Charge-compensated nido-carborane derivatives in the synthesis of iron(II) bis(dicarbollide) complexes.

A series of stable iron(II) bis(dicarbollide) derivatives [8,8'-(RNHC(Et)HN)2-3,3'-Fe(1,2-C2B9H10)2] (R = Pr, R = Ph, (CH2)2OH, (CH2)3OH, (CH2)2NMe2) was prepared starting from FeCl2 or [FeCl2(dppe)] and the corresponding nido-carboranyl amidines [10-RNHC(Et)HN-7,8-C2B9H11]. In a similar way, the reactions of the oxonium derivatives of nido-carborane with FeCl2 in tetrahydrofuran in the presence of t-BuOK lead to the corresponding stable oxonium derivatives iron(II) bis(dicarbollide) [8,8'-(RR'O)2-3,3'-Fe(1,2-C2B9H10)2] (RR' = (CH2)4, (CH2)2O(CH2)2, (CH2)5; R = R' = Et), which can be alternatively prepared by the reaction of the parent iron(II) bis(dicarbollide) with tetrahydrofuran or 1,4-dioxane in the presence of Me2SO4. The cyclic voltammetry studies of the synthesized iron(II) bis(dicarbollide) derivatives revealed that the introduction of amidinium and oxonium substituents leads to a significant increase in the Fe2+/Fe3+ redox potential relative to the parent iron(II) bis(dicarbollide). The redox potentials of the oxonium derivatives are close to the redox potential of ferrocene and somewhat lower than redox potentials of sulfonium and phosphonium derivatives of iron(II) bis(dicarbollide).

Development of a Gadolinium-Boron-Conjugated Albumin for MRI-Guided Neutron Capture Therapy.

Noninvasive monitoring of boron agent biodistribution is required in advance of neutron capture therapy. In this study, we developed a gadolinium-boron-conjugated albumin (Gd-MID-BSA) for MRI-guided neutron capture therapy. Gd-MID-BSA was prepared by labeling bovine serum albumin with a maleimide-functionalized gadolinium complex and a maleimide-functionalized closo-dodecaborate orthogonally. The accumulation of Gd-MID-BSA in tumors in CT26 tumor-bearing mice reached a maximum at 24 h after the injection, as confirmed by T1-based MRI and biodistribution analysis using inductively coupled plasma optical emission spectrometry. The concentrations of boron and gadolinium in the tumors exceeded the thresholds required for boron neutron capture therapy (BNCT) and gadolinium neutron capture therapy (GdNCT), respectively. The boron concentration ratios of tumor to blood and tumor to normal tissues satisfied the clinical criteria, indicating the reduction of undesired nuclear reactions of endogenous nuclei. The molar ratio of boron to gadolinium in the tumor was close to that of Gd-MID-BSA, demonstrating that the accumulation of Gd-MID-BSA in the tumor can be evaluated by MRI. Thermal neutron irradiation with Gd-MID-BSA resulted in significant suppression of tumor growth compared to the group injected with a boron-conjugated albumin without gadolinium (MID-BSA). The neutron irradiation with Gd-MID-BSA did not cause apparent side effects. These results demonstrate that the conjugation of gadolinium and boron within the albumin molecule offers a novel strategy for enhancing the therapeutic effect of BNCT and the potential of MRI-guided neutron capture therapy as a promising treatment for malignant tumors.

Nickel(II) and Palladium(II) Complexes with η5:κ1(N)-Coordinated Dicarbollide Ligands Containing Pendant Pyridine Group.

A series of C- and B-substituted nido-carborane derivatives with a pendant pyridyl group was prepared. The synthesized compounds were used as ligands in the complexation reactions with bis(triphenylphosphine)nickel(II) and palladium(II) chlorides to give six new metallacomplexes with unusual η5:κ1(N)-coordination of the metal center. The single crystal structures of 1-(NC5H4-2'-S)-1,2-C2B10H11, 1-(NC5H4-2'-CH2S)-1,2-C2B10H11, Cs [7-(NC5H4-2'-CH2S)-7,8-C2B9H11] closo- and nido-carboranes and 3-Ph3P-3-(4(7)-NC5H4-2'-S)-closo-3,1,2-NiC2B9H10 and 3-Ph3P-3-(4(7)-NC5H4-2'-CH2S)-closo-3,1,2-NiC2B9H10 metallacarboranes were determined using single crystal X-ray diffraction.

Decaborane: From Alfred Stock and Rocket Fuel Projects to Nowadays.

The review covers more than a century of decaborane chemistry from the first synthesis by Alfred Stock to the present day. The main attention is paid to the reactions of the substitution of hydrogen atoms by various atoms and groups with the formation of exo-polyhedral boron-halogen, boron-oxygen, boron-sulfur, boron-nitrogen, boron-phosphorus, and boron-carbon bonds. Particular attention is paid to the chemistry of conjucto-borane anti-[B18H22], whose structure is formed by two decaborane moieties with a common edge, the chemistry of which has been intensively developed in the last decade.

Composites and Materials Prepared from Boron Cluster Anions and Carboranes.

Here, we present composites and materials that can be prepared starting with boron hydride cluster compounds (decaborane, decahydro-closo-decaborate and dodecahydro-closo-dodecaborate anions and carboranes). Recent examples of their utilization as boron protective coatings including using them to synthesize boron carbide, boron nitride, metal borides, metal-containing composites, and neutron shielding materials are discussed. The data are generalized demonstrate the versatile application of materials based on boron cluster anions and carboranes in various fields.

New Boron Containing Acridines: Synthesis and Preliminary Biological Study.

The synthesis of the first conjugates of acridine with cobalt bis(dicarbollide) are reported. A novel 9-azido derivative of acridine was prepared through the reaction of 9-methoxyacridine with N3CH2CH2NH2, and its solid-state molecular structure was determined via single-crystal X-ray diffraction. The azidoacridine was used in a copper (I)-catalyzed azide-alkyne cycloaddition reaction with cobalt bis(dicarbollide)-based terminal alkynes to give the target 1,2,3-triazoles. DNA interaction studies via absorbance spectroscopy showed the weak binding of the obtained conjugates with DNA. The antiproliferative activity (IC50) of the boronated conjugates against a series of human cell lines was evaluated through an MTT assay. The results suggested that acridine derivatives of cobalt bis(dicarbollide) might serve as a novel scaffold for the future development of new agents for boron neutron capture therapy (BNCT).

How the Position of Substitution Affects Intermolecular Bonding in Halogen Derivatives of Carboranes: Crystal Structures of 1,2,3- and 8,9,12-Triiodo- and 8,9,12-Tribromo ortho-Carboranes.

The crystal structures of two isomeric triiodo derivatives of ortho-carborane containing substituents in the three most electron-withdrawing positions of the carborane cage, 1,2,3-I3-1,2-C2B10H9, and the three most electron-donating positions, 8,9,12-I3-1,2-C2B10H9, as well as the crystal structure of 8,9,12-Br3-1,2-C2B10H9, were determined by single-crystal X-ray diffraction. In the structure of 1,2,3-I3-1,2-C2B10H9, an iodine atom attached to the boron atom (position 3) donates its lone pairs simultaneously to the σ-holes of both iodine atoms attached to the carbon atoms (positions 1 and 2) with the I⋯I distance of 3.554(2) Å and the C-I⋯I and B-I⋯I angles of 169.2(2)° and 92.2(2)°, respectively. The structure is additionally stabilized by a few B-H⋯I-shortened contacts. In the structure of 8,9,12-I3-1,2-C2B10H9, the I⋯I contacts of type II are very weak (the I⋯I distance is 4.268(4) Å, the B8-I8⋯I12 and B12-I12⋯I8 angles are 130.2(3)° and 92.2(3)°) and can only be regarded as dihalogen bonds formally. In comparison with the latter, the structure of 8,9,12-Br3-1,2-C2B10H9 demonstrates both similarities and differences. No Br⋯Br contacts of type II are observed, while there are two Br⋯Br halogen bonds of type I.

New approaches to the functionalization of the 1-carba-closo-decaborate anion.

Two new approaches to the functionalization of the 1-carba-closo-decaborate anion [1-CB9H10]- at boron atoms via the ring-opening of its 1,4-dioxane derivative with various nucleophiles and Pd-catalysed cross-coupling of its iodo derivative with aromatic amines and heteroaromatics were developed.

Synthesis of 3-Aryl-ortho-carboranes with Sensitive Functional Groups.

A simple and efficient method was developed for the one-pot synthesis of 3-aryl derivatives of ortho-carborane with sensitive functional groups using 3-iodo-ortho-carborane and aryl zinc bromides that were generated in situ. A series of 3-aryl-ortho-carboranes, including those containing nitrile and ester groups, 3-RC6H4-1,2-C2B10H11 (R = p-Me, p-NMe2, p-OCH2OMe, p-OMe, o-CN, p-CN, o-COOEt, m-COOEt, p-COOEt) was synthesized using this approach. The solid-state structures of 3-RC6H4-1,2-C2B10H11 (R = p-OMe, o-CN, and p-CN) were determined by single crystal X-ray diffraction. The intramolecular hydrogen bonding involving the ortho-substituents of the aryl ring and the CH and BH groups of carborane was discussed.

Synthesis of Boronated Amidines by Addition of Amines to Nitrilium Derivative of Cobalt Bis(Dicarbollide).

A series of novel cobalt bis(dicarbollide) based amidines were synthesized by the nucleophilic addition of primary and secondary amines to highly activated B-N+≡C-R triple bond of the propionitrilium derivative [8-EtC≡N-3,3'-Co(1,2-C2B9H10)(1',2'-C2B9H11)]. The reactions with primary amines result in the formation of mixtures of E and Z isomers of amidines, whereas the reactions with secondary amines lead selectively to the E-isomers. The crystal molecular structures of E-[8-EtC(NMe2)=HN-3,3'-Co(1,2-C2B9H10)(1',2'-C2B9H11)], E-[8-EtC(NEt2)=HN-3,3'-Co(1,2- C2B9H10)(1',2'-C2B9H11)] and E-[8-EtC(NC5H10)=HN-3,3'-Co(1,2-C2B9H10)(1',2'-C2B9H11)] were determined by single crystal X-ray diffraction.

Synthesis and crystal structures of nickel(ii) and palladium(ii) complexes with o-carboranyl amidine ligands.

A number of new nido-carboranyl amidines 10-R(CH2)nNHC(Et)[double bond, length as m-dash]HN-7,8-C2B9H11 (n = 2, R = OH, OMe, and NMe2; n = 3, R = OH) were synthesized by the nucleophilic addition of amino alcohols and N,N-dimethylethylenediamine to the highly activated -C[triple bond, length as m-dash]N+- triple bond of the 10-propionitrilium derivative of nido-carborane. A similar reaction of 10-EtC[triple bond, length as m-dash]N-7,8-C2B9H11 with ethylenediamine unexpectedly resulted in the cleavage of the C[triple bond, length as m-dash]N bond to form the ammonium derivative 10-H3N-7,8-C2B9H11. The complexation of the synthesized carboranyl amidines 10-MeO(CH2)2NHC(Et)[double bond, length as m-dash]HN-7,8-C2B9H11 and 10-Me2N(CH2)2NHC(Et)[double bond, length as m-dash]HN-7,8-C2B9H11 with nickel and palladium phosphine complexes [(Ph3P)2MCl2] (M = Ni, Pd) was studied. The reactions with 10-MeO(CH2)2NHC(Et)[double bond, length as m-dash]HN-7,8-C2B9H11 result in half-sandwiched metallacarborane complexes with the retention of one triphenylphosphine ligand [3-Ph3P-3-(8-MeOCH2CH2N[double bond, length as m-dash]C(Et)NH)-3,1,2-MC2B9H10], while the reactions with 10-Me2N(CH2)2NHC(Et)[double bond, length as m-dash]HN-7,8-C2B9H11 proceed with the complete loss of the phosphine ligands and lead to the formation of complexes with the η5:κ2(N,N')-coordinated carboranyl amidine ligand [3,3-(8-Me2NCH2CH2N[double bond, length as m-dash]C(Et)NH)-3,1,2-MC2B9H10]. The crystal molecular structures of the synthesized complexes were determined by single crystal X-ray diffraction.

Synthesis of Bis(Carboranyl)amides 1,1'-µ-(CH2NH(O)C(CH2)n-1,2-C2B10H11)2 (n = 0, 1) and Attempt of Synthesis of Gadolinium Bis(Dicarbollide).

Bis(carboranyl)amides 1,1'-µ-(CH2NH(O)C(CH2)n-1,2-C2B10H11)2 (n = 0, 1) were prepared by the reactions of the corresponding carboranyl acyl chlorides with ethylenediamine. Crystal molecular structure of 1,1'-µ-(CH2NH(O)C-1,2-C2B10H11)2 was determined by single crystal X-ray diffraction. Treatment of bis(carboranyl)amides 1,1'-µ-(CH2NH(O)C(CH2)n-1,2-C2B10H11)2 with ammonium or cesium fluoride results in partial deboronation of the ortho-carborane cages to the nido-carborane ones with formation of [7,7'(8')-µ-(CH2NH(O)C(CH2)n-7,8-C2B9H11)2]2-. The attempted reaction of [7,7'(8')-µ-(CH2NH(O)CCH2-7,8-C2B9H11)2]2- with GdCl3 in 1,2-dimethoxy- ethane did not give the expected metallacarborane. The stability of different conformations of Gd-containing metallacarboranes has been estimated by quantum-chemical calculations using [3,3-µ-DME-3,3'-Gd(1,2-C2B9H11)2]- as a model. It was found that in the most stable conformation the CH groups of the dicarbollide ligands are in anti,anti-orientation with respect to the DME ligand, while any rotation of the dicarbollide ligand reduces the stability of the system. This makes it possible to rationalize the design of carborane ligands for the synthesis of gadolinium metallacarboranes on their base.

The unexpected reactivity of 9-iodo-nido-carborane: from nucleophilic substitution reactions to the synthesis of tricobalt tris(dicarbollide) Na[4,4',4''-(MeOCH2CH2O)3-3,3',3''-Co3(µ3-O)(µ3-S)(1,2-C2B9H10)3].

An unusual reactivity of 9-iodo-nido-carborane [9-I-7,8-C2B9H11]- towards nucleophiles under strong basic conditions was revealed. The nucleophilic substitution of iodine with O- and N-nucleophiles results in [9-RO-7,8-C2B9H11]- (R = H, CH2CH2OMe) and [9-L-7,8-C2B9H11] (L = Py, NEt3, Me2NCH2CH2NMe2), respectively. Reaction of [9-I-7,8-C2B9H11]- with CoCl2 in 1,2-dimethoxyethane in the presence of t-BuOK, depending on the order of addition of the reagents, leads either to a diastereomeric mixture of diiodo derivatives cobalt bis(dicarbollide) rac-[4,4'-I2-3,3'-Co(1,2-C2B9H10)2]- and meso-[4,7'-I2-3,3'-Co(1,2-C2B9H10)2]- or to the corresponding mixture of 2-methoxyethoxy derivatives rac-[4,4'-(MeOCH2CH2O)2-3,3'-Co(1,2-C2B9H10)2]- and meso-[4,7'-(MeOCH2CH2O)2-3,3'-Co(1,2-C2B9H10)2]-. In the presence of accidental admixture of sodium thiosulfate, the reactions of 9-iodo-nido-carborane and 9-(2'-methoxyethoxy)-nido-carborane with CoCl2 in 1,2-dimethoxyethane were found to produce additionally unprecedented tricobalt tris(dicarbollide) cluster Na[4,4',4''-(MeOCH2CH2O)3-3,3',3''-Co3(µ3-O)(µ3-S)(1,2-C2B9H10)3], the central fragment of which is a trigonal bipyramid with apical oxygen and sulfur atoms, and the base is formed by the Co3 triangle flanked by three dicarbollide ligands. In addition, the 2-methoxyethoxy substituents of the dicarbollide ligands chelate the sodium cation in such a way that they form a helix whose rotation direction depends on the enantiomer of the parent ligand. Thus, in this case, induction of the helical chirality of the complex occurs due to the point chirality of the initial inorganic ligand. It is worth noting that in the case of symmetrically substituted 2-methoxyethoxy derivative of nido-carborane [10-MeOCH2CH2O-7,8-C2B9H11]- only formation of the corresponding cobalt bis(dicarbollide) complex [8,8'-(MeOCH2CH2O)2-3,3'-Co(1,2-C2B9H10)2]- was observed.

Effects of Linkers on the Development of Liposomal Formulation of Cholesterol Conjugated Cobalt Bis(dicarbollides).

Boron neutron capture therapy (BNCT) remains an important treatment arm for cancer patients with locally invasive malignant tumors. This therapy needs a significant amount of boron to deposit in cancer tissues selectively, sparing other healthy organs. Most of the liposomes contain water-soluble polyhedral boron salts stay in the core of the liposomes and have low encapsulation efficiency. Thus, modifying the polyhedral boron core to make it hydrophobic and incorporating those into the lipid layer could be one of the ways to increase drug loading and encapsulation efficiency. Additionally, a systematic study about the linker-dependent effect on drug encapsulation and drug-release is lacking, particularly for the liposomal formulation of hydrophobic-drugs. To achieve these goals, liposomal formulations of a series of lipid functionalized cobalt bis(dicarbollide) compounds have been prepared, with the linkers of different hydrophobicity. Hydrophobicity of the linkers have been evaluated through logP calculation and its effect on drug encapsulation and release have been investigated. The liposomes have shown high drug loading, excellent encapsulation efficiency, stability, and non-toxic behavior. Release experiment showed minimal release of drug from liposomes in phosphate buffer, ensuring some amount of drug, associated with liposomes, can be available to tumor tissues for Boron Neutron Capture Therapy.

The First Nickelacarborane with closo-nido Structure.

The first nickelacarborane with closo-nido structure [10',11'-(Py)2-3,9'-Ni(1,2-C2B9H11)(7',8'-C2B8H8)] was isolated from the reaction of nickel(IV) bis(dicarbollide) with pyridine. The molecular structure of this complex was determined by single crystal X-ray diffraction. The nickel atom is a common vertex for the closo-NiC2B9 cluster and the nido-NC2B8 cluster where it is located together with carbon atoms in the open NiC2B2 pentagonal face. It is assumed that its formation proceeds through the nucleophile-induced removal of the B(6)H vertex followed by rearrangement of the forming 11-vertex cluster, which most likely proceeds through a sequence of closing and opening reactions.

Bis(dicarbollide) Complexes of Transition Metals as a Platform for Molecular Switches. Study of Complexation of 8,8'-Bis(methylsulfanyl) Derivatives of Cobalt and Iron Bis(dicarbollides).

Complexation of the 8,8'-bis(methylsulfanyl) derivatives of cobalt and iron bis(dicarbollides) [8,8'-(MeS)2-3,3'-M(1,2-C2B9H10)2]- (M = Co, Fe) with copper, silver, palladium and rhodium leads to the formation of the corresponding chelate complexes, which is accompanied by a transition from the transoid to the cisoid conformation of the bis(dicarbollide) complex. This transition is reversible and can be used in design of coordination-driven molecular switches based on transition metal bis(dicarbollide) complexes. The solid-state structures of {(Ph3P)ClPd[8,8'- (MeS)2-3,3'-Co(1,2-C2B9H10)2-κ2-S,S']} and {(COD)Rh[8,8'-(MeS)2-3,3'-Co(1,2-C2B9H10)2-κ2-S,S']} were determined by single crystal X-ray diffraction.

Boron-Containing Lipids and Liposomes: New Conjugates of Cholesterol with Polyhedral Boron Hydrides.

A series of boron-containing lipids were prepared by reactions of cyclic oxonium derivatives of polyhedron boranes and metallacarboranes (closo-dodecaborate anion, cobalt and iron bis(dicarbollides)) with amine and carboxylic acids which are derived from cholesterol. Stable liposomal formulations, on the basis of synthesized boron-containing lipids, hydrogenated soybean l-α-phosphatidylcholine and (HSPC) 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG) as excipients, were prepared and then characterized by dynamic light scattering (DLS) that revealed the formation of particles to be smaller than 200 nm in diameter. The resulting liposomal formulations showed moderate to excellent loading and entrapment efficiency, thus justifying the design of the compounds to fit in the lipid bilayer and ensuring ease of in vivo use for future application. The liposomal formulations based on cobalt and iron bis(dicarbollide)-based lipids were found to be nontoxic against both human breast normal epithelial cells MCF-10A and human breast cancer cells MCF-7.

Conjugate of chlorin е6 with iron bis(dicarbollide) nanocluster: synthesis and biological properties.

Background: Efficiency of both photodynamic and boron-neutron capture anticancer therapies (BNCT) depends on the properties of the used photo- and neutronsensitizer. We report on the synthesis and properties of the advanced photo- and neutronsensitizer designed as a conjugate of chlorin e6 with iron bis(dicarbollide) nanocluster. Results: The conjugate is shown to accumulate efficiently in rat glioblastoma C6 cells delivering >109 boron atoms per cell and thus meeting requirements for BNCT agents, to provide photoinduced 50% death of C6 cells at 35 ± 3 nM, to be not toxic for cells without activating stimulus. Conclusions: The conjugate is a prospective theranostic agent for photodynamic, BNCT and fluorescent diagnostics of tumors.

Synthesis and study of C-substituted methylthio derivatives of cobalt bis(dicarbollide).

The C-methylthio derivatives of cobalt bis(dicarbollide) were synthesized by reaction of anhydrous CoCl2 with nido-carborane [7-MeS-7,8-C2B9H11]- and isolated as a mixture of rac-[1,1'-(MeS)2-3,3'-Co(1,2-C2B9H10)2]- and meso-[1,2'-(MeS)2-3,3'-Co(1,2-C2B9H10)2]- isomers. The structures of both isomers were studied using DFT quantum chemical calculations. The most preferable geometry of rotamers and the stabilization energy of C-methylthio derivatives of cobalt bis(dicarbolide) were calculated. The (BEDT-TTF)[1,1'-(MeS)2-3,3'-Co(1,2-C2B9H10)2] salt was prepared and its structure was determined by single crystal X-ray diffraction. The cisoid conformation of the rac-[1,1'-(MeS)2-3,3'-Co(1,2-C2B9H10)2]- anion is stabilized by short intramolecular CH⋯S hydrogen and BH⋯S chalcogen bonds between the dicarbollide ligands, that is in good agreement with the data of quantum chemical calculations.

Synthesis and Structure of Methylsulfanyl Derivatives of Nickel Bis(Dicarbollide).

Symmetrically and unsymmetrically substituted methylsulfanyl derivatives of nickel(III) bis(dicarbollide) (Bu4N)[8,8'-(MeS)2-3,3'-Ni(1,2-C2B9H10)2], (Bu4N)[4,4'-(MeS)2-3,3'-Ni(1,2-C2B9H10)2], and (Bu4N)[4,7'-(MeS)2-3,3'-Ni(1,2-C2B9H10)2] were synthesized, starting from [Ni(acac)2]3 and the corresponding methylsulfanyl derivatives of nido-carborane (Bu4N)[10-MeS-7,8-C2B9H11] and (Bu4N)[10-MeS-7,8-C2B9H11]. Structures of the synthesized metallacarboranes were studied by single-crystal X-ray diffraction and quantum chemical calculations. The symmetrically substituted 8,8'-isomer adopts transoid conformation stabilized by two pairs of intramolecular C-H···S hydrogen bonds between the dicarbollide ligands. The unsymmetrically substituted 4,7'-isomer adopts gauche conformation, which is stabilized by two nonequivalent C-H···S hydrogen bonds and one short chalcogen B-H···S bond (2.53 Å, -1.4 kcal/mol). The gauche conformation was found to be also preferred for the 4,7'-isomer.