Water-soluble Fullerene Derivatives Research Articles

Nafion-based composite solid electrolytes containing water-soluble fullerene C60 derivatives

Nafion-based composite solid polyelectrolytes containing fullerene C60 and its water-soluble derivatives fullerenol-C60 and tris-malonate-C60 were studied by the impedance spectroscopy method. It was found that introduction of these dopants in Nafion leads to a substantial increase in proton conductivity of the composites in the region of low relative humidity. The reasons for the influence of dopants on proton conductivity of composites were discussed.

Self-organization of a water-soluble fullerene derivative studied by pulsed field gradient NMR spectroscopy

The self-organization of a water-soluble sulfur-containing fullerene adduct with captopril in deuterated water was studied by a pulsed field gradient NMR technique. Two types of fullerene particles characterized by the self-diffusion coefficients Ds1 and Ds2 of (4.0±0.5)×10–10 and (6.5±0.3)×10–11 m2 s–1, respectively, were revealed.

The cytotoxicology of water-soluble fullerene derivatives with different surface covalent modification

The cytotoxicology of water-soluble fullerene derivatives with different surface covalent modification

A proline-type fullerene derivative inhibits adipogenesis by preventing PPARγ activation

Obesity and its associated metabolic diseases represent some of the most rapidly expanding health issues worldwide, and, thus, the development of a novel chemical compound to suppress adipogenesis is strongly expected. We herein investigated the effects of water-soluble fullerene derivatives: a bis-malonic acid derivative and three types of proline-type fullerene derivatives, on adipogenesis using NIH-3T3 cells overexpressing PPARγ. One of the proline-type fullerene derivatives (P3) harboring three carboxy groups significantly inhibited lipid accumulation and the expression of adipocyte-specific genes, such as aP2, induced by the PPARγ agonist rosiglitazone. On the other hand, the bis-malonic acid derivative (M) and the 2 other proline-type fullerene derivatives (P1, P2), which have two carboxy groups, had no effect on PPARγ-mediated lipid accumulation or the expression of aP2. P3 fullerene also inhibited lipid accumulation induced by the combined stimulation with 3-isobutyl-1-methylxanthine (IBMX), dexamethasone, and insulin in 3T3-L1 preadipocytes. During the differentiation of 3T3-L1 cells into adipocytes, P3 fullerene did not affect the expression of C/EBPδ, C/EBPβ, or PPARγ, but markedly inhibited that of aP2 mRNA. These results suggest that P3 fullerene exhibits anti-obesity activity by preventing the activation of PPARγ.

Surface enhanced Raman scattering detection of water-soluble derivatives of fullerene C60 and their covalent conjugates with dyes in biological model systems

The potential of surface enhanced Raman spectroscopy (SERS) for the detection of water-soluble fullerene derivatives and their covalent conjugates with xanthene dyes was investigated in model biological liposome membranes and in the albumin protein structure. It was shown that in liposomes and in albumin, fullerene derivatives and their covalent conjugates with dyes show characteristic SERS spectra, which allows detection of water-soluble fullerene derivatives in phosphatidylcholine liposomes at the lipid/fullerene derivative ratio of 100 as well as fullerene–dye conjugates in liposomes and albumin.

Improving the Visible Light Photoactivity of Supported Fullerene Photocatalysts through the Use of [C₇₀] Fullerene.

We herein present the first instance of employing [C₇₀] fullerene for photocatalytic ¹O₂ production in water, through covalent immobilization onto a mesoporous silica support via nucelophilic amine addition directly to fullerene's cage. This attachment approach prevents the aggregation of individual fullerene molecules in water, thus allowing fullerene to retain its photoactivity, yet is much less complex than other techniques commonly pursued to create such supported-fullerene materials, which typically rely on water-soluble fullerene derivatives and elaborate immobilization methods. The solid-supported C₇₀ material exhibits significantly improved aqueous visible-light photoactivity compared to previous C₆₀- and C₆₀-derivative-based supported fullerene materials. Further, this material rapidly inactivates MS2 bacteriophage under sunlight illumination, oxidizes various organic contaminants, and does not appear to be significantly fouled by natural organic matter (NOM), highlighting the potential of these materials in real-world applications. Collectively, the ease of preparation and significantly enhanced visible-light photoactivity of these materials advance fullerene-based technologies for water treatment.

An Easy Stereo-Specific and Regio-Selective Reaction for the Synthesis of Ester-[70]-Fullerene Derivatives

Medicinal chemistry is one of the many fields where fullerene derivatives have been shown to be active and useful.[1,2] Wudl and coworkers reported the interactions of [60]-fullerene derivatives with the active site of HIV protease, driven by the lipophilicity of the carbon cage.[3] Unfortunately, fullerene derivative applications in this field are hindered mainly by their low water-solubility. To date, water-soluble fullerene C70 derivatives have not been extensively investigated. The lack of low symmetry of the C70 cage makes its selective functionalization more challenging than for C60. Therefore, just a few C70 water-soluble derivatives have been reported. [4,5] Here we report an efficient stereo-specific and regio-selective reaction for the synthesis of ester-pyrrolidinofullerene derivatives. These compounds are good precursors for the synthesis of their corresponding water-soluble carboxylic acid-pyrrolidinofullerenes. Figure 1. Stereo-specific and regio-selective 1,3-dipolar cyclo-addition reaction of ester-[70]-fullerene derivatives. A. Jensen, S. Wilson, D. Schuster, Bioorg. Med. Chem. 1996, 4, 767.T. Da Ros, M. Prato, Chem. Commun. 1999, 663.S. Friedman, D. DeCamp, R. Sijbesma, G. Srdanov, F. Wudl, G. Kenyon, J. Am. Chem. Soc. 1993, 115, 6506-6509.P. Witte, F. Beuerle, U. Hartnagel, R. Lebovitz, A. Savouchkina, S. Sali, D. Guldi, N. Chronakisd, A. Hirsch, Org. Biomol. Chem. 2007, 5, 3599.A. Kornev, A. Peregudov, V. Martynenko, J. Balzarini, B. Hoorelbekec, P. Troshin, Chem. Commun. 2011, 47, 8298–8300. Figure 1

Comparative effects of sulfhydryl compounds on target organellae, nuclei and mitochondria, of hydroxylated fullerene-induced cytotoxicity in isolated rat hepatocytes.

DNA damage and cytotoxicity induced by a hydroxylated fullerene [C60 (OH)24 ], which is a spherical nanomaterial and/or a water-soluble fullerene derivative, and their protection by sulfhydryl compounds were studied in freshly isolated rat hepatocytes. The exposure of hepatocytes to C60 (OH)24 at a concentration of 50 μM caused time (0 to 3 h)-dependent cell death accompanied by the formation of cell surface blebs, the loss of cellular levels of ATP and reduced glutathione, accumulation of glutathione disulfide, and induction of DNA fragmentation assayed using alkali single-cell agarose-gel electrophoresis. C60 (OH)24 -induced cytotoxicity was effectively prevented by pretreatment with sulfhydryl compounds. N-acetyl-L-cysteine (NAC), L-cysteine and L-methionine, at a concentration of 2.5 mM, ameliorated cell death, accompanied by a decrease in cellular ATP levels, formation of cell surface blebs, induction of reactive oxygen species (ROS) and loss of mitochondrial membrane potential caused by C60 (OH)24 . In addition, DNA fragmentation caused by C60 (OH)24 was also inhibited by NAC, whereas an antioxidant ascorbic acid did not affect C60 (OH)24 -induced cell death and DNA damage in rat hepatocytes. Taken collectively, these results indicate that incubation of rat hepatocytes with C60 (OH)24 elicits DNA damage, suggesting that nuclei as well as mitochondria are target sites of the hydroxylated fullerene; and induction of DNA damage and oxidative stress is ameliorated by an increase in cellular GSH levels, suggesting that the onset of toxic effects may be partially attributable to a thiol redox-state imbalance caused by C60 (OH)24 .

Study of the cytotoxic effects of the new synthetic Isothiocyanate CM9 and its fullerene derivative on human T-leukemia cells.

One important strategy to develop effective anticancer agents is based on natural products. Many active phytochemicals are in human clinical trials and have been used for a long time, alone and in association with conventional anticancer drugs, for the treatment of various types of cancers. A great number of in vitro, in vivo and clinical reports document the multi-target anticancer activities of isothiocyanates and of compounds characterized by a naphthalenetetracarboxylic diimide scaffold. In order to search for new anticancer agents with a better pharmaco-toxicological profile, we investigated hybrid compounds obtained by inserting isothiocyanate group(s) on a naphthalenetetracarboxylic diimide scaffold. Moreover, since water-soluble fullerene derivatives can cross cell membranes thus favoring the delivery of anticancer therapeutics, we explored the cytostatic and cytotoxic activity of hybrid compounds conjugated with fullerene. We studied their cytostatic and cytotoxic effects on a human T-lymphoblastoid cell line by using different flow cytometric assays. In order to better understand their pharmaco-toxicological potential, we also analyzed their genotoxicity. Our global results show that the synthesized compounds reduced significantly the viability of leukemia cells. However, the conjugation with a non-toxic vector did not increase their anticancer potential. This opens an interesting research pattern for certain fullerene properties.

High performance planar heterojunction perovskite solar cells with fullerene derivatives as the electron transport layer.

In this study, we report the utilization of solution-processed high electrical conductive [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM) combined with solution-processed TiO2 as the electron transport layer (ETL) to overcome extremely low electrical conductivity of solution-processed TiO2 ETL in planar heterojunction (PHJ) perovskite hybrid solar cells (pero-HSCs). Due to the much more preferable electron extraction and transportation of PC61BM at the cathode side, a tremendously boosted short-circuit current density (JSC), fill factor (FF) and enhanced power conversion efficiency (PCE) are observed. To further address the wettability issues of perovskite materials on the top of PC61BM, water-soluble fullerene derivative is applied to modulate the surface of PC61BM. Consequently, further advanced FF with slightly enlarged JSC and open-circuit voltage (VOC) are observed. The resulted PCE is comparable with the meso-superstructured solar cells in which high PCEs can be produced. Our studies certainly provide a simple approach to boost the efficiency of PHJ pero-HSCs.

Application of SERS spectroscopy for detection of water-soluble fullerene C60 derivatives and their covalent conjugates with dyes

Application of SERS spectroscopy for detection of water-soluble fullerene C60 derivatives and their covalent conjugates with dyes

Evaluation of the influence of fullerenol on aging and stress resistance using Caenorhabditis elegans

Fullerene derivatives have attracted extensive attention in biomedical fields and polyhydroxyl fullerene (fullerenol), a water-soluble fullerene derivative, is demonstrated as a powerful antioxidant. To further assess their anti-aging and anti-stress potential, we employed Caenorhabditis elegans (C. elegans) as a model organism to evaluate the effects of fullerenol on the growth, development, behavior and anti-stress ability in vivo. The data show that fullerenol has no obviously toxic effect on nematodes and can delay C. elegans aging progress under normal condition. Further studies demonstrate that fullerenol attenuates endogenous levels of reactive oxygen species and provides protection to C. elegans under stress conditions by up-regulating stress-related genes in a DAF-16 depend manner and improving lifespan. In summary, our data suggest that fullerenol might be a safe and reasonable anti-aging candidate with great potential in vivo.

Photophysical properties and singlet oxygen generation efficiencies of water-soluble fullerene nanoparticles.

As various fullerene derivatives have been developed, it is necessary to explore their photophysical properties for potential use in photoelectronics and medicine. Here, we address the photophysical properties of newly synthesized water-soluble fullerene-based nanoparticles and polyhydroxylated fullerene as a representative water-soluble fullerene derivative. They show broad emission band arising from a wide-range of excitation energies. It is attributed to the optical transitions from disorder-induced states, which decay in the nanosecond time range. We determine the kinetic properties of the singlet oxygen (1O2) luminescence generated by the fullerene nanoparticles and polyhydroxylated fullerene to consider the potential as photodynamic agents. Triplet state decay of the nanoparticles was longer than 1O2 lifetime in water. Singlet oxygen quantum yield of a series of the fullerene nanoparticles is comparably higher ranging from 0.15 to 0.2 than that of polyhydroxylated fullerene, which is about 0.06.

Pyrrolidinium fullerene induces apoptosis by activation of procaspase-9 via suppression of Akt in primary effusion lymphoma

Primary effusion lymphoma (PEL) is a subtype of non-Hodgkin’s B-cell lymphoma and is an aggressive neoplasm caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients. In general, PEL cells are derived from post-germinal center B-cells and are infected with KSHV. To evaluate potential novel anti-tumor compounds against KSHV-associated PEL, seven water-soluble fullerene derivatives were evaluated as potential drug candidates for the treatment of PEL. Herein, we discovered a pyrrolidinium fullerene derivative, 1,1,1′,1′-tetramethyl [60]fullerenodipyrrolidinium diiodide, which induced apoptosis of PEL cells via a novel mechanism, the caspase-9 activation by suppressing the caspase-9 phosphorylation, causing caspase-9 inactivation. Pyrrolidinium fullerene treatment reduced significantly the viability of PEL cells compared with KSHV-uninfected lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9 via procaspase-9 cleavage. Pyrrolidinium fullerene additionally reduced the Ser473 phosphorylation of Akt and Ser196 of procaspase-9. Ser473-phosphorylated Akt (i.e., activated Akt) phosphorylates Ser196 in procaspase-9, causing inactivation of procaspase-9. We also demonstrated that Akt inhibitors suppressed the proliferation of PEL cells compared with KSHV-uninfected cells. Our data therefore suggest that Akt activation is essential for cell survival in PEL and a pyrrolidinium fullerene derivative induced apoptosis by activating caspase-9 via suppression of Akt in PEL cells. In addition, we evaluated whether pyrrolidinium fullerene in combination with the HSP90 inhibitor (geldanamycin; GA) or valproate, potentiated the cytotoxic effects on PEL cells. Compared to treatment with pyrrolidinium fullerene alone, the addition of low-concentration GA or valproate enhanced the cytotoxic activity of pyrrolidinium fullerene. These results indicate that pyrrolidinium fullerene could be used as a novel therapy for the treatment of PEL.

Interactions of a water-soluble fullerene derivative with amyloid-β protofibrils: dynamics, binding mechanism, and the resulting salt-bridge disruption.

Alzheimer's disease (AD) is associated with the pathological self-assembly of amyloid-β (Aβ) peptides into β-sheet-rich oligomers and insoluble amyloid fibrils. Experimental studies reported that 1,2-(dimethoxymethano)fullerene (DMF), a water-soluble fullerene derivative, inhibits strongly Aβ peptide aggregation at the early stage. However, the interaction and binding mechanisms are not well understood. In this study, we have investigated the detailed interaction of a DMF molecule with a fibrillar hexamer of full-length Aβ42 and the resulting structural alterations by performing multiple all-atom explicit solvent molecular dynamics (MD) simulations. Starting from different initial states with a minimum distance of 2 nm between the DMF and the Aβ protofibril, our MD simulations show that the DMF binds to the Aβ protofibril via both slow and fast binding processes. Three dominant binding sites are identified: the central hydrophobic core (CHC) site (17LVFFA21), the turn site (27NKGAI31), and the C-terminal β-sheet site consisting of the smallest side-chain residue glycine and hydrophobic residues (31IIGLMVGGVVI41). Binding energy analyses reveal the importance of π-stacking interactions, especially in the CHC site, hydrophobic interactions, and curvature matching. Strikingly, we find that the binding of DMF to the turn region can disrupt the D23-K28 salt-bridge that is important for the Aβ fibrillation. These results provide molecular insight into the binding mechanism of fullerene to Aβ protofibrils and offer new routes for the therapeutic drug design using fullerene derivatives against AD.

Fullerene derivatives as a new class of inhibitors of protein tyrosine phosphatases

In this study, we identified water-soluble C60 and C70 fullerene derivatives as a novel class of protein tyrosine phosphatase inhibitors. The evaluated compounds were found to inhibit CD45, PTP1B, TC-PTP, SHP2, and PTPβ with IC50 values in the low micromolar to high nanomolar range. These results demonstrate a new strategy for designing effective nanoscale protein tyrosine phosphatase inhibitors.

Novel Treatment of Radiculopathy with Fullerol Nanoparticles

Introduction Back pain is ubiquitous and costs the United States an estimated $100 billion each year, second only to the common cold. Degeneration of intervertebral discs (IVDs) is considered to be the major cause of back pain, yet despite decades of efforts focused around treatment of disc degeneration, the predominant treatment option continues to be symptomatic care. Moreover, the mechanisms underlying degeneration are poorly lucidated. Compelling evidence suggests that reactive oxygen species (ROS) plays a pivotal role in disc degeneration. In disc tissues, oxidative stress may initiate or participate in matrix destruction and cell apoptosis that ultimately result in disc degeneration. Fullerol nanoparticles have been demonstrated outstanding ability to scavenge ROS. The goal of this study is to investigate the role of its antioxidative and anti-inflammatory in preventing and antagonizing disc degeneration. Materials and Methods Fullerol, a water soluble fullerene derivative, was characterized with UV-Vis spectrometry, dynamic light scattering, and zeta-potential analyses. The scavenging efficiencies against superoxide anions, hydroxyl radicals, and nitric oxide were determined by the pyrogallol auto-oxidation, Fenton-type reaction, and Griess reaction, respectively. For in vitro cellular experiments, a pro-oxidant H2O2 or an inflammatory cytokine interleukin (IL)-1β was employed to induce degenerated phenotypes in human nucleus pulposus (NP) cells encapsulated in alginate beads, and the effects of fullerol on matrix, ROS, and cell viability were assessed with real-time reverse-transcriptase polymerase chain reaction (RT-PCR), biochemistry, and immunofluorescence microscopy. In the animal study, an annulus degeneration model was induced with needle puncture method, and then 25 μL of fullerol (40 μg/mL) or phosphate-buffered saline (PBS) was injected intradiscally. The outcome was evaluated with magnetic resonance imaging (MRI), histology, and biochemistry. Results The absorption peak of fullerol suspension is 293 nm (UV-Vis spectrum), particle size is between 25 and 45 nm (dynamic light scattering), and average potential between − 40 and − 60 mV (zeta-potential analyzer). The nanofullerol suspension eliminated the radical and hydroxyl radicals in a dose-dependent manner, which is comparable to SOD and mannitol in high concentrations. Furthermore, nitric oxide was decreased by nanofullerol in a dose-dependent fashion. In alginate bead culture, H2O2 treatment significantly reduced the glycosaminoglycan content and the cellular amount of aggrecan in human NP cells. However, cotreatment with nanofullerol reversed the adverse effects of H2O2. Similar results were obtained in the case of type II collagen. While H2O2 caused a significant elevation in messenger RNA (mRNA) expression of matrix degradation enzymes MMP3, MMP9, and ADAMTS5, nanofullerol stopped the effect. The protective effects of fullerol on IL-1β-induced degeneration were also assessed in human NP cells. Human NP cells were treated with 10 ng/mL of IL-1β for up to 7 days in the presence or absence of fullerol. IL-1β caused an increase in nitric oxide secretion at day 3, as well as a decrease in cellular proteoglycan content at both day 3 and day 7. Fullerol elicited a significant counteraction against the IL-1b. Gene expression analysis by real-time RT-PCR showed that IL-1β induced a robust decrease in mRNA levels of aggrecan, type I and II collagens at day 7. Cotreatment with fullerol rescued the decreased mRNA expression of aggrecan and type II collagen but not type I. In addition, with nanofullerol itself, the expression of type II collagen was significantly upregulated. In the in vivo study, the anterior surfaces of rabbit lumbar IVDs were exposed under general anesthesia. Selected discs were punctured with an 18G needle and 25 µL of a nanofullerene suspension, or PBS, injected into the disc. The images from a morphological study and the X-ray and MRI scans showed that discs that were punctured and then injected with PBS showed a blurred annulus fibrosus (AF)/NP junction, narrowed disc space and a lower T2-weighted MRI signal, which indicated disc degeneration. However, discs punctured and then treated with fullerene showed a distinct AF/NP junction, improved disc height and strong T2-weighted MRI signals. Conclusion This study presented both in vitro and in vivo evidences supporting that the potent antioxidant fullerol rescues disc degeneration, which could be a novel therapeutic remedy for disc degeneration. Disclosure of Interest None declared

Synthesis of a cluster-forming sialylthio-d-galactose fullerene conjugate and evaluation of its interaction with influenza virus hemagglutinin and neuraminidase

In order to obtain self assembling, multivalent ligand for influenza virus hemagglutinin α-N-acetylneuraminyl-(2-6)-d-galactopyranose has been synthesized and bonded to a water soluble fullerene derivative using 1,3-dipolar cycloaddition click reaction. The aggregating amphiphilic compound did not inhibit the influenza virus hemagglutinin, but it proved to be an inhibitor of its neuraminidase with a 50% inhibitory concentration of 81μM.

Synthesis of Water-Soluble Cyclen-Functionalised Fullerene C60 Derivatives

The fullerene family has interesting photophysical, electrochemical and mechanical properties with applications in organic solar cells, nanotechnology, superconductivity, chemosensors and biomedicine. Water-soluble cyclen-functionalised fullerene derivatives cyclen-C60-1 and bis(cyclen)-C60-2 have been synthesised. The whole synthetic routes are simple and the total yields are relatively high.

Simple Synthetic Method Toward Solid Supported C60 Visible Light-Activated Photocatalysts

Solid supported fullerene materials are prepared in aims of creating a fullerene-based photocatalyst that is capable of producing (1)O2 in the aqueous phase. Past studies of using fullerene as a photocatalyst in water have exclusively focused on using water soluble fullerene derivatives and employed sophisticated chemistry to create immobilized fullerene materials. The method presented herein is much less synthetically complex and utilizes pristine fullerene, providing a drastically simpler route to supported fullerene materials and furthering their potential for use in environmental applications. Covalent immobilization was achieved through the nucleophilic addition of a terminal amine (located on a solid support) across a [6,6] fullerene double bond, resulting in attachment directly to C60's cage. Immobilization allowed supported fullerene moieties to produce (1)O2 in water under various illumination conditions and inactivate MS2 bacteriophages. In a water with natural organic matter, supported fullerene materials produced (1)O2 under visible light irradiation without exhibiting significant loss of photocatalytic activity after successive cycling.