were performed to evaluate the influence of mutarotation on the chromatographic peak shapes of two interconverting sugar anomers. The potential of such materials was shown in the separation of other highly polar compounds, including amino acids and flavonoids.