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ISSN: 1385-2728 eISSN: 1875-5348 Sugar-Functionalized Fullerenes

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Shengju Zhou1,3, Piotr Trochimczyk2, Lili Sun2, Sen Hou2,* and Hongguang Li1,*

BENTHAM SCIENCE

1Laboratory of Clean Energy Chemistry and Materials, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, China; 2Institute of Physical Chemistry Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; 3University of Chinese Academy of Sciences, Beijing 100049, China

Abstract: Being the first member in the family of nanocarbon superstructures, fullerene C60 (refers to C60 hereafter) continues to be a research focus in physics, chemistry, materials science, biology and life science. The readily

available functionalization methods that can be realized on C60 further expand the potential applications of C60 in various fields. Carbohydrates distribute widely in a variety of forms in mammalian animals and the glycan-protein

interactions play important roles in many biological processes. Covalently attaching sugar units to C60 yields glycofullerenes, which exhibit interesting physicochemical properties and biological activities. Here, we give a compre-

hensive review on the syntheses, properties and applications of this novel class of C60 derivatives. Directions in which efforts should be devoted to in near future have also been discussed.

Keywords: Fullerene C60, carbohydrates, glycofullerenes, biological activities, cycloaddition.

INTRODUCTION Here, we summarize the studies on sugar-functionalized C60 carried out during the past decades. Although such topics have par- Since its discovery [1] and large-scale production [2], fullerene tially been mentioned in the review papers by Nierengarten et al. C (refers to C hereafter) has received much attention due to its 60 60 and Roy et al., respectively [21, 22], emphases have been put on highly symmetric geometry and unique physicochemical properties. recently developed globular fullerene sugar balls. A comprehensive Its appearance strengthens interests of scientists on cage molecules. review reflecting all the aspects of sugar-functionalized C is still Moreover, it induces the subsequent revolution of nanocarbon ma- 60 needed. In this review, we would like to first give a brief introduc- terials, during which a variety of nanocarbon superstructures with tion of the chemical reactivity of C , followed by a detailed presen- different dimensionalities and properties have been discovered [3]. 60 tation of glycofullerenes organized mainly by the type of reactions These include carbon nanotubes (CNTs), graphene and carbon through which the sugar units are covalently attached. Hopefully quantum dots. this review can serve as a guide for those who are interested on When comprehensive investigations on C60 start in different fullerene chemistry and/or sugar-containing hybrid materials. disciplines, its poor solubility becomes a big obstacle. This is especially true for the studies in aqueous solutions due to the extremely -24 -1 CHEMICAL REACTIVITY OF C60 low solubility of C60 in water, which is only ~2 10 molL [4]. Post-functionalization is thus mandatory before a variety of poten- The discovery of C60 introduces a thoroughly new and intrigu- tial applications, especially its biological activities [5-10], can be ing substrate for organic synthesis. Investigations on its chemical realized. This triggers the interests on the syntheses of water soluble reactivity were initiated soon after its production in gram-scale. C60 derivatives which bear a variety of hydrophilic groups such as Earlier studies indicated that C60 has some aromaticity [23]. How- quaternary ammonium salts [11, 12], carboxylic groups [13-15] and ever, deeper investigations revealed that it is more like an electron- oligo-(ethylene oxide)s [16]. deficient alkene and can accept up to six electrons [24]. C60 also Sugars are important components in mammalian cells. They are acts like a radical sponge and can react with various radicals utmost important due to their biological activities such as glycan- through addition reaction [25]. This occurs easily especially when protein interactions [17-19]. However, such interaction between a C60 is exposed to the light. One of the disadvantages of the radical single sugar unit and protein is normally quite weak and multivalent addition reaction, however, is the formation of a mixture with mul- display is thus required [20]. Aromatic scaffolds have recently been tiple functional groups attached onto C60 in a single reaction, which recognized as ideal candidates for multivalent glycoconjugate syn- makes subsequent purification quite sophisticated or impossible. theses and applications [21], among which sugar-functionalized Recently, this obstacle has been partially solved by applying transi- tion metal-based catalysts, leading to the formation of well-defined C60, i.e., glycofullerenes, received special attention. Grafting sugar C monoadducts [26]. units to C60 can not only impart C60 water solubility to realize its 60 intriguing biological activities, but also give the hybrid the ability The most comprehensively studied and useful reactions on C60 for molecular recognition through glycan-protein interactions. are probably the various cycloadditions. Accordingly to the reaction pathway and the number of atoms involved in the ring which bridges C and the addends, they can be categorized by [1+2], *Address correspondence to these authors at the Institute of Physical Chemistry Polish 60 Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; Tel: + 0048 [3+2] and [4+2] cycloadditions, respectively. Typical examples in 790662634; E-mail: [email protected] and Laboratory of Clean Energy Chemis- each case include Bingle-Hirsch reaction [27, 28], Prato reaction try and Materials, Lanzhou Institute of Chemical Physics, Chinese Academy of Sci- [29] and Diels-Alder reaction [30], respectively. To date, glyco- ences, Lanzhou 730000, China; Tel: +86-931-4968829 Fax: +86-931-4968163; E-mail: [email protected] fullerenes have been prepared mainly through these cycloadditions. Current Organic Chemistry 1875-5348/16 $58.00+.00 © 2016 Bentham Science Publishers Sugar-Functionalized Fullerenes Current Organic Chemistry, 2016, Vol. 20, No. 14 1491

Scheme 1.

In the following, the presentation will be divided mainly based on was then subjected to react with 1,2:3,4-di-O-isopropylidene-D- the reaction pathway and/or the sugar-based precursors, which will galactopyranose-6-chloroformate to give glycofullerene 6 through then be ended with C60 derivatives functionalized with - amide coupling (Scheme 2) [35]. cyclodextrin (-CD), a cyclic oligosaccharide with seven -D- Besides preparation of glycofullerene through amide coupling glucopyranoside units linked through 1,4-glucosidic bonds. Finally, between acyl chloride-based sugar unit and C60 amine as demon- conclusions will be given together with a brief discussion of per- strated in Scheme 2, a more popular synthetic pathway involves spectives. installing an azide group onto the sugar units which were then directly subjected to react with C60 (Scheme 3). For the monoadducts REACTION WITH DIAZONIUMS obtained this way, theoretically there are four isomers, i.e., 5.6- The first report on glycofullerenes appeared in 1992, i.e., one open, 5,6-close, 6,6-open and 6,6-close. In most reports accom- plished by different authors, however, only one (or two) dominant year after the report on the gram-scale production of C60 [31]. In this work, Vasella et al. prepared O-benzyl (Bn) and O-pivaloylated isomer(s) have been claimed, among which 5.6-open and/or 6,6- (Piv) protected sugar units which bear diazoniums, which were then close are the most popular. It is also claimed that alkyl azides prefer to afford 5,6-addition type glycofullerenes while acyl azides prefer- subjected to react with C60 to give glycofullerene 1 and 2 (Scheme 1). The mechanism involved in the reaction between fullerene and entially give the adducts with 6,6-addition pattern [34-37]. Mean- diazonium will not be repeated here. For details, one can refer to a while, bisadduct can be also obtained where the two addends are recent paper co-authored by Olmstead, Balch, Wudl and Echegoyen joint at the end of the C=C double bond in between two six- et al., which discusses the regioselective synthesis of easily isolable membered rings on C60 (Scheme 3). pure bismethano derivatives of fullerene C60 and C70 with high Kobayashi et al. prepared a series of glycofullerenes in 13-28% steric congestion using 1,3-dibenzoylpropane bis-p-toluenesulfonyl yields by reacting C60 with per-O-acetyl glycosyl azide of D- hydrazone as the addend precursor [32]. The protecting groups on glucopyranose, D-galactopyranose, lactose, maltose, and maltotri- the sugar units were later expanded to 4,6-O-benzylidene (3) and ose, respectively (Scheme 3, 7-11) [38]. The glycofullerenes were 2,3:4,6-di-O-isopropylidene (4), and glycofullerene 5 with unpro- identified to be 5,6-addition type due to the absence of the signals 3 tected sugar unit was also prepared [33]. from sp carbons of C60 which should appear between 80-90 ppm as well as the disappearance of the bands between 420-440 nm in UV- REACTION WITH AZIDES vis absorptions. Even though the addition pattern has been fixed, the authors found by 1H NMR analysis that each of these glyco- The addition of azides to C60 was demonstrated by Prato and fullerenes is a mixture of two steroisomers with a molar ratio of Wudl in 1993 [34]. Utilizing this synthetic route, Taylor et al. re- ~2:1. ported the preparation of an isolable and stable C derivative, az- 60 In another work, Kobayashi and Shinohara et al. prepared gly- iridino[2,3:1,2]C (6a), by thermal elimination of isobutene and 60 cofullerenes carrying mono- and bis--D-mannosyl linkages on the CO from N-tert-butoxycarbonylaziridino[2,3:1,2]C (6b). 6a 2 60 surface via the reaction between 2-azidoethyl -D-mannoside and 1492 Current Organic Chemistry, 2016, Vol. 20, No. 14 Zhou et al.

Scheme 2.

Scheme 3. Sugar-Functionalized Fullerenes Current Organic Chemistry, 2016, Vol. 20, No. 14 1493

Scheme 4.

C60 followed by polyhydroxylation with NaOH aqueous solution except the rare example (for example, when HGC-27 cells were (Scheme 3, 12-14 and 12-14) [39]. The two monoadducts, i.e., incubated at the presence of 18) in most cases the bisadducts were 5,6-open (12) and 6,6-close (13) form, were separated in 5:2 ratio found to produce few reactive oxygen species (ROS) when incu- on an HPLC column. The glycofullerenes in the deprotected forms bated with cells. Similar work has been done by Yano et al. who (12-14) were then subjected to the tests of binding affinity to lect- prepared Ac-protected (Scheme 3, 19-28) and deprotected (Scheme ins. It was found that fullerenols without the glycoside linkage pos- 3, 19-28) glycofullerenes and investigated in detail their phototox- sess notable biological activities of erythrocyte aggregation and icity [42]. In this case the monoadducts were not separated. Instead, binding to a -galactoside specific protein (RCA120), while these they were obtained as a mixture mainly composed of 5,6-open gly- activities can be reduced by the mono-substituted glycofullerenes cofullerenes. It was found that the normalized emission intensities (12 and 13) and diminished by the bisadduct (14) as demon- divided by the absorption at 355 nm for the deprotected monoad- strated by hemagglutination assay and surface plasmon resonance. ducts (19, 21, 23, 25, 27) are only ~5% of the parent C60 and These effects could be, at least partially, ascribed to the strong ag- approximately half of the Ac-protected monoadducts (19, 21, 23, gregate formation of the glycofullerenes in aqueous solutions. Fur- 25, 27), which is assumed to the disruption of fullerene aromaticity ther studies showed that the colloidal suspension of mono- and high aggregation property of the deprotected glycofullerenes. substituted glycofullerenes turned to binding to -D-mannose Only negligible influence of the nature of the pendant sugar moiety specific lectin (Con A) and the binding is more effectively for 12 on the singlet oxygen yields has been noticed. Again, the depro- than 13 [40]. tected bisadducts (20, 22, 24, 26, 28) do not exhibit photocyto- Otake et al. synthesized glycofullerenes functionalized with D- toxicity probably because they produce very little of singlet oxygen glucose and maltohexaose residue, respectively (Scheme 3, 15-18), under the experimental conditions. and utilized them as photosensitizers for photodynamic therapy Hirsch et al. synthesized an Ac-protected dendritic glyco- (PDT) [41]. It was found that PDT alone induced significant cyto- fullerene which contains six sugar building blocks (Scheme 3, 29) toxicity while that with the glycofullerenes 15 and 17 exhibited no [43]. After deprotection, the sugar-appended fullerene dendrimer 30 significant cytotoxicity against normal fibroblasts, indicating that is very soluble in water. Its amphiphilic nature forces the formation PDT with these compounds targeted cancer cells. Similar with the of small supramolecular aggregates in aqueous solutions to shield phenomena observed in the tests of binding affinity to lectins [39], the hydrophobic C60 units from the water subphase. DOSY NMR 1494 Current Organic Chemistry, 2016, Vol. 20, No. 14 Zhou et al.

Scheme 5. spectroscopy and TEM investigation reveal micellar sugar balls of azides as mentioned above as well as by Bingle-Hirsch reaction ~4 nm with an extremely narrow size distribution. A small pity of (see below). Dondoni et al. prepared a series of fulleropyrrolidines this work is, however, the total yield of this interesting molecule is bearing sugar units by refluxing a mixture of C60, N-methylglycine somehow low, which is less than 10%. (sarcosine), and sugar aldehydes in toluene (Scheme 4, 31-37) [46]. This procedure leads to the formation of a mixture of mono- and Through Prato Reaction multi- adducts, from which the monoadducts were isolated in 10- The 1,3-dipolar cycloaddition reaction of C with azomethine 14% yields. Nogueras et al. synthesized several glycofullerenes 60 ylides, i.e., Prato reaction, is one of the most frequently used syn- containing a 4-( -D-glycopyranosylamino) pyrimidin-4-one moiety (Scheme 4, 38-43) from the corresponding 5-formylpyrimidin-4- thetic pathways to functionalize C60. It belongs to the [3+2] cy- one derivatives, C60 and N-methylglycine [47]. The mixtures of the cloaddition pattern and yields C60 derivatives named fulleropyrrolidines [44, 45]. It has several advantages including simple reac- diastereoisomers of 38-43 were separated by column chromatogra- tion conditions, readily available starting materials and high yields. phy. Single-crystal X-ray crystallography of one diastereoisomer of A minor shortcoming of this synthetic route is the formation of a 41 shows that individual molecules pack closely in the solid state, racemic mixture created by the chiral carbon center in the pyrrol forming inﬁnite tapes. The main core of these tapes is constituted ring (Scheme 4). While in many cases this is not a problem, in ap- by the glycopyranosylaminopyrimidin-4-one units while the C60 plications related to biology and life science the racemic mixture is moieties point outwards. These supramolecular tapes are distributed probably mandatory to be separated, which makes the material in the crystal structure of the compound in a typical herringbone preparation tedious and time-consuming. Probably for this reason, fashion. In these two examples mentioned above, no further bio- there have been not so many reports on glycofullerenes prepared by logical evaluations of the glycofullerenes have been carried out. In another example, attachment of oligosaccharides to fullerene was this method compared to those obtained by the reaction of C60 with Sugar-Functionalized Fullerenes Current Organic Chemistry, 2016, Vol. 20, No. 14 1495

Scheme 6. demonstrated through an oxylamine-functionalized fullerene de- luminescence measurements. It was found that the transient absorp- rivative [48]. However, details of the molecular characterizations tion spectral profiles are solvent independent although small differ- are missing. ences are observed in the transient absorption maximum, i.e., 720 ± 5 nm for toluene, 710 ± 5 nm for benzonitrile and 700 ± 5 nm for Through Penta-Addition acetonitrile. Triplet state molar absorption coefficients (T)of C60 ± -1 -1 One important and unique synthetic pathway in fullerene chem- derivatives vary from 9456 2090 M cm for 52 in toluene, and ± -1 -1 istry is penta-addition introduced by Nakamura et al. [49-51]. This 15,272 4462 M cm for 50 in acetonitrile. In toluene and ben- route has also been utilized to obtain glycofullerenes [52, 53]. In zonitrile, is found to be close to unity and triplet state lifetimes ± ± this case a penta-substituted C intermediate was synthesized first, ( T) are similar (47.5 1.1 s T 51.4 2.0 s). In acetonitrile, 60 ± ± to which the sugar units were coupled through either thiolate/alkyl however, T is lower (31.8 0.6 s T 43.0 1.1 s). Hirsch halide coupling or click coupling (Scheme 5). By the latter means, et al. also prepared a glycofullerene with a similar molecular structure but the connections are amide groups instead of ester groups up to 15 sugar units have been successfully grafted to the C60 core (Scheme 7, 54, 55) [43]. In this case fully acetyl-protected bis(-D- (Scheme 5, 47, 48) [53]. mannopyranose)malonamide was first synthesized, which was then Through Bingle-Hirsch Reaction coupled to C60 through Bingle-Hirsch reaction. Investigations on the fully deprotected glycofullerene 55 indicate that it is soluble in Bingle-Hirsch reaction, which belongs to [1+2] cycloaddition, DMSO, DMF and mixtures of water and DMSO while insoluble in is probably the most frequently used synthetic pathway to obtain pure water, MeOH, EtOH, acetone, THF, CH2Cl2 and CHCl3. The glycofullerenes. This reaction was first introduced by Bingle et al. 1 H NMR spectrum of 55 in d6-DMSO revealed very broadened [27] and later was improved by Hirsch et al. [28] and Sun et al. [54, signals, which suggests the formation of aggregates. 55]. Unlike the [3+2] cycloadditions such as Prato reaction and the Besides preparing glycofullerenes directly by reaction between reaction between C60 and azides which give stero- or racemic mixtures of glycofullerenes, Bingle-Hirsch reaction produces mono- C60 and sugar-based malonate, an alternative way is to couple sugar and multi- adducts with defined molecular structures. This is a big units to an intermediate C60 derivative obtained from Bingle-Hirsch advantage which accouts for its widespread application to synthe- reaction. This method is preferentially adopted when the attached size glycofullerenes. McGarvey et al. synthesized glycofullerenes functional groups are huge, where directing attachment is difficult or even impossible. Stoddart et al. synthesized two dendritic glyco- containing one or two D-galactose or D-glucose units where C60 and sugar units are connected by ester groups (Scheme 6, 49-53) fullerenes which contain three and six sugar units, respectively, by [56]. For this purpose, sugar-malonate derivatives were first synthe- amide coupling a sugar-based dendron to mono- and di- C60 carboxylic acids (Scheme 8, 56, 57) [57]. The ability of 56 and 57 to sized, followed by a cyclopropanation reaction with C60. The photophysical properties of 49-53 were investigated in different sol- form Lanmuir and Langmuir-Blodgett films was evaluated. It was vents by nanosecond laser flash photolysis coupled with kinetic found that the bulky glycodendron headgroups in 56 and 57 are UV-vis absorption spectroscopy and time-resolved singlet oxygen very effective in suppressing fullerene aggregation, which has been 1496 Current Organic Chemistry, 2016, Vol. 20, No. 14 Zhou et al.

Scheme 7.

Scheme 8.

a severe problem in C60-based two-dimensional superstructures adduct which bears twelve terminal alkyne or azide groups was first formed at the air/water interface [58]. As a result, stable, ordered prepared, to which sugar units bearing azide or alkyne groups were monomolecular layers with reversible compression and expansion grafted through click coupling. By this means, a variety of globular behavior form at the air/water interface, which can be further trans- glycofullerenes with 12, 24 or 36 terminal sugar units have been ferred as X-type Langmuir-Blodgett films onto quartz slides. Freitas obtained (scheme 10, 64-84). Due to the large number of appended et al. prepared a bis-malonate C60 derivative bearing terminal al- sugar units, the water solubility has been significantly improved kyne groups, to which sugar units with different structures and/or and the glycan-protein interactions have been enlarged due to the protecting groups were attached through click coupling (Scheme 9, multivalent effect. This facilitates the investigations on their bio- 58-63) [59]. It was claimed that the use of the click reaction as the logical properties including molecular recognation of Con A [62] last step to functionalize the fullerene presents the advantage of and inbibition of Escherichia Coli FimH [63], Liposaccharide Hep- higher global yields when compared with a cycloaddition reaction tosyltransferase WaaC [64], glycosidase [65] as well as viral infec- or the Bingel reaction using highly functionalized malonates. tion [66]. This part has been nicely reviewed by Nierengarten et al. Besides obtaining structurally pure target molecules, another [21] and is also included in the review paper written by Roy et al. advantage of Bingle-Hirsch reaction is that it can easily lead to the [22]. The readers can thus kindly refer to them for further details. formation of C60 hexakis-adducts. In recent years, this advantage Using the same strategy, more recently Martìn and Nierengar- has been kindly introduced to prepare glycofullerenes by Martìn ten et al. prepared giant globular multivalent glycofullerenes deco- and Nierengarten et al. [60-66]. Generally, a globular C60 hexakis- rated with up to 120 peripheral sugar units (Scheme 11, 85-87) [67], Sugar-Functionalized Fullerenes Current Organic Chemistry, 2016, Vol. 20, No. 14 1497

Scheme 9.

Scheme 10. 1498 Current Organic Chemistry, 2016, Vol. 20, No. 14 Zhou et al.

Scheme 11. which represent sugar-functionalized fullerenes with the largest Through Diels-Alder Reaction number of sugar units reported to date. These molecules are termed Synthesis of C60 derivatives through Diels-Alder reaction, “superballs”. Despite the complexity of the molecules leads to dif- which belongs to [4+2] cycloaddition, has received increasing at- ficulties of structural characterizations, good overall synthetic tention. A typical example is the synthesis of indene-C60 mono- and yields and reproducibility have been obtained. Their abilities to bisadducts which have been successfully used as the n-type semi- inhibit the infection of cells by an artificial Ebola virus have been conducting materials in polymer solar cells [30, 68-70]. Toshima tested. It was found that 85 and 87 with mannose residues showed et al. prepared glycofullerenes by coupling a glycosyl bromide to a very strong antiviral activity at picomolar to nanomolar concentra- C60 cyclohexanone derivative which was obtained through Diels- tions, while 86 which was decorated by galactoses did not exhibit Alder reaction (Scheme 12, 88, 89) [71]. Investigations on 89 re- such activity. Sugar-Functionalized Fullerenes Current Organic Chemistry, 2016, Vol. 20, No. 14 1499

Scheme 12.

Scheme 13. vealed that it can eectively and selectively degrade HIV-1 prote- a flexible linker at the secondary face of -CD (Scheme 13, 91, 92) ase under long-wavelength UV or visible photo-irradiation. [74]. It was found that both 91 and 92 display good water solubility. When associated with rhodamine B (RhB) in aqueous buffer solu- C60--CD Conjugates tions with pH = 7.20, an enhancement of the fluorescence of RhB Cyclodextrins (CDs) are cyclic oligosaccharides, each of which was observed. Rassat et al. reported the synthesis of a 2 : 1 (per- has a hydrophilic outer surface and a hydrophobic interior. They methylated- -CD)-C60 conjugate where the linker is attached to the can be classified as -, - and -CD which has six, seven and eight secondary rim of -CD (Scheme 13, 93) [75]. It exhibits high solu- -D-glucopyranoside units in the molecule, respectively. It is well- bility in cold water with a negative solubility coefficient. When octanol was added, a partition coefficient of 1.58 was obtained, known that pristine C60 can be embedded in the cavities of -CD which is a cyclic oligosaccharide poccessing eight -D- which is in the suitable range for biological studies. This molecular glucopyranoside units [72]. The so-obtained C /-CD complexes design was later developed by Zhang et al. who obtained more C60- 60 exhibit interesting physicochemical properties. However, there is no -CD conjugates by varying the spacers in between C60 and -CD [76]. report about covalently-linked C60--CD conjugate, which is also the case for -CD. Instead, studies in this case were carried out CONCLUSIONS AND FUTURE PERSPECTIVES using -CD, presumably because it is much more available compared to - and -CD. Liu et al. prepared a water-soluble C60--CD The marriage of fullerene chemistry and carbohydrate chemis- conjugate through Diels-Alder reaction between anthryl--CD and try gives birth to the intriguing research focus of glycofullerenes. C60 (Scheme 13, 90), which displays a satisfactory DNA-cleavage The attachment of sugar units, especially in their deprotected forms, ability under visible-light irradiation [73]. Zhang et al. synthesized improves the solubility of C60 in water. It has been figured out that two C60--CD conjugates where -CD was coupled to C60 through glycofullerenes with good water solubility can be obtained when 1500 Current Organic Chemistry, 2016, Vol. 20, No. 14 Zhou et al. the number of attached sugar units is > 3, which can be realized by [13] Brettreich, M.; Burghardt, S.; Böttcher, Ch.; Bayerl, Th.; Bayerl, S.; Hirsch, A. Globular amphiphiles: Membrane-forming hexaadducts of C60. Angew. coupling sugar-based dendrons or by multiple additions such as Chem. Int. Ed., 2000, 39, 1845-1848. penta- and hexakis- additions. In these interesting hybrids, the in- [14] Braun, M.; Hartnagel, U.; Ravanelli, E.; Schade, B.; Böttcher, C.; Vos- trinsic properties of C and the sugar units can be preserved al- trowsky, O.; Hirsch, A. Amphiphilic [5:1]- and [3:3]-hexakisadducts of C60. 60 Eur. J. Org. Chem., 2004, 9, 1983-2001. though mutual influences have also been observed. Since both C60 [15] Burghardt, S.; Hirsch, A.; Schade, B.; Ludwig, K.; Böttcher, C. Switchable and the sugar units exhibit interesting biological activities, it is not supramolecular organization of structurally defined micelles based on an surprising that glycofullerenes received increasing research inter- amphiphilic fullerene. Angew. Chem. Int. Ed., 2005, 44, 2976-2979. [16] Song, T.; Dai, S.; Tam, K.C.; Lee, S.Y.; Goh, S.H. Aggregation behavior of ests in biology and life science. C60-end-capped poly(ethylene oxide)s. Langmuir, 2003, 19, 4798-4803. Of course, there is still plenty of room for novelty in the re- [17] Barthel, S.R.; Gavino, J.D.; Descheny, L.; Dimitroff, C.J. Targeting selectins and selectin ligands in inflammation and cancer. Exp. Opin. Ther. Targets., search of glycofullerenes. First, new molecules are yet to come 2007, 11, 1473-1491. considering the high flexibility in molecular design. Second, up to [18] Kannagi, R.; Izawa, M.; Koike, T.; Miyazaki, K.; Kimura, N. Carbohydrate- mediated cell adhesion in cancer metastasis and angiogenesis. Cancer Sci., now nearly all the reported molecules only contain sugar units, 2004, 95, 377-384. multifunctional glycofullerenes are yet to be synthesized. For ex- [19] Lahm, H.; Andre, S.; Hoeflich, A.; Kaltner, H.; Siebert, H.C.; Sordat, B.; ample, it is highly desired to integrate fluorescent probes and/or Von der Lieth, C.W.; Wolf, E.; Gabius, H.J. Tumor galectinology: Insights into the complex network of a family of endogenous lectins. Glycoconjugate drug molecules together with sugar units on the C60 core, which J., 2004, 20, 227-238. will significantly enlarge the potential applications of glyco- [20] Chabre, Y.M.; Roy, R. Design and creativity in synthesis of multivalent fullerenes. Third, investigations on glycofullerenes should not be neoglycoconjugates. Adv. Carbohyd. Chem. Biochem., 2010, 63, 165-393. [21] Chabre, Y.M.; Roy, R. Multivalent glycoconjugate syntheses and applica- confined in biology and life science, other aspects such as their tions using aromatic scaffolds. Chem. Soc. Rev., 2013, 42, 4657-4708. properties in solvent-free states and potentials as water-based n- [22] Nierengarten, I.; Nierengarten, J.F. Fullerene sugar balls: A new class of type semiconducting materials in photovoltaic devices should be biologically active fullerene derivatives. Chem. Asian J., 2014, 9, 1436-1444. [23] Bühl, M.; Hirsch, A. Spherical aromaticity of fullerenes. Chem. 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Received: August 15, 2015 Revised: October 19, 2015 Accepted: December 05, 2015