Synthesis and in vivo study of metallofullerene based MRI contrast agent

Gd@C₈₂(OH)₄₀ has been developed as a new generation of MRI contrast agent. But recently, it was found that Gd@C₈₂(OH) _x with a larger number of OH (x>36) would lead to cage break and hence, release of highly toxic Gd ions. We synthesized the more stable Gd@C₈₂(OH) _x with less OH-number, Gd@C₈₂(OH)₁₆, and studied its proton relaxivity and MRI images. The results indicate that Gd@C₈₂(OH)₁₆ also gives high proton relaxivity, even higher than that of (NMG)₂-Gd-DTPA. The bio-distribution indicated that Gd@C₈₂(OH)₁₆ tends to be entrapped in the liver and kidney and remained in tissue for about 2 hours. The results suggest that the more stable metallofullerene derivative Gd@C₈₂(OH)₁₆ can be the potential candidate of the new MRI contrast agent.     

Metallofullerenol Inhibits Cellular Iron Uptake by Inducing Transferrin Tetramerization

Herein, A549 tumor cell proliferation was confirmed to be positively dependent on the concentration of Fe³⁺ or transferrin (Tf). Gd@C₈₂(OH)₂₂ or C₆₀(OH)₂₂ effectively inhibited the iron uptake and the subsequent proliferation of A549 cells. The conformational changes of Tf mixed with FeCl₃, GdCl₃, C₆₀(OH)₂₂ or Gd@C₈₂(OH)₂₂ were obtained by SAXS. The results demonstrate that Tf homodimers can be decomposed into monomers in the presence of FeCl₃, GdCl₃ or C₆₀(OH)₂₂, but associated into tetramers in the presence of Gd@C₈₂(OH)₂₂. The larger change of SAXS shapes between Tf+C₆₀(OH)₂₂ and Tf+FeCl₃ implies that C₆₀(OH)₂₂ is bound to Tf, blocking the iron‐binding site. The larger deviation of the SAXS shape from a possible crystal structure of Tf tetramer implies that Gd@C₈₂(OH)₂₂ is bound to the Tf tetramer, thus disturbing iron transport. This study well explains the inhibition mechanism of Gd@C₈₂(OH)₂₂ and C₆₀(OH)₂₂ on the iron uptake and the proliferation of A549 tumor cells and highlights the specific interactions of a nanomedicine with the target biomolecules in cancer therapy.     

Voltammetric Behavior of Water‐Soluble Endohedral Metallofullerene Derivatives

Voltammetric behavior of water‐soluble endohedral metallofullerene derivatives Gd@C₈₂(OH)₅(NHCH₂COOH)₉ (GN) and Gd@C₈₂(OH)₆(NHCH₂CH₂SO₃H)₈ (GS) was characterized in 0.1 M KCl solution by CV and DPV. They showed similar redox behavior, that is, a reversible electroreduction process on HMDE was found; in the mean time, an irreversible oxidation process and an irreversible reduction process on GC electrodes were also observed. The results reveal that these two water‐soluble endohedral metallofullerene derivatives have good electron donating ability and poor electron accepting ability due to hydroxy groups, aminoacetic acid and aminoethyl sulfonic acid connected to the C₈₂ cage in comparison with Gd@C₈₂.     

Theoretical and Quantitative Structural Relationship Studies of Electrochemical Properties of the Nanostructures of Cis-Unsaturated Thiocrown Ethers and Their Supramolecular Complexes [X-UT-Y][M@C82] (M˭Ce,Gd)

The endohedral lanthanidofullerenes, an important type of organolanthanides, are stabilized by the delocalization of the negative charges on the cages of fullerenes. Since the discovery of these classes of carbon compounds and their unusual structures and properties of these molecules, many potential applications have been suggested. Unsaturated thiocrown ethers with cis-geometry are a group of crown ethers that, in light of the size of their cavities and their conformational restriction compared to a corresponding saturated system (1–9), demonstrate interesting properties for physicochemical studies. Endohedral lanthanidofullerenes M@C_x (x = 82 and M = Ce, Gd) were introduced as a new class of the spherical fullerene group with unique properties. Formation of endohedral metallofullerenes is thought to involve the transfer of electrons from the encapsulated metal atom(s) to the surrounding fullerene cage. Two of these molecules are the Ce@C₈₂ (10) and Gd@C₈₂ (11). The supramolecular complexes of 1–9 with Ce@C₈₂ (10) and Gd@C₈₂ (11) have been shown to possess a host–guest interaction for electron transfer processes, and these behaviors have previously been reported. Topological indices have been successfully used to construct effective and useful mathematical methods for finding good relationships between structural data and the various chemical and physical properties. To establish a good structural relationship between the structures of 1–9 and M@C_x that were introduced here, an index that is represented as μ_cs was utilized. This index is the ratio of summation of the number of carbon atoms (n_c ) and the number of sulfur atoms (n_s ) to the product of these two numbers for 1–9. In this study, the relationship between this index and oxidation potential ( ^oxE₁ ) of 1–9, as well as the free energy of electron transfer (ΔG_et , by the Rehm-Weller equation) between 1–9 and 10 and 11 as [X-UT-Y][Ce@C₈₂] (12) and [X-UT-Y][Gd@C₈₂] (13) complexes, is presented.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Quantitative analysis of Gd@C<Subscript>82</Subscript>(OH)<Subscript>22</Subscript> and cisplatin uptake in single cells by inductively coupled plasma mass spectrometry

Cisplatin is a commonly used chemotherapeutic drug in cancer treatment, whereas Gd@C₈₂(OH)₂₂ is a new nanomaterial anti-tumor agent. In this study, we determined intracellular Gd@C₈₂(OH)₂₂ and cisplatin after treatment of Hela and 16HBE cells by single cell inductively coupled plasma-mass spectrometry (SC-ICP-MS), which could provide quantitative information at a single-cell level. The cell digestion method validated the accuracy of the SC-ICP-MS. The concentrations of Gd@C₈₂(OH)₂₂ and cisplatin in cells at different exposure times and doses were studied. The SC-ICP-MS is a promising complement to available methods for single cell analysis and is anticipated to be applied further to biomedical research.

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Graphical Abstract The quantitative results of Gd@C₈₂(OH)₂₂ in single cells determined by SC-ICP-MS and acid digestion method, respectively

     

Electrochemical Survey: The Effect of the Cage Size and Structure on the Electronic Structures of a Series of Ytterbium Metallofullerenes

The electrochemical properties of a series of metallofullerenes with different cages, namely, Yb@C₇₄(II), Yb@C₇₆(I, II), Yb@C₇₈, Yb@C₈₀, Yb@C₈₂(I, II, III), and Yb@C₈₄(II, III, IV), have been systematically investigated by cyclic and differential pulse voltammetry experiments for the first time. This article discusses the electronic structures of these metallofullerenes based on the results from these experiments. From previous electrochemical work and the above discussion, it is concluded that the nondegenerate LUMO is a common characteristic of the electronic structures of the higher fullerenes and monometallofullerenes. In addition, the effect of the cage on the electronic structure and properties of the metallofullerene is estimated from the plot of the reduction potential versus the carbon number of the metallofullerene. This estimation shows that usually the electronic structure and properties of the metallofullerene vary with cage size and structure. The cage structure is of particular importance for determining the electronic structure and properties. Moreover, an explanation concerning the abundance and stability of C₈₂‐based trivalent monometallofullerenes is given from an electronic structural standpoint.     

Study of multihydroxylated processes of Gd@C<Subscript>82</Subscript> by ICP-MASS

The water-solubilization of metallofullerenes is important for their potential applications, but their formation processes are still not clear, and the formation yield is uncontrollable. In this paper, we quantitatively studied the water-solubilizing process of Gd@C₈₂ with hydroxylation reaction using ICP-MASS techniques. For the first time, it was found that the formation yield of the multihydroxylated Gd@C₈₂ is declined quickly with the break up of carbon cage of Gd@C₈₂ in the hydroxylated processes. The observation revealed a way to control the hydroxylation processes and increase the formation yield.     

Electrochemical properties of Gd@C82 and its anions

Cyclic voltammogram (CV) and differential pulse voltammogram (DPV) of Gd@C₈₂ were measured by using mixed solvent system and low temperature. The sixth and seventh electron transfers for Gd@C₈₂ were observed under this condition. Analysis of its electrochemical data and the changes of its UV–VIS–NIR spectrum indicated that Gd@C₈₂(n−) (n=1,3) anions had been generated by chemical method.     

Role of metal co-cations in improving CuY zeolite performance for DMC synthesis: A theoretical study

First principle calculations based on density functional theory are conducted to investigate the influence of metal cations including Mg²⁺, Ca²⁺, Sr²⁺, Ba²⁺, La (OH)²⁺ and Ce (OH)²⁺ in the small cage of zeolite on the electronic environment of adjacent active center, Cu⁺ in CuY zeolite as well as the process of CO insertion into CH₃O to form CH₃OCO for oxidative carbonylation of methanol. The study explains the theoretical reasons for the effects of metal cations on the catalytic activity of zeolites. It was found that, the presence of co-cations in the small cage can affect the electronic properties and also the catalytic activity in two ways. Firstly, the presence of co-cations, viz., Ca²⁺, Sr²⁺, Mg²⁺, Ba²⁺ and La species in small cage hinders the migration of active Cu⁺ cations from the super cage to small cage. Secondly, the co-cations greatly affect the charge transfer from zeolite framework to Cu⁺ present in the adjacent super cage, leading to the increase of the net charge and binding energy of Cu⁺. The findings can improve the CO adsorption and insertion efficiencies, and the stability of transition states, which results in the enhanced catalytic activity of corresponding zeolites.     

Crystallographic and Theoretical Investigations of Er2@C2 n (2 n=82, 84, 86): Indication of Distance-Dependent Metal–Metal Bonding Nature

Successful isolation and characterization of a series of Er-based dimetallofullerenes present valuable insights into the realm of metal–metal bonding. These species are crystallographically identified as Er₂@C_s(6)-C₈₂, Er₂@C_3v(8)-C₈₂, Er₂@C₁(12)-C₈₄, and Er₂@C_2v(9)-C₈₆, in which the structure of the C₁(12)-C₈₄ cage is unambiguously characterized for the first time by single-crystal X-ray diffraction. Interestingly, natural bond orbital analysis demonstrates that the two Er atoms in Er₂@C_s(6)-C₈₂, Er₂@C_3v(8)-C₈₂, and Er₂@C_2v(9)-C₈₆ form a two-electron-two-center Er−Er bond. However, for Er₂@C₁(12)-C₈₄, with the longest Er⋅⋅⋅Er distance, a one-electron-two-center Er−Er bond may exist. Thus, the difference in the Er⋅⋅⋅Er separation indicates distinct metal bonding natures, suggesting a distance-dependent bonding behavior for the internal dimetallic cluster. Additionally, electrochemical studies suggest that Er₂@C_82–86 are good electron donors instead of electron acceptors. Hence, this finding initiates a connection between metal–metal bonding chemistry and fullerene chemistry.     

Visible and near-IR spectroscopy of endohedral Gd@C82(C 2v ) and Ho@C82(C 2v ) metallofullerenes and their monoanions

Solutions of endohedral Gd@C₈₂(C _2v ) and Ho@C₈₂(C _2v ) metallofullerenes are studied by means of visible and near-IR spectroscopy upon their conversion from neutral to the anionic form via a redox reaction with the electron donor potassium perchlorotriphenylmethide K(18-crown-6)[C(C₆Cl₅)₃]. The concentrations of the studied solutions of endohedral Gd@C₈₂(C _2v ) and Ho@C₈₂(C _2v ) metallofullerenes in o-dichlorobenzene were determined from the spectroscopic data, and their molar extinction coefficients are calculated.

     

Synthesis,Structures, and Thermal Properties of Symmetric and Janus “Lantern Cage” Siloxanes

Symmetric and asymmetric (Janus-type) new “lantern cage” siloxanes (PhSiO_1.5)₄(Me₂SiO)₄(RSiO_1.5)₄ (R=Ph or iBu) were synthesized through reaction of all-cis-[PhSi(OSiMe₂Br)O]₄ with all-cis-[RSi(OH)O]₄ (R=Ph or iBu). These precursors were obtained by facile two or three-step reactions from commercially available compounds. The spectroscopic properties of the resulting products were fully characterized and they showed high thermal stability and sublimation without decomposition. The crystal structures clearly indicated that the internal vacancy volumes of the lantern cages are considerably larger than that of octaphenylsilsesquioxane (PhSiO_1.5)₈. DFT calculations of the lantern cage showed a distinctly different electronic state from that of octasilsesquioxane. These results suggest that lantern cage siloxanes have a characteristic “field” in the molecule.     

Inorganic–Organic Hybrid Polyoxoniobates: Polyoxoniobate Metal Complex Cage and Cage Framework

The combination of polyoxoniobates (PONbs) with 3d metal ions, azoles, and organoamines is a general synthetic procedure for making unprecedented PONb metal complex cage materials, including discrete molecular cages and extended cage frameworks. By this method, the first two PONb metal complex cages K₄@{[Cu₂₉(OH)₇(H₂O)₂(en)₈(trz)₂₁][Nb₂₄O₆₇(OH)₂(H₂O)₃]₄} and [Cu(en)₂]@{[Cu₂(en)₂(trz)₂]₆(Nb₆₈O₁₈₈)} have been made. The former exhibits a huge tetrahedral cage with more than 120 metal centers, which is the largest inorganic–organic hybrid PONb known to date. The later shows a large cubic cage, which can act as building blocks for cage‐based extended assembly to form a 3D cage framework {[Cu(en)₂]@{[Cu₂(trz)₂(en)₂]₆[H₁₀Nb₆₈O₁₈₈]}}. These materials exhibit visible‐light‐driven photocatalytic H₂ evolution activity and high vapor adsorption capacity. The results hold promise for developing both novel cage materials and largely unexplored inorganic–organic hybrid PONb chemistry.     

Isolation and Crystallographic Characterization of the Labile Isomer of Y@C82 Cocrystallized with Ni(OEP): Unprecedented Dimerization of Pristine Metallofullerenes

Although the major isomers of M@C₈₂ (namely M@C_2v(9)‐C₈₂, where M is a trivalent rare‐earth metal) have been intensively investigated, the lability of the minor isomers has meant that they have been little studied. Herein, the first isolation and crystallographic characterization of the minor Y@C₈₂ isomer, unambiguously assigned as Y@C_s(6)‐C₈₂ by cocrystallization with Ni(octaethylporphyrin), is reported. Unexpectedly, a regioselective dimerization is observed in the crystalline state of Y@C_s(6)‐C₈₂. In sharp contrast, no dimerization occurs for the major isomer Y@C_2v(9)‐C₈₂ under the same conditions, indicating a cage‐symmetry‐induced dimerization process. Further experimental and theoretical results disclose that the regioselective dimer formation is a consequence of the localization of high spin density on a special cage‐carbon atom of Y@C_s(6)‐C₈₂ which is caused by the steady displacement of the Y atom inside the C_s(6)‐C₈₂ cage.     

Endohedral gadolinium-containing metallofullerenes in the trifluoromethylation reaction

An efficient method for the synthesis of trifluoromethyl derivatives of endohedral gadolinium-containing metallofullerenes was proposed. High-purity (98–99%) trifluoromethyl derivatives Gd@C₈₂(CF₃)₅ (two isomers) and Gd₂@C₈₀(CF₃) have been synthesized for the first time. They were isolated and characterized by HPLC, MALDI-TOF mass spectrometry, and UV-Vis spectroscopy. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1457–1462, July, 2008.     

The Unanticipated Dimerization of Ce@C2v(9)‐C82 upon Co‐crystallization with Ni(octaethylporphyrin) and Comparison with Monomeric M@C2v(9)‐C82 (M = La,Sc, and Y)

We report that Ce@C_2v(9)‐C₈₂ forms a centrosymmetric dimer when co‐crystallized with Ni(OEP) (OEP = octaethylporphyrin dianion). The crystal structure of {Ce@C_2v(9)‐C₈₂}₂?2[Ni(OEP)]?4 C₆H₆ shows that a new C?C bond with a bond length of 1.605(5) Å connects the two cages. The high spin density of the singly occupied molecular orbital (SOMO) on the cage and the pyramidalization of the cage are factors that favor dimerization. In contrast, the treatment of Ni(OEP) with M@C_2v(9)‐C₈₂ (M = La, Sc, and Y) results in crystallization of monomeric endohedral fullerenes. A systematic comparison of the X‐ray structures of M@C_2v(9)‐C₈₂ (M = Sc, Y, La, Ce, Gd, Yb, and Sm) reveals that the major metal site in each case is located at an off‐center position adjacent to a hexagonal ring along the C₂ axis of the C_2v(9)‐C₈₂ cage. DFT calculations at the M06‐2X level revealed that the positions of the metal centers in these metallofullerenes M@C_2v(9)‐C₈₂ (M = Sc, Y, and Ce), as determined by single‐crystal X‐ray structure studies, correspond to an energy minimum for each compound.     

Quantum-chemical modeling of endohedral derivatives of buckminsterfullerenes Gd@C<Subscript>60</Subscript>(CHR)<Subscript>2</Subscript> and Gd@C<Subscript>80</Subscript>(CHR)<Subscript>2</Subscript>

The structural energies of the endohedral derivatives of buckminsterfullerenes Gd@C₆₀(CHR)₂ and Gd@C₈₀(CHR)₂ were calculated by quantum-chemical methods – semiempirical PM3 and nonempirical RHF SCF MO LCAO with the S. Huzinaga MINI minimum basis set and GAMESS software.     

Assembly of 1-D and decanuclear cage compounds from copper halide,cyclohexenephosphonic acid,and 3-(2-pyridyl)pyrazole

The reactions of cyclohexenephosphonic acid (C₆H₉PO₃H₂) and 3-(2-pyridyl)pyrazole (2-pyPzH) with copper(II) chloride and copper(II) bromide affords a 1-D compound [Cu(2-pyPz)Cl] (1) and a decanuclear [Cu₁₀(OH)₄(C₆H₉PO₃)₆(2-pyPz)₄] (2) cage complex. In 1, adjacent copper ions are bridged by two 2-pyPz ligands into dimers, which are further linked by Cl^? into a ladder-like chain. Compound 2 has a decanuclear cage structure, the overall cage can be viewed as composed of two Cu₄(OH)₂(2-pyPz)₂ wings that are bridged by a central Cu₂P₂O₆ rim. Variable-temperature magnetic susceptibility studies indicate that both compounds show antiferromagnetic interactions between copper centers.     

Synthesis and characterization of carbene derivatives of Th@C3v(8)-C82 and U@C2v(9)-C82: exceptional chemical properties induced by strong actinide–carbon cage interaction

Chemical functionalization of endohedral metallofullerenes (EMFs) is essential for the application of these novel carbon materials. Actinide EMFs, a new EMF family member, have presented unique molecular and electronic structures but their chemical properties remain unexplored. Here, for the first time, we report the chemical functionalization of actinide EMFs, in which the photochemical reaction of Th@C_3v(8)-C₈₂ and U@C_2v(9)-C₈₂ with 2-adamantane-2,3′-[3H]-diazirine (AdN₂, 1) was systematically investigated. The combined HPLC and MALDI-TOF analyses show that carbene addition by photochemical reaction afforded three isomers of Th@C_3v(8)-C₈₂Ad and four isomers of U@C_2v(9)-C₈₂Ad (Ad = adamantylidene), presenting notably higher reactivity than their lanthanide analogs. Among these novel EMF derivatives, Th@C_3v(8)-C₈₂Ad(I, II, III) and U@C_2v(9)-C₈₂Ad(I, II, III) were successfully isolated and were characterized by UV-vis-NIR spectroscopy. In particular, the molecular structures of first actinide fullerene derivatives, Th@C_3v(8)-C₈₂Ad(I) and U@C_2v(9)-C₈₂Ad(I), were unambiguously determined by single crystal X-ray crystallography, both of which show a [6,6]-open cage structure. In addition, isomerization of Th@C_3v(8)-C₈₂Ad(II), Th@C_3v(8)-C₈₂Ad(III), U@C_2v(9)-C₈₂Ad(II) and U@C_2v(9)-C₈₂Ad(III) was observed at room temperature. Computational studies suggest that the attached carbon atoms on the cages of both Th@C_3v(8)-C₈₂Ad(I) and U@C_2v(9)-C₈₂Ad(I) have the largest negative charges, thus facilitating the electrophilic attack. Furthermore, it reveals that, compared to their lanthanide analogs, Th@C_3v(8)-C₈₂ and U@C_2v(9)-C₈₂ have much closer metal–cage distance, increased metal-to-cage charge transfer, and strong metal–cage interactions stemming from the significant contribution of extended Th-5f and U-5f orbitals to the occupied molecular orbitals, all of which give rise to their unusual high reactivity. This study provides first insights into the exceptional chemical properties of actinide endohedral fullerenes, which pave ways for the future functionalization and application of these novel EMF compounds.

Photochemical reaction of Th@C_3v(8)-C₈₂ and U@C_2v(9)-C₈₂ with 2-adamantane-2,3′-[3H]-diazirine (AdN₂, 1) afforded three isomers of Th@C_3v(8)-C₈₂Ad and four isomers of U@C_2v(9)-C₈₂Ad (Ad = adamantylidene), respectively.     

On Structural Features Necessary for Near‐IR‐Light Photocatalysts

In the search for photocatalysts that can directly utilize near‐IR (NIR) light, we investigated three oxides Cu₃(OH)₄SO₄ (antlerite), Cu₄(OH)₆SO₄, and Cu₂(OH)₃Cl by photodecomposing 2,4‐dichlorophenol over them under NIR irradiation and by comparing their electronic structures with that of the known NIR photocatalyst Cu₂(OH)PO₄. Both Cu₃(OH)₄SO₄ and Cu₄(OH)₆SO₄ are NIR photocatalysts, but Cu₂(OH)₃Cl is not. Thus, in addition to the presence of two different CuO_m and Cu′O_n polyhedra linked with Cu?O?Cu′ bridges, the presence of acceptor groups (e.g., SO₄, PO₄) linked to the metal oxygen polyhedra is necessary for NIR photocatalysts.