Julien Iehl

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

Fullerene sugar balls

Fullerene hexakis-adducts bearing 12 peripheral carbohydrate moieties have been prepared by grafting sugar derivatives onto the fullerene core through the copper mediated Huisgen 1,3-dipolar cycloaddition of azides and alkynes.

Artificial light-harvesting arrays: electronic energy migration and trapping on a sphere and between spheres.

A sophisticated model of the natural light-harvesting antenna has been devised by decorating a C(60) hexa-adduct with ten yellow and two blue boron dipyrromethene (Bodipy) dyes in such a way that the dyes retain their individuality and assist solubility of the fullerene. Unusually, the fullerene core is a poor electron acceptor and does not enter into light-induced electron-transfer reactions with the appended dyes, but ineffective electronic energy transfer from the excited-state dye to the C(60) residue competes with fluorescence from the yellow dye. Intraparticle electronic energy transfer from yellow to blue dyes can be followed by steady-state and time-resolved fluorescence spectroscopy and by excitation spectra for isolated C(60) nanoparticles dissolved in dioxane at 293 K and at 77 K. The decorated particles can be loaded into polymer films by spin coating from solution. In the dried film, efficient energy transfer occurs such that photons absorbed by the yellow dye are emitted by the blue dye. Films can also be prepared to contain C(60) nanoparticles loaded with the yellow Bodipy dye but lacking the blue dye and, under these circumstances, electronic energy migration occurs between yellow dyes appended to the same nanoparticle and, at higher loading, to dye molecules on nearby particles. Doping these latter polymer films with the mixed-dye nanoparticle coalesces these multifarious processes in a single system. Thus, long-range energy migration occurs among yellow dyes attached to different particles before trapping at a blue dye. In this respect, the film resembles the natural photosynthetic light-harvesting complexes, albeit at much reduced efficacy. The decorated nanoparticles sensitize amorphous silicon photocells.

Sequential copper catalyzed alkyne-azide and thiol-ene click reactions for the multiple functionalization of fullerene hexaadducts.

A fullerene hexakis-adduct incorporating complementary reactive centres with very different and selective reactivity has been prepared and functionalized with three different peripheral groups by successive alkyne-azide and thiol-ene click reactions.

A Supramolecular Photosynthetic Model Made of a Multiporphyrinic Array Constructed around a C60 Core and a C60–Imidazole Derivative

The photophysical properties of a supramolecular fullerene-porphyrin ensemble resulting from the self-assembly of a pyrrolidinofullerene-imidazole derivative (F1) with a multimetalloporphyrin array constructed around a hexasubstituted fullerene core (F(ZnP)12) have been investigated. The fullerene hexa-adduct core of the host system does not play any active role in the cascade of photoinduced events of the supramolecular ensemble, indeed no intercomponent photoinduced processes could be observed in host F(ZnP)12. In contrast, upon axial coordination with the monosubstituted fullerene guest F1, a quantitative quenching of the fluorescence signal of the metalloporphyrins was observed for the supramolecular complex [F(ZnP)12(F1)n] both in polar and nonpolar solvents. In toluene, the supramolecular ensemble exhibits a charge transfer emission centered around nm, suggesting the occurrence of intramolecular face-to-face interactions of F1 with neighboring metalloporphyrin moieties within the self-assembled photoactive array. This mechanism is supported by the fact that a one order of magnitude increase in the binding constant was observed for the supramolecular complex [F(ZnP)12(F1)n] when compared with a reference system lacking the pyrrolidinofullerene unit. In benzonitrile, a long-lived charge-separated state (τ=0.3 μs) has been detected for the supramolecular adduct.

Photoinduced electron transfer in a clicked fullerene–porphyrin conjugate

A stable C60 derivative bearing an azide functional group has been prepared and used as a building block for the preparation of a fullerene–porphyrin conjugate (F–P–F) by reaction with a Zn(II)–porphyrin bearing two terminal alkyne groups under the copper mediated Huisgen 1,3-dipolar cycloaddition conditions. The electrochemical and photophysical properties of the resulting multicomponent system have been investigated in detail. In benzonitrile, F–P–F undergoes photoinduced electron transfer and the resulting charge separated state is relatively long lived (τ = 0.48 µs). In contrast, intramolecular energy transfer has been evidenced in toluene, with the generation of the fullerene triplet level upon selective excitation of the porphyrin moiety. In this solvent, a CT emission band is observed in the near-infrared region (λmax = 940 nm) as a consequence of a conformational equilibrium causing, to a minor extent, the formation of intramolecular porphyrin–fullerene tight pairs. This finding is supported by measurements of singlet oxygen sensitization and quenching of the long-lived fullerene centered triplet state in the oxygen free solution.

A soluble hybrid material combining carbon nanohorns and C60

A soluble hybrid nanomaterial that combines fullerenes and carbon nanohorns (CNHs) has been prepared and fully characterized. Electrochemical investigations revealed that the CNHs modify the electron accepting ability of C(60) in the hybrid material.

Photo-induced Energy Transfer in a Th-Symmetrical Hexakis-adduct of C60 Substituted with π-Conjugated Oligomers

A stilbene derivative bearing a terminal alkyne unit has been prepared and grafted onto a Th-symmetrical C60 hexakis-adduct building block under alkyne/azide copper mediated Huisgen 1,3-dipolar cycloaddition conditions. The photophysical properties of the resulting fullerene derivative surrounded by 12 conjugated oligomers have been investigated. Upon excitation of the peripheral chromophores, an efficient intramolecular energy transfer to the C60 core has been evidenced.

Efficient Photoinduced Energy and Electron Transfer in ZnII-Porphyrin/Fullerene Dyads with Interchromophoric Distances up to 2.6 nm and No Wire-like Connectivity

The dyads 1-3 made of an alkynylated ZnII -porphyrin and a bis-methanofullerene derivative connected through a copper-catalyzed azide-alkyne cycloaddition have been synthesized. The porphyrin and fullerene chromophores are separated through a bridge made of a bismethanofullerene tether linked to different spacers conjugated to the porphyrin moiety [i.e., m-phenylene (1), p-phenylene (2), di-p-phenylene-ethynylene (3)]. Compounds 1-3 exhibit relatively rigid structures with an interchromophoric separation of 1.7, 2.0, and 2.6 nm, respectively, and no face-to-face or direct through-bond conjugation. The photophysical properties of compounds 1-3 have been investigated in toluene and benzonitrile with steady-state and time-resolved techniques as well as model calculations on the Förster energy transfer. Excited-state interchromophoric electronic interactions are observed with a distinct solvent and distance dependence. The latter effect is evidenced in benzonitrile, where compounds 1 and 2 exhibit a photoinduced electron transfer in the Marcus-inverted region, with charge-separated (CS) states living for 0.44 and 0.59 μs, respectively, whereas compound 3 only undergoes energy transfer, as in apolar toluene. The quantum yield of the charge separation (φCS ) of compounds 1 and 2 in benzonitrile is ≥0.75. It is therefore demonstrated that photoinduced energy and electron transfers in porphyrin-fullerene systems with long interchromophoric distances may efficiently occur also when the bridge does not provide a wire-like conjugation and proceed through the triplet states of the chromophoric moieties.

Designing liquid-crystalline dendronised hexa-adducts of [60]fullerene via click chemistry

ABSTRACT Liquid-crystalline [60]fullerodendrimers were constructed via click chemistry based on the reaction between hexa-adducts of [60]fullerene (C60) bearing 12 azide groups and alkyne-terminated cyanobiphenyl dendrons of first- and second-generation. The structure of all the new compounds was confirmed by IR, UV, 1H and 13C NMR spectroscopies and mass spectrometry. The mesomorphic properties were studied by polarised optical microscopy, differential scanning calorimetry and small-angle X-ray scattering. The hexa-adduct of C60 functionalised with the first-generation dendrons gave rise to the formation of a smectic A phase and a rectangular columnar phase (c2mm symmetry) while the hexa-adduct of C60 decorated with the second-generation dendrons displayed only a rectangular columnar phase (c2mm symmetry). Our results show that the hexa-adduct of C60 is a unique synthetic platform for the design of fullerodendrimers and dendronised materials. GRAPHICAL ABSTRACT