Substituted carborane-appended water-soluble single-wall carbon nanotubes: new approach to boron neutron capture therapy drug delivery

Substituted C(2)B(10) carborane cages have been successfully attached to the side walls of single-wall carbon nanotubes (SWCNTs) via nitrene cycloaddition. The decapitations of these C(2)B(10) carborane cages, with the appended SWCNTs intact, were accomplished by the reaction with sodium hydroxide in refluxing ethanol. During base reflux, the three-membered ring formed by the nitrene and SWCNT was opened to produce water-soluble SWCNTs in which the side walls are functionalized by both substituted nido-C(2)B(9) carborane units and ethoxide moieties. All new compounds are characterized by EA, SEM, TEM, UV, NMR, and IR spectra and chemical analyses. Selected tissue distribution studies on one of these nanotubes, {([Na(+)][1-Me-2-((CH(2))(4)NH-)-1,2-C(2)B(9)H(10)][OEt])(n)(SWCNT)} (Va), show that the boron atoms are concentrated more in tumors cells than in blood and other organs, making it an attractive nanovehicle for the delivery of boron to tumor cells for an effective boron neutron capture therapy in the treatment of cancer.     

Modular Synthetic Approach to Carboranyl‒Biomolecules Conjugates

The development of novel, tumor-selective and boron-rich compounds as potential agents for use in boron neutron capture therapy (BNCT) represents a very important field in cancer treatment by radiation therapy. Here, we report the design and synthesis of two promising compounds that combine meta-carborane, a water-soluble monosaccharide and a linking unit, namely glycine or ethylenediamine, for facile coupling with various tumor-selective biomolecules bearing a free amino or carboxylic acid group. In this work, coupling experiments with two selected biomolecules, a coumarin derivative and folic acid, were included. The task of every component in this approach was carefully chosen: the carborane moiety supplies ten boron atoms, which is a tenfold increase in boron content compared to the l-boronophenylalanine (l-BPA) presently used in BNCT; the sugar moiety compensates for the hydrophobic character of the carborane; the linking unit, depending on the chosen biomolecule, acts as the connection between the tumor-selective component and the boron-rich moiety; and the respective tumor-selective biomolecule provides the necessary selectivity. This approach makes it possible to develop a modular and feasible strategy for the synthesis of readily obtainable boron-rich agents with optimized properties for potential applications in BNCT.     

碳十硼烷及其衍生物的反应性及应用

碳十硼烷(C₂B₁₀H₁₂)是由2个C原子和10个B原子组成的二十面体笼状结构大分子,有邻位、间位和对位三种异构体。碳十硼烷庞大的体积以及类芳香族三维刚性结构使它具有优异的高温稳定性和化学稳定性,良好的溶解性使其具有广泛而灵活的应用。本文总结了近年来碳十硼烷和碳十硼烷衍生物在C原子、B原子上的化学反应性以及在环加成和金属络合方面的研究。另外,由于碳十硼烷衍生物特殊的立体结构,优异的耐高温性、热氧化性及高硼含量,本文综述了碳十硼烷衍生物近年来在功能材料、催化剂及生物医药等多个领域的应用进展。     

Synthesis and properties of carborane-functionalized aliphatic polyester dendrimers

The incorporation of multiple p-carborane cages within an aliphatic polyester dendrimer was accomplished through the preparation of a bifunctional carborane synthon. A p-carborane derivative having an acid and a protected alcohol functionality was found to efficiently couple to peripheral hydroxyl groups of low-generation dendrimers under standard esterification conditions. Deprotection of carborane hydroxyl groups allowed for further dendronization through a divergent approach using the highly reactive anhydride of benzylidene-protected 2,2-bis(hydroxymethyl)propanoic acid. This approach was used to prepare fourth- and fifth-generation dendrimers that contain 4, 8, and 16 carborane cages within their interior. Upon peripheral deprotection to liberate a polyhydroxylated dendrimer exterior, these structures exhibited aqueous solubility as long as a minimum of eight hydroxyl groups per carborane were present. Several of the water-soluble structures were found to exhibit a lower critical solution temperature. Additionally, irradiation of these materials with thermal neutrons resulted in emission of gamma radiation that is indicative of boron neutron capture events occurring within the carborane-containing dendrimers.     

[C2B10]---[B12] double cage boron compounds—a new approach to the synthesis of water-soluble boron-rich compounds for BNCT

A new approach in the synthesis of water-soluble boron-rich compounds was proposed. The closo-dodecaborate cage is used as a hydrophilic substitutent providing for the water-solubility of the molecule whereas the carborane cage can be used for attachment to biomolecules using earlier developed methods. The double-cage molecules [o-, m-, and p-CB₁₀H₁₀C(CH₂)₄OB₁₂H₁₁]²⁻ were prepared by the reaction of the tetramethylene oxonium derivative of the closo-dodecaborate anion, [B₁₂H₁₁O(CH₂)₄]⁻, with the corresponding lithiated carboranes. The compounds obtained have doubled the boron contents and could serve for the synthesis of agents for boron neutron capture therapy (BNCT).     

MRI-guided neutron capture therapy by use of a dual gadolinium/boron agent targeted at tumour cells through upregulated low-density lipoprotein transporters

The upregulation of low-density lipoprotein (LDL) transporters in tumour cells has been exploited to deliver a sufficient amount of gadolinium/boron/ligand (Gd/B/L) probes for neutron capture therapy, a binary chemio-radiotherapy for cancer treatment. The Gd/B/L probe consists of a carborane unit (ten B atoms) bearing an aliphatic chain on one side (to bind LDL particles), and a Gd(III)/1,4,7,10-tetraazacyclododecane monoamide complex on the other (for detection by magnetic resonance imaging (MRI)). Up to 190 Gd/B/L probes were loaded per LDL particle. The uptake from tumour cells was initially assessed on cell cultures of human hepatoma (HepG2), murine melanoma (B16), and human glioblastoma (U87). The MRI assessment of the amount of Gd/B/L taken up by tumour cells was validated by inductively coupled plasma-mass-spectrometric measurements of the Gd and B content. Measurements were undertaken in vivo on mice bearing tumours in which B16 tumour cells were inoculated at the base of the neck. From the acquisition of magnetic resonance images, it was established that after 4-6 hours from the administration of the Gd/B/L-LDL particles (0.1 and 1 mmol kg(-1) of Gd and (10)B, respectively) the amount of boron taken up in the tumour region is above the threshold required for successful NCT treatment. After neutron irradiation, tumour growth was followed for 20 days by MRI. The group of treated mice showed markedly lower tumour growth with respect to the control group.     

A new strategy for molecular modeling and receptor-based design of carborane containing compounds

Difficulties associated with computer-aided molecular design (CAMD) of carborane containing molecules have hampered drug development in boron neutron capture therapy (BNCT). A new approach of modeling and docking of carborane containing molecules with the readily available software packages , and is described. This new method is intended as a guide for boron chemists interested in using CAMD of carborane containing agents for medical applications such as BNCT.     

Theoretical investigation of carboranylpyrrole structures and the thermal resistance and conducting properties of carboranylpyrrole polymers

The carboranylpyrrole polymers are functional materials with superior thermal resistance and conducting performances. The carboranylpyrrole structures and Laplacian bond order (LBO) of carborane moiety, as well as the thermal resistance and conducting properties of carboranylpyrrole dimers or polymers, were investigated theoretically. The ¹¹B NMR chemical shifts of 3-(2-methyl-o-carboranyl)alkyl-1H-pyrrole monomers (CP-1 to CP-5) were calculated and analyzed. The average LBO values of some characteristic chemical bonds in the carborane cages of CP-1 to CP-5 molecules were calculated. It is found that the average LBO values of carborane moieties change slightly with the increase in alkyl chain length. The temperature resulting in about 15–20 % weight loss for CP-1, CP-3, CP-4 and CP-5 polymers is predicted to be more than 700 °C. Apart from the C–C bonds in carborane moieties of 3-(2-R-o-carboranyl)propyl-1H-pyrrole (R = CH₂OH, CH₂OCH₃, CN, COCl, Ph) substituents, the LBO values of other bonds in these cages change slightly relative to that in the molecule of 3-(2-methyl-o-carboranyl)propyl-1H-pyrrole (CP-3). The C–C bond LBO values in the carborane cages of these substituents with electron-donating groups (R = CH₂OH, CH₂OCH₃) are bigger than that in CP-3, while those values in those substituents with electron-withdrawing groups (R = CN, COCl, Ph) are smaller than that in CP-3. The polymerization activity calculated for CP-1 to CP-5 monomers increases with the increase in alkyl chain length. The calculated orbital energy gap (?E _LUMO?HOMO) of CP-1 to CP-5 dimers decreases with the increase in alkyl chain length, and accordingly, the electronic conductivity has the potential to increase. In addition, the calculated band gaps of CP-1 to CP-5 dimers cell models also decrease with the increase in alkyl chain length.     

In silico carborane docking to proteins and potential drug targets

The presence of boron atoms has made carboranes, C(2)B(10)H(12), attractive candidates for boron neutron capture therapy. Because of their chemistry and possible conjugation with proteins, they can also be used to enhance interactions between pharmaceuticals and their targets and to increase the in vivo stability and bioavailability of compounds that are normally metabolized rapidly. Carboranes are isosteric to a rotating phenyl group, which they can substitute successfully in biologically active systems. A reverse ligand-protein docking approach was used in this work to identify binding proteins for carboranes. The screening was carried out on the drug target database PDTD that contains 1207 entries covering 841 known potential drug targets with structures taken from the Protein Data Bank. First, for validation, the protocol was applied to three crystal structures of proteins in which carborane derivatives are present. Then, the model was applied to systems for which the protein structure is available, but the binding site of carborane has not been reported. These systems were used for further validation of the protocol, while simultaneously providing new insight into the interactions between cage and protein. Finally, the screening was carried out on the database to reveal potential carborane binding targets of interest for biological and pharmacological activity. Carboranes are predicted to bind well to protease and metalloprotease enzymes. Other carborane pharmaceutical targets are also discussed, together with possible protein carriers.     

Synthesis and Characterization of a Boronated Metallophthalocyanine for Boron Neutron Capture Therapy

Synthesis of the first fully characterized, water-soluble boronated phthalocyanine is reported. Reaction of 4-nitrophthalonitrile with dimethyl malonate in the presence of base yielded dimethyl (3,4-dicyanophenyl)malonate which was converted into dimethyl (3,4-dicyanophenyl)propargylmalonate by sequential treatment with potassium hydroxide and propargyl bromide. Formation of the o-carborane cage was accomplished by reaction of the alkyne with decaborane in acetonitrile at reflux. High-temperature solid state condensation of the resulting o-carboranylphthalonitrile with cobalt(II) chloride followed by ester deprotection and cation exchange provided the water-soluble closo-carbonylphthalocyanine product. The product contains 40 boron atoms (27% boron by weight) and may be useful as a tumor-seeking boron delivery agent for boron neutron capture therapy of cancer.     

A Versatile Methodology for the Controlled Synthesis of Photoluminescent High‐Boron‐Content Dendrimers

Fluorescent star‐shaped molecules and dendrimers with a 1,3,5‐triphenylbenzene moiety as the core and 3 or 9 carborane derivatives at the periphery, have been prepared in very good yields by following different approaches. One procedure relies on the nucleophilic substitution of Br groups in 1,3,5‐tris(4‐(3‐bromopropoxy)phenyl)benzene with the monolithium salts of methyl and phenyl‐o‐carborane. The second method is the hydrosilylation reactions on the peripheral allyl ether functions of 1,3,5‐tris(4‐allyloxy‐phenyl)benzene and 1,3,5‐tris(4‐(3,4,5‐trisallyloxybenzyloxy)phenyl)benzene with suitable carboranyl‐silanes to produce different generations of dendrimers decorated with carboranyl fragments. This approach is very versatile and allows one to introduce long spacers between the fluorescent cores and the boron clusters, as well as to obtain a high loading of boron clusters. The removal of one boron atom from each cluster leads to high‐boron‐content water‐soluble macromolecules. Thermogravimetric analyses show a higher thermal stability for the three‐functionalized compounds than for those containing 9 clusters. All compounds exhibit photoluminescent properties at room temperature under ultraviolet irradiation with high quantum yields; these depend on the nature of the cluster and the substituent on the C_cluster. Cyclic voltammetry indicates that there is no electronic communication between the core and the peripheral carboranyl fragments. Due to the high boron content of these molecules, we currently focus our research on their biocompatibility, biodistribution in cells cultures, and potential applications for boron neutron capture therapy (BNCT).     

From Mono‐ to Poly‐Substituted Frameworks: A Way of Tuning the Acidic Character of Cc?H in o‐Carborane Derivatives

The incorporation of iodine atoms onto the boron vertices of the o‐carborane framework causes, according to spectroscopic data, a uniform increase in the acidic character of the C_c? H (C_c= cluster carbon) vertices, whereas the incorporation of methyl groups onto the boron vertices of the o‐carborane framework reduces their acidity. Methyl groups when attached to boron are electron‐withdrawing in boron clusters, whereas iodine atoms bonded to boron act as electron donors. This has been proven on B‐methyl and B‐iodinated o‐carboranes with NMR spectroscopy measurements and DFT calculations of natural bond orbital (NBO) charges, which show a cumulative buildup of positive cluster‐only total charge (CTC) on B‐methyl o‐carboranes and a cumulative buildup of negative cluster‐only total charge for B‐iodinated o‐carboranes.     

Synthesis of novel texaphyrins containing lanthanides and boron

Texaphyrin macrocycles that contain gadolinium or lutetium, such as motexafin gadolinium and motexafin lutetium, are versatile anticancer therapeutics and diagnostics. Gadolinium texaphyrins substituted with carborane clusters could also find application in combined gadolinium and boron neutron capture therapy (GdB-NCT). The synthesis and characterization of novel texaphyrins containing gadolinium or lutetium in the pentaaza core and two carborane clusters bound to opposite pyrrol units of the macrocycle are described.     

Synthesis, structural, spectroscopic and electrochemical studies of carborane substituted naphthyl selenides

New unsymmetrical selenides bearing an o-carborane and a naphthalene ring as the substituents were prepared by the cleavage of the corresponding diselenides. The compounds were characterized by means of spectroscopic and analytical methods. (77)Se NMR signals of the selenium atoms attached to the carbon atoms of the carborane cages are shifted downfield in comparison to those bonded only to the aromatic rings, indicating an electron withdrawing effect of the o-carboranyl substituent. Compounds 1-(2-R-1,2-dicarba-closo-carboranyl)naphthyl selenides (R = Me, 1; Ph, 2) were characterized by means of single crystal X-ray diffraction. The influence of the electronic nature of the substituents attached to the selenium atoms on the structural parameters and packing properties of naphthyl selenides are discussed. Theoretical calculations and cyclic voltammetry (CV) studies were carried out to compare the bonding nature of carboranyl and analogous aryl selenium compounds. Cyclic voltammetry studies of naphthyl carboranyl mono and diselenides have shown that the carboranyl fragment polarizes the Se lone pair making it less prone to generate a Se-Se bond.     

Pairing Heterocyclic Cations with closo-Icosahedral Borane and Carborane Anions,II: Benchtop Alternative Synthetic Methodologies for Binary Triazolium and Tetrazolium Salts with Significant Water Solubility

Two efficient processes for the synthesis of 12 relatively water-soluble binary triazolium and the first tetrazolium borane [B₁₂H₁₂] and carborane [CB₁₁H₁₂] salts by a one-step, open-air metathesis reaction have been developed. First, a combination of exhaustive trituration of the two solid reactant salts with refluxing anhydrous acetonitrile followed by flash filtration through a plug of silica gel afforded excellent recovery for a broad series of otherwise water-soluble heterocyclium salts. Second, an alternative aqueous metathesis, driven to completion by precipitation of silver halides, followed by removal of water, redissolution in acetonitrile, and filtration through a silica-gel plug, also yielded such heterocyclium borane and carborane salts. Mixed 1:1 dication heterocyclium borane salts were first synthesized using this second procedure, and one example showed melting-point depression behavior.     

Novel types of carborane-carrier hyaluronan derivatives via "click chemistry"

Two new HA derivatives bearing carborane rings were synthesized by click chemistry. The optimal conditions were assessed for the preparation of biocompatible boron carriers, potentially suitable for application in BNCT and capable of targeting the CD44 antigen. The new polymeric samples were characterized by means of NMR-spectroscopy techniques that gave degrees of 17 and 8% for HAAACB and HapACB, respectively. Both HAAACB and HApACB turned out to be nontoxic for colorectal, ovarian and bladder tumor cell lines, to disclose a specific interaction with the CD44 antigen as the native hyaluronan moiety, and to deliver boron-atom concentrations largely sufficient for BNCT therapy when accumulated in cancer cells.     

Synthesis of Periphery‐Decorated and Core‐Initiated Borane Polyanionic Macromolecules

A new class of globular polybranched macromolecules that contain multiple anionic metallacarborane clusters at the o‐carborane periphery is reported. The water soluble high boron rich containing molecules could be of interest for boron neutron capture therapy (BNCT) as well as for drug delivery. The reinforced electrostatic noncovalent interactions between anionic polyethylene glycol cobaltabisdicarbollide (PEG‐COSAN) branches and the ammonium cation have been shown using ESI‐MS.     

Synthesis of boroxifen, a nido-carborane analogue of tamoxifen.

A nido-carborane analogue of tamoxifen, the widely employed breast cancer therapy agent, was prepared as an archetype of a potential new class of antiestrogen and boron neutron capture therapy agent in which the carborane is incorporated within the framework of the parent compound. The carborane was introduced through the reaction of 6,9-bis(acetonitrile)decaborane with a unique and highly conjugated ene-yne, which was prepared stereoselectively. NMR spectroscopy and a crystal structure of a key intermediate, the carborane analogue of chloro-tamoxifen, demonstrated the structural similarities between the tamoxifen carboranes and their corresponding phenyl analogues.     

Potent estrogen agonists based on carborane as a hydrophobic skeletal structure. A new medicinal application of boron clusters

BACKGROUND: Carboranes (dicarba-closo-dodecaboranes) are a class of carbon-containing polyhedral boron-cluster compounds having remarkable thermal stability and exceptional hydrophobicity. Applications of the unique structural and chemical properties offered by icosahedral carboranes in boron neutron capture therapy have received increasing attention over the past 30 years. However, these features of carboranes may allow another application as a hydrophobic pharmacophore in biologically active molecules that interact hydrophobically with receptors. RESULTS: We have designed candidate estrogen-receptor-binding compounds having carborane as a hydrophobic skeletal structure and synthesized them. The most potent compound bearing a carborane cage exhibited activity at least 10-fold greater than that of 17beta-estradiol in the luciferase reporter gene assay. Estrogen receptor-alpha-binding data for the compound were consistent with the results of the luciferase reporter gene assay. The compound also showed potent in vivo effects on the recovery of uterine weight and bone loss in ovariectomized mice. CONCLUSION: Further development of the potent carborane-containing estrogenic agonists described here, having a new skeletal structure and unique characteristics, should yield novel therapeutic agents, especially selective estrogen receptor modulators. Furthermore, the suitability of the spherical carborane cage for binding to the cavity of the estrogen receptor-alpha ligand-binding domain should provide a basis for a similar approach to developing novel ligands for other steroid receptors.     

半夹芯16电子化合物CpCo(S_2C_2B_(10)H_(10))与乙炔基二茂铁在甲醇中的反应性

半夹芯16电子化合物CpCo(S2C2B10H10)(1)(Cp:cyclopentadienyl)与过量乙炔基二茂铁(FcC≡CH)(Fc:ferrocenyl)在甲醇中反应,分离得到了化合物(CHCFc)(CH=CFc)(S2C2B9H10)(8)和2个乙炔基二茂铁环三聚产物1,2,4-三二茂铁基苯和1,3,5-三二茂铁基苯。在8中,2个乙炔基二茂铁分子以"头对头"方式聚合连接到CpCo(S2C2B10H10)分子中的2个S原子上,导致CpCo结构单元的丢失。碳硼烷笼体B(3)位上的BH键发生活化,该B原子与1个乙炔基二茂铁分子的乙炔基末端C原子连接生成C-B键;同时,B(6)位的BH碎片在甲醇作用下失去,从而closo-C2B10闭式结构转变成nido-C2B9巢式结构。化合物8用单晶X-射线衍射分析方法进行了表征。