Search

Carbohydrate–lectin interactions are involved in a number of relevant biological events including fertilization, immune response, cell adhesion, tumour cell metastasis, and pathogen infection. Lectins are also tissue specific, making carbohydrates not only promising drug candidates but also excellent low molecular weight ligands for active drug delivery system decorations. In order for these interactions to be effective multivalency is essential, as the interaction of a lectin with its cognate monovalent carbohydrate epitope usually takes place with low affinity. Unlike the covalent approach, supramolecular self-assembly of glyco-monomers mediated by non-covalent forces allows accessing multivalent systems with diverse topology, composition, and assembly dynamics in a single step. In order to fine-tune the size and sugar adaptability of spherical micelles at the nanoscale for an optimal glycoside cluster effect, herein we report the synthesis of mannose-coated static micelles from diacetylene-based mannopyranosyl glycolipids differing in the length of the poly(ethyleneglycol) (PEG) chains and the oxidation state of the anomeric sulfur atom. The reported shot-gun like synthetic approach for the synthesis of dilution-insensitive micelles is based on the ability of diacetylenic-based neoglycolipids to self-assemble into micelles in water and to undergo an easy photopolymerization by a simple irradiation at 254 nm. The affinity of the obtained 6 nanosystems was assessed by enzyme-linked lectin assay (ELLA) using the mannose-specific concanavalin A lectin as a model receptor. Relative binding potency enhancements, compared to methyl α- D -mannopyranoside used as control, from 20-, to 29- to 300-fold on a sugar molar basis were observed for micelles derived from sulfonyl-, sulfinyl- and thioglycoside monomers with a tatraethyleneglycol spacer, respectively, indicative of a significant cluster glycoside effect. Moreover, pMic1 micelles are able to solubilize and slowly liberate lipophilic clinically relevant drugs, and show the enhanced cytotoxic effect of docetaxel toward prostate cancer cells. These findings highlight the potential of mannose-coated photopolymerized micelles pMic1 as an efficient nanovector for active delivery of cytotoxic hydrophobic molecules. [ABSTRACT FROM AUTHOR]

2-Acetamido-1,2-dideoxyiminosugars are selective and potent inhibitors of hexosaminidases and therefore show high therapeutic potential for the treatment of various diseases, including several lysosomal storage disorders. A stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc), the iminosugar analog of N-acetylglucosamine, with a high overall yield is here described. This novel procedure further allowed accessing ureido-DNJNAc conjugates through derivatization of the endocyclic amine on a key pivotal intermediate. Remarkably, some of the ureido-DNJNAc representatives behaved as potent and selective inhibitors of β-hexosaminidases, including the human enzyme, being the first examples of neutral sp(2)-iminosugar-type inhibitors reported for these enzymes. Moreover, the amphiphilic character of the new ureido-DNJNAc is expected to confer better drug-like properties.

A new series of fluoroallylamines derived from hydroxypiperidines was prepared and evaluated against various glycosidases. The short synthesis of target molecules involved the modified Julia reaction between aldehydes and functionalized fluoroaminosulfones. Biological studies revealed good and selective β-glucosidase inhibition in the micromolar range for two compounds, while the non-fluorinated analogue of the most active compound was selective towards α-glucosidase.

Biomimetic nanoparticles prepared by self-assembly of iminosugar-based glycopolypeptides evidenced remarkable multivalency properties when inhibiting α-mannosidase activity. This approach paves the way to obtain biologically active drug delivery systems having glycosidase inhibition potency.

A series of fluorine and non-fluorine-substituted C-glucosylidenes (exo-glucals) has been synthesized via a modified Julia olefination. The deprotected exo-glucals were prepared in five steps from commercially available d-gluconolactone. The evaluation of this original family of compounds against a panel of glycosidases showed a highly specific in vitro activity towards mammalian β-glucosidase depending on the double bond substituents.

Competitive inhibitors of either α-galactosidase (α-Gal) or β-galactosidase (β-Gal) with high affinity and selectivity have been accessed by exploiting aglycone interactions with conformationally locked sp(2)-iminosugars. Selected compounds were profiled as potent pharmacological chaperones for mutant lysosomal α- and β-Gal associated with Fabry disease and GM(1) gangliosidosis.