Glycosidase inhibition with fullerene iminosugar balls: a dramatic multivalent effect.

The electronic and structural properties of fullerene derivatives make them very attractive candidates for the construction of nanostructures that are potentially useful for applications in materials science and biological chemistry. In particular, the C60 hexakis adducts with a Th-symmetrical octahedral addition pattern initially developed by Hirsch and co-workers are unique organic molecules with an appealing compact spherical scaffold for the construction of multifunctional nanomaterials. However, the synthesis of functionalized fullerene hexakis adducts from malonates and C60 is difficult. 4] This major problem limits the applications of such systems and has been recently solved by the development of synthetic methodologies based on the postfunctionalization of easily accessible building blocks of fullerene hexakis adducts. 6] It has been shown that fullerene hexakis adducts that bear 12 peripheral carbohydrate moieties can be prepared in excellent yields by grafting unprotected sugar derivatives onto the fullerene core. Although these fullerene sugar balls are obviously perfectly suited for applications in the field of carbohydrate–lectin interactions, the evaluation of carbohydrate-processing enzyme inhibition with such multivalent derivatives is less obvious. Indeed, among the possible strategies to attain specific potent glycosidase inhibition, the concept of multivalent design has been clearly overlooked. Most enzymes actually have a single, deep active site that is usually less accessible than the shallow binding pockets or grooves on the lectin surfaces. Consequently, a limited number of binding mechanisms, including statistical rebinding, are possible, whereas multivalent ligands may interact with multiple receptors by additional mechanistic options (e.g., the chelate effect, receptor clustering). It is likely that these factors may have hampered interest in projects directed towards the design of multivalent glycosidase inhibitors. In addition, the experimental results obtained to date were not particularly encouraging. Dito tetravalent analogues of 1-deoxynojirimycin, which is a well-known glycosidase inhibitor, generally displayed comparable if not decreased inhibition compared with their monomeric counterparts. The best result reported to date was found for a trivalent iminosugar that showed a sixfold affinity enhancement towards Jack bean a-mannosidase. Herein we report the synthesis of a fullerene hexakis adduct decorated with 12 iminosugar residues. The inhibition profile of this fullerene iminosugar ball has been systematically evaluated against various glycosidases, and dramatic multivalent effects have been observed for the first time. In order to explore the potential of multivalency on glycosidase inhibition with a globular polytopic ligand constructed around the fullerene scaffold, an N-alkyl analogue of 1-deoxynojirimycin was selected as the peripheral ligand. This class of compounds is indeed poorly selective and displays modest to good glycosidase inhibition. It was thus anticipated that these compounds could be excellent models for the examination of the influence of multivalency on inhibition selectivity over a large range of glycosidases. In addition, the alkyl chain on the endocyclic nitrogen atom of the iminosugar is an ideal spacer that may allow for easy grafting onto the central C60 core by means of a cycloaddition reaction. [16] The synthesis of the azide building block is based on the optimization of a strategy reported independently by Overkleeft et al. and Vasella and co-workers. As shown in Scheme 1, the d-hydroxy amide 2 was obtained directly from commercially available tetra-O-benzyl d-glucopyranose (1) in 78% yield by oxidative amidation with iodine in 30% aqueous ammonia (30%). The main advantage of this onepot process is that aldehyde oxidation and C N bond formation are performed in a single synthetic step. Oxidation of the hydroxy group at C5 followed by intramolecular [*] Prof. P. Compain, C. Decroocq, Dr. D. Hazelard Laboratoire de Synth se Organique et Mol cules Bioactives Universit de Strasbourg et CNRS (UMR 7509) Ecole Europ enne de Chimie, Polym res et Mat riaux 25 rue Becquerel, 67087 Strasbourg (France) Fax: (+ 33)3-6885-2754 E-mail: philippe.compain@unistra.fr