Histone Deacetylase 2 (HDAC2) Inhibitors Containing Boron.

Histone deacetylase enzymes (HDACs) are responsible for the global silencing of tumour-suppressor genes. Treatment with a histone deacetylase inhibitor (HDACi) can reverse this process and restore normal cell function. Herein, we report a small series of boron-based (boronic acid, boronate ester and closo-1,2-carborane) HDAC2 inhibitors with IC50 values in the nanomolar range. The boronate ester 4 b was the most potent compound assessed in this study (IC50 =40.6±1.5 nM), followed closely by the 1,2-closo-carborane (IC50 =42.9±1.5 nM). Compound 4 b exceeds the potency of the related gold-standard HDAC pan-inhibitor vorinostat (1) toward this particular HDAC isoform.

Remarkable Enhancement in Boron Uptake Within Glioblastoma Cells With Carboranyl-Indole Carboxamides.

Novel boron-rich, carboranyl-indole carboxamide ligands were prepared and found to effectively target the 18 kDa translocator protein (TSPO), an upregulated mitochondrial membrane-bound protein which has been observed in variety of tumor cell lines and its expression appears to be proportional to the degree of tumorigenicity, emphasizing a key role in cancer cell proliferation. Both boronated compounds displayed remarkably high affinities for the TSPO. In addition, the in vitro uptake of these compounds into T98G human glioma cells was found to be 25- to 100-fold greater than that of clinical boron neutron capture therapy (BNCT) agents.

Site-specific synthesis of a hybrid boron-graphene salt.

We report the first example of an ionic graphene salt containing boron. An anionic charge is introduced to the graphene surface by means of 7,8-nido-[C2B9H11](-) carborane clusters covalently and electronically bound to the graphene lattice, and this new material was isolated as its Cs(+) salt.

Syntheses and reductions of C-dimesitylboryl-1,2-dicarba-closo-dodecaboranes.

Two C-dimesitylboryl-1,2-dicarba-closo-dodecaboranes, 1-(BMes2)-2-R-1,2-C2B10H10 (1, R = H, 2, R = Ph), were synthesised by lithiation of 1,2-dicarba-closo-dodecaborane and 1-phenyl-1,2-dicarba-closo-dodecaborane, respectively, with n-butyllithium and subsequent reaction with fluorodimesitylborane. These novel compounds were structurally characterised by X-ray crystallography. Compounds 1 and 2 are hydrolysed on prolonged exposure to air to give mesitylene and boronic acids 1-(B(OH)2)-2-R-1,2-C2B10H10 (3, R = H, 4, R = Ph respectively). Addition of fluoride anions to 1 and 2 resulted in boryl-carborane bond cleavage to give dimesitylborinic acid HOBMes2. UV absorption bands at 318-333 nm were observed for 1 and 2 corresponding to local π-π*-transitions within the dimesitylboryl groups while visible emissions at 541-664 nm with Stokes shifts of 11 920-16 170 cm(-1) were attributed to intramolecular charge transfer transitions between the mesityl and cluster groups. Compound was shown by cyclic voltammetry to form a stable dianion on reduction. NMR spectra for the dianion [](2-) were recorded from solutions generated by reductions of 2 with alkali metals and compared with NMR spectra from reductions of 1,2-diphenyl-ortho-carborane 5. On the basis of observed and computed (11)B NMR shifts, these nido-dianions contain bowl-shaped cluster geometries. The carborane is viewed as the electron-acceptor and the mesityl group is the electron-donor in C-dimesitylboryl-1,2-dicarba-closo-dodecaboranes.

Carborane functionalization of the aromatic network in chemically-synthesized graphene.

The conjugated aromatic system of graphene was used to trap the reactive, boron-rich 1,2-carborane cluster. Functionalization of the graphene surface was confirmed by solid-state MAS (11)B NMR spectroscopy and quantified by X-ray photoelectron spectroscopy. This work represents the first confirmed example of direct functionalization of a graphene lattice with carboranes.

The first indoleamine-2,3-dioxygenase-1 (IDO1) inhibitors containing carborane.

Indoleamine-2,3-dioxygenase-1 (IDO1) is a critical immunoregulatory enzyme responsible for the metabolism of tryptophan during inflammation and disease. Based upon a pyranonaphthoquinone framework, the first examples of indoleamine-2,3-dioxygenase-1 (IDO1) inhibitors containing a carborane cage are reported. The novel closo-1,2-carboranyl-N-pyranonaphthoquinone derivatives display low µM binding affinity for the human recombinant enzyme, with IC50 values ranging from 0.78 to 1.77 µM.

Crystal structures of the carborane dianions [1,4-(PhCB10H10C)2C6H4]²â» and [1,4-(PhCB10H10C)2C6F4]²â» and the stabilizing role of the para-phenylene unit on 2n+3 skeletal electron clusters.

While carboranes with 2 n+2 and 2 n+4 (n=number of skeletal atoms) skeletal electrons (SE) are widely known, little has been reported on carboranes with odd SE numbers. Electrochemical measurements on two-cage assemblies, where two C-phenyl-ortho-carboranyl groups are linked by a para-phenylene or a para-tetrafluorophenylene bridge, revealed two well separated and reversible two-electron reduction waves indicating formation of stable dianions and tetraanions. The salts of the dianions were isolated by reduction with sodium metal and their unusual structures were determined by X-ray crystallography. The diamagnetic dianions contain two 2 n+3 SE clusters where each cluster has a notably long carborane C-carborane C distance of ca 2.4 Å. The π conjugation within the phenylene bridge plays an important role in the stabilization of these carboranes with odd SE counts.

C,C'-bis(benzodiazaborolyl)dicarba-closo-dodecaboranes: synthesis, structures, photophysics and electrochemistry.

Six new C,C'-bis(benzodiazaborolyl)dicarba-closo-dodecaboranes, 1,A-R2-1,A-C2B10H10, where R represents the group 2-(1,3-Et2-1,3,2-N2BC6H4) or 2-(1,3-Ph2-1,3,2-N2BC6H4) and A is 2, 7 or 12, were synthesized from o-, m-, and p-dicarbadodecaboranes (carboranes) by lithiation and subsequent treatment with the respective 2-bromo-1,3,2-benzodiazaboroles. UV-visible and fluorescence spectra of all carboranes display low energy charge transfer emissions. While such emissions with Stokes shifts between 17,330 and 21,290 cm(-1) are typical for C,C'-bis(aryl)-ortho-carboranes, the observed low-energy emissions with Stokes shifts between 8320 and 15,170 cm(-1) for the meta- and para-isomers are unusual as high-energy emissions are typical for meta- and para-dicarbadodecaboranes. Fluorescence quantum yields (φF) for the novel 1,7- and 1,12-bis(benzodiazaborolyl)-carboranes depend on the substituents at the nitrogen atoms of the heterocycle. Thus, the para-carborane with N-ethyl substituents 1,12-(1',3'-Et2-1',3',2'-N2BC6H4)2-1,12-C2B10H10 has a φF value of 41% in cyclohexane solution and only of 9% in the solid state, whereas the analogous 1,12-(1',3'-Ph2-1',3',2'-N2BC6H4)2-1,12-C2B10H10 shows quantum yields of 3% in cyclohexane solution and 72% in the solid state. X-ray crystallographic, computational and cyclic voltammetry studies for these carboranes are also presented.

The translocator protein (TSPO): a novel target for cancer chemotherapy.

The translocator protein (TSPO) is an 18 kDa transmembrane protein primarily found in the outer mitochondrial membrane where it forms a key part of the mitochondrial permeability transition pore (MPTP). Omnipresent in almost all tissues, TSPO up-regulation has been connected to neuronal damage and inflammation, making the protein an important bio-imaging marker for disease progression. More recently, TSPO has attracted attention as a possible molecular target for tumour imaging and chemotherapy. In this review we summarize TSPO's molecular characteristics and highlight research progress in recent years in the field of TSPO-targeted cancer diagnostics and treatments.

Electrochemical and spectroelectrochemical studies of C-benzodiazaborolyl-ortho-carboranes.

Fifteen C-diazaborolyl-ortho-carboranes, 1-R'-2-R''-1,2-C(2)B(10)H(10), where R' represents the groups 2-(1,3-Et(2)-1,3,2-N(2)BC(6)H(4))-, 2-(1,3-Ph(2)-1,3,2-N(2)BC(6)H(4))-, 2-(1,3-Ph(2)-5,6-Me(2)-1,3,2-N(2)BC(6)H(2))-, 2-(1,3-(i)Pr(2)-1,3,2-N(2)BC(6)H(4))-, and 2-(1,3,2-N(2)BC(6)H(6))- and where R'' is H, Me, Ph, (t)Bu or SiMe(3), were synthesized. Cyclic voltammetry studies of the compounds showed irreversible oxidation waves which are caused by the oxidation of the heterocycle. Those C-diazaborolyl-ortho-carboranes with Ph, tBu and SiMe(3) substituents at the adjacent C-atom of the cage displayed two one-electron reduction waves reflecting the formation of stable radical monoanions with unusual (2n + 3) skeletal electron counts. The geometries of these anions were determined by combinations of infrared, UV-visible spectroelectrochemical and computational studies. Additionally the structures of seven new C-diazaborolyl-ortho-carboranes and one new 2-bromo-1,3,2-benzodiazaborole were determined by X-ray crystallography and compared with previously obtained structures.

Diazaborolyl-boryl push-pull systems with ethynylene-arylene bridges as 'turn-on' fluoride sensors.

Two linear π-conjugated systems with 1,3-diethyl-1,3,2-benzodiazaborolyl [C(6)H(4)(NEt)(2)B-] as a donor group and dimesitylboryl (-BMes(2)) as acceptor were synthesised with -ethynylene-phenylene- (-C≡C-1,4-C(6)H(4)-, 3) and -ethynylene-thiophene- (-C≡C-2,5-C(4)H(2)S-12) bridges between the boron atoms. An assembly (20) consisting of two diazaborolyl-ethynylene-phenylene-boryl units, [C(6)H(4)(NCy)(N')B-C≡C-1,4-C(6)H(4)-BMes(2)] joined via a 1,4-phenylene unit at the nitrogen atoms (N') of the diazaborolyl units was also synthesised. The three push-pull systems, 3, 12 and 20, form salts on fluoride addition with the BMes(2) groups converted into (BMes(2)F)(-) anions. The molecular structures of 3, 12 and (NBu(4))(12·F) were elucidated by X-ray diffraction analyses. The borylated systems 3, 12 and 20 show intense blue luminescence in cyclohexane with quantum yields (Φ(fl)) of 0.99, 0.44 and 0.94, respectively, but weak blue-green luminescence in tetrahydrofuran (Φ(fl) = 0.02-0.05). The charge transfer nature of these transitions is supported by TD-DFT computations with the CAM-B3LYP functional. Addition of tetrabutylammonium fluoride to tetrahydrofuran solutions of 3 and 20 resulted in strong violet-blue luminescence with emission intensities up to 46 times more than the emission intensities observed prior to fluoride addition. Compounds 3 and 20 are demonstrated here as remarkable 'turn-on' fluoride sensors in tetrahydrofuran solutions.

Luminescence properties of C-diazaborolyl-ortho-carboranes as donor-acceptor systems.

Seven derivatives of 1,2-dicarbadodecaborane (ortho-carborane, 1,2-C(2)B(10)H(12)) with a 1,3-diethyl- or 1,3-diphenyl-1,3,2-benzodiazaborolyl group on one cage carbon atom were synthesized and structurally characterized. Six of these compounds showed remarkable low-energy fluorescence emissions with large Stokes shifts of 15100-20260 cm(-1) and quantum yields (Φ(F)) of up to 65% in the solid state. The low-energy fluorescence emission, which was assigned to a charge-transfer (CT) transition between the cage and the heterocyclic unit, depended on the orientation (torsion angle, ψ) of the diazaborolyl group with respect to the cage C-C bond. In cyclohexane, two compounds exhibited very weak dual fluorescence emissions with Stokes shifts of 15660-18090 cm(-1) for the CT bands and 1960-5540 cm(-1) for the high-energy bands, which were assigned to local transitions within the benzodiazaborole units (local excitation, LE), whereas four compounds showed only CT bands with Φ(F) values between 8-32%. Two distinct excited singlet-state (S(1)) geometries, denoted S(1)(LE) and S(1)(CT), were observed computationally for the benzodiazaborolyl-ortho-carboranes, the population of which depended on their orientation (ψ). TD-DFT calculations on these excited state geometries were in accord with their CT and LE emissions. These C-diazaborolyl-ortho-carboranes were viewed as donor-acceptor systems with the diazaborolyl group as the donor and the ortho-carboranyl group as the acceptor.