Enhanced reversal of ABCG2-mediated drug resistance by replacing a phenyl ring in baicalein with a meta-carborane.

Success of chemotherapy is often hampered by multidrug resistance. One mechanism for drug resistance is the elimination of anticancer drugs through drug transporters, such as breast cancer resistance protein (BCRP; also known as ABCG2), and causes a poor 5-year survival rate of human patients. Co-treatment of chemotherapeutics and natural compounds, such as baicalein, is used to prevent chemotherapeutic resistance but is limited by rapid metabolism. Boron-based clusters as meta-carborane are very promising phenyl mimetics to increase target affinity; we therefore investigated the replacement of a phenyl ring in baicalein by a meta-carborane to improve its affinity towards the human ABCG2 efflux transporter. Baicalein strongly inhibited the ABCG2-mediated efflux and caused a fivefold increase in mitoxantrone cytotoxicity. Whereas the baicalein derivative 5,6,7-trimethoxyflavone inhibited ABCG2 efflux activity in a concentration of 5 µm without reversing mitoxantrone resistance, its carborane analogue 5,6,7-trimethoxyborcalein significantly enhanced the inhibitory effects in nanomolar ranges (0.1 µm) and caused a stronger increase in mitoxantrone toxicity reaching similar values as Ko143, a potent ABCG2 inhibitor. Overall, in silico docking and in vitro studies demonstrated that the modification of baicalein with meta-carborane and three methoxy substituents leads to an enhanced reversal of ABCG2-mediated drug resistance. Thus, this seems to be a promising basis for the development of efficient ABCG2 inhibitors.

Donor-acceptor complex formation by social self-sorting of polycyclic aromatic hydrocarbons and perylene bisimides.

Self-assembly versus complexation with polycyclic aromatic hydrocarbon (PAH) guest molecules is studied for a series of perylene bisimides (PBIs). Bulky imide substituents at the PBI guide their self-assembly into dimer aggregates with null-type exciton coupling. Host-guest titration experiments with perylene and triphenylene PAHs afford 1 : 1 and 1 : 2 complexes whose properties are studied by single crystal X-ray analysis and UV/Vis and fluorescence spectroscopy.

Boron-based octahedral dication experimentally detected: DFT surface confirms its availability.

Borane and heteroborane clusters have been known as neutral or anionic species. In contrast to them, several ten-vertex monocationic nido and closo dicarbaborane-based systems have recently emerged from the reaction of the parent bicapped-square antiprismatic dicarbaboranes with N-heterocyclic carbenes followed by the protonization of the corresponding nido intermediates. The expansion of these efforts has afforded the very first closo-dicationic octahedral phosphahexaborane along with new closo-monocationic pnictogenahexaboranes of the same shapes. All are the products of the one-pot procedure that consists in the reaction of the same carbenes with the parent closo-1,2-Pn2B4Br4 (Pn = As, P). Whereas in the case of phosphorus such a monocation appears to be a mixture of stable intermediates, and arsenahexaboranyl monocation has occurred as the final product, all of them without using any subsequent reaction. The well-established DFT/ZORA/NMR approach has unambiguously confirmed the existence of these species in solution, and computed electrostatic potentials have revealed the delocalization of the positive charge in these monocations and in the very first dication, namely within the octahedral shapes in both cases.

The Telluraboranes closo-TeB5 Cl5 and closo-TeB11 Cl11 with Exceptionally Long Body Diagonals: Synthetic and Bonding Motifs for Innovative Octahedral and Icosahedral Geometries.

Six-vertex closo-TeB5 Cl5 (1) and twelve-vertex closo-TeB11 Cl11 (2) telluraboranes have been prepared via co-pyrolysis of B2 Cl4 with TeCl4 in vacuo at temperatures between 360 °C and 400 °C. Both compounds are sublimable, off-white solids, and they have been characterized by one- and two-dimensional 11 B NMR and high-resolution mass spectroscopy. Both ab initio/GIAO/NMR and DFT/ZORA/NMR computations support octahedral and icosahedral geometries for 1 and 2, respectively, as expected due to their closo-electron counts. The octahedral structure of 1 has been confirmed by single-crystal X-ray diffraction on an incommensurately modulated crystal. The corresponding bonding properties have been analyzed in terms of the intrinsic bond orbital (IBO) approach. 1 is the first example of a polyhedral telluraborane with a cluster size smaller than 10 vertices.

Activating Organic Phosphorescence via Heavy Metal-π Interaction Induced Intersystem Crossing.

Heavy-atom-containing clusters, nanocrystals, and other semiconductors can sensitize the triplet states of their surface-bonded chromophores, but the energy loss, such as nonradiative deactivation, often prevents the synergistic light emission in their solid-state coassemblies. Cocrystallization allows new combinations of molecules with complementary properties for achieving functionalities not available in single components. Here, the cocrystal formation that employs platinum(II) acetylacetonate (Pt(acac)2 ) as a triplet sensitizer and electron-deficient 1,4,5,8-naphthalene diimides (NDIs) as organic phosphors is reported. The hybrid cocrystals exhibit room-temperature phosphorescence confined in the low-lying, long-lived triplet state of NDIs with photoluminescence (PL) quantum yield (ΦPL ) exceeding 25% and a phosphorescence lifetime (τPh ) of 156 µs. This remarkable PL property benefits from the noncovalent electronic and spin-orbital coupling between the constituents.

Carboranyl Analogues of Mefenamic Acid and Their Biological Evaluation.

Mefenamic acid represents a widely used nonsteroidal anti-inflammatory drug (NSAID) to treat the pain of postoperative surgery and heavy menstrual bleeding. Like other NSAIDs, mefenamic acid inhibits the synthesis of prostaglandins by nonselectively blocking cyclooxygenase (COX) isoforms COX-1 and COX-2. For the improved selectivity of the drug and, therefore, reduced related side effects, the carborane analogues of mefenamic acid were evaluated. The ortho-, meta-, and para-carborane derivatives were synthesized in three steps: halogenation of the respective cluster, followed by a Pd-catalyzed B-N coupling and hydrolysis of the nitrile derivatives under acidic conditions. The COX inhibitory activity and cytotoxicity for different cancer cell lines revealed that the carborane analogues have stronger antitumor potential compared to their parent organic compound.

Exploring the Reactivity of B-Connected Carboranylphosphines in Frustrated Lewis Pair Chemistry: A New Frame for a Classic System.

The primary phosphines MesPH2 and tBuPH2 react with 9-iodo-m-carborane yielding B9-connected secondary carboranylphosphines 1,7-H2 C2 B10 H9 -9-PHR (R=2,4,6-Me3 C6 H2 (Mes; 1 a), tBu (1 b)). Addition of tris(pentafluorophenyl)borane (BCF) to 1 a, b resulted in the zwitterionic compounds 1,7-H2 C2 B10 H9 -9-PHR(p-C6 F4 )BF(C6 F5 )2 (2 a, b) through nucleophilic para substitution of a C6 F5 ring followed by fluoride transfer to boron. Further reaction with Me2 SiHCl prompted a H-F exchange yielding the zwitterionic compounds 1,7-H2 C2 B10 H9 -9-PHR(p-C6 F4 )BH(C6 F5 )2 (3 a, b). The reaction of 2 a, b with one equivalent of R'MgBr (R'=Me, Ph) gave the extremely water-sensitive frustrated Lewis pairs 1,7-H2 C2 B10 H9 -9-PR(p-C6 F4 )B(C6 F5 )2 (4 a, b). Hydrolysis of the B-C6 F4 bond in 4 a, b gave the first tertiary B-carboranyl phosphines with three distinct substituents, 1,7-H2 C2 B10 H9 -9-PR(p-C6 F4 H) (5 a, b). Deprotonation of the zwitterionic compounds 2 a, b and 3 a, b formed anionic phosphines [1,7-H2 C2 B10 H9 -9-PR(p-C6 F4 )BX(C6 F5 )2 ]- [DMSOH]+ (R=Mes, X=F (6 a), R=tBu, X=F (6 b); R=Mes, X=H (7 a), R=tBu, X=H (7 b)). Reaction of 2 a, b with an excess of Grignard reagents resulted in the addition of R' at the boron atom yielding the anions [1,7-H2 C2 B10 H9 -9-PR(p-C6 F4 )BR'(C6 F5 )2 ]- (R=Mes, R'=Me (8 a), R=tBu, R'=Me (8 b); R=Mes, R'=Ph (9 a), R=tBu, R'=Ph (9 b)) with [MgBr(Et2 O)n ]+ as counterion. The ability of the zwitterionic compounds 3 a, b to hydrogenate imines as well as the Brønsted acidity of 3 a were investigated.

Borcalein: a Carborane-Based Analogue of Baicalein with 12-Lipoxygenase-Independent Toxicity.

12-Lipoxygenase is crucial for tumour angiogenesis. 5,6,7-Trihydroxy-2-phenyl-4H-1-benzopyran-4-one (baicalein) is a suitable inhibitor for this enzyme but is rapidly metabolised in vivo. Thus, an improvement of the metabolic stability is necessary to enhance the therapeutic efficiency. An emerging approach to enhance metabolic stability of carbon-based pharmaceuticals is the use of metabolically stable, non-toxic boron clusters, such as dicarba-closo-dodecaborane(12)s (carboranes) as phenyl mimetics. Therefore, the unsubstituted phenyl ring of baicalein was replaced by meta-carborane, resulting in borcalein, the carborane analogue of baicalein. This substitution resulted in a decreased inhibitory activity toward 12-lipoxygenase, but led to increased toxicity in melanoma (A375, B16, B16F10) and colon cancer cell lines (SW480, HCT116, CT26CL25) with decreased tumour selectivity in comparison to baicalein. Surprisingly, borcalein displays a different mechanism of cytotoxicity with increased intracellular production of reactive oxygen species (ROS), reactive nitrogen species (RNS) and nitric oxide (NO).

Borinostats: solid-phase synthesis of carborane-capped histone deacetylase inhibitors with a tailor-made selectivity profile.

The elevated expression of histone deacetylases (HDACs) in various tumor types renders their inhibition an attractive strategy for epigenetic therapeutics. One key issue in the development of improved HDAC inhibitors (HDACis) is the selectivity for single HDAC isoforms over unspecific pan inhibition to minimize off-target toxicity. Utilizing the carborane moiety as a fine-tuning pharmacophore, we herein present a robust solid phase synthetic approach towards tailor-made HDACis meeting both ends of the selectivity spectrum, namely pan inhibition and highly selective HDAC6 inhibition.

Reductive Rearrangement of a 1-Phospha-2-azanorbornene.

The reduction of the 1-phospha-2-azanorbornene derivate endo-1 with lithium aluminium hydride leads to an unprecedented 1-phosphabicyclo[3.2.1]octa-2,5-diene, while a phospholide anion is formed with lithium. The latter can be protonated resulting in formation of an unusual 2H-phosphole dimer. Furthermore, 3H-phospholes, previously assumed to have no synthetic relevance as intermediates, were proposed to act as dienophile in the dimerisation of 3,4-dimethyl-1-phenylphosphole at elevated temperatures based on theoretical calculations.

Benchmark Data Sets of Boron Cluster Dihydrogen Bonding for the Validation of Approximate Computational Methods.

The success of approximate computational methods, such as molecular mechanics, or dispersion-corrected density functional theory, in the description of non-covalent interactions relies on accurate parameterizations. Benchmark data sets are thus required. This area is well developed for organic molecules and biomolecules but practically non-existent for boron clusters, which have been gaining in importance in modern drug as well as material design. To fill this gap, we have introduced two data sets featuring the most common non-covalent interaction of boron clusters, the dihydrogen bond, and calculated reference interaction energies at the "golden standard" CCSD(T)/CBS level. The boron clusters studied interact with formamide, methanol, water and methane at various distances and in two geometrical arrangements. The performance of the tested approximate methods is variable and recommendations for further use are given.

Cathepsin S Alterations Induce a Tumor-Promoting Immune Microenvironment in Follicular Lymphoma.

Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional, and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from an enzymatically inactive profrom to active CTSS and increased substrate cleavage, including CD74, which regulates major histocompatibility complex class II (MHC class II)-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4+ T cells in vitro. Tumors with hyperactive CTSS showed increased CD4+ T cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment.

New keys for old locks: carborane-containing drugs as platforms for mechanism-based therapies.

Icosahedral carboranes in medicine are still an emerging class of compounds with potential beneficial applications in drug design. These highly hydrophobic clusters are potential "new keys for old locks" which open up an exciting field of research for well-known, but challenging important therapeutic substrates, as demonstrated by the numerous examples discussed in this review.

Modular triazine-based carborane-containing carboxylic acids - synthesis and characterisation of potential boron neutron capture therapy agents made of readily accessible building blocks.

Based on a modular combination of s-triazine, the well-known 9-mercapto-1,7-dicarba-closo-dodecaborane(12) and commercially available carboxylic acids, namely thioglycolic acid, glycine, and Nα-Boc-l-lysine, several carboxylic acid derivatives were synthesised and fully characterised. The thioglycolic acid derivative was introduced into a peptide hormone by solid phase peptide synthesis. High activity and selective internalisation into peptide receptor-expressing cells was observed. With a very high boron content of twenty boron atoms, these derivatives are interesting as selective Boron Neutron Capture Therapy (BNCT) agents.

Access to 1-Phospha-2-azanorbornenes by Phospha-aza-Diels-Alder Reactions.

The unprecedented phospha-aza-Diels-Alder reaction between an activated electron-poor imine and 2H-phospholes yields 1-phospha-2-azanorbornenes in a highly chemoselective and moderately diastereoselective reaction. The intermediate 2H-phospholes, which act as dienes, are formed in situ from the corresponding 1H-phospholes. Theoretical calculations confirm that the phospha-aza-Diels-Alder reaction is of normal electron demand. The reactive P-N bond in 1-phospha-2-azanorbornenes can be cleaved by nucleophiles leading to the formation of 2,3-dihydrophospholes.

A Sixteen-Membered Au8 P8 Macrocycle Based on Gold(I) and Diphospha(III)guanidine.

The reaction of cyclo-P4 Mes4 C(NCy) (1) with two equivalents of [AuCl(tht)] (tht=tetrahydrothiophene) resulted in the formation of unusual sixteen-membered Au-P macrocycle 2. This macrocycle contains diphospha(III)guanidinate as a coordinating ligand, which is formed by P-P bond cleavage of 1. Macrocycle 2 was characterized by multinuclear NMR spectroscopy, mass spectrometry and X-ray crystallography.

C2-Symmetric P,N Ligands Derived from Carborane-Based Diphosphetanes: Synthesis and Coordination Chemistry.

Racemic carborane-based bisphosphanes were obtained by dismutation reactions between a carborane-based diphosphetane and diaryl dichalogenides. NMR spectroscopic and theoretical studies revealed a two-step mechanism explaining the high stereoselectivity of these reactions. The coordination chemistry of the multidentate P,N ligands 6c and 6d in copper(I) and silver(I) complexes was studied. While 6d acted exclusively as tetradentate ligand, 6c showed either tridentate or tetradentate coordination depending on the metal and the counterion.

Unusual Reactivity of Sodium Tetramesityltetraphosphanediide towards Cyclohexyl Isocyanide.

The reaction of [Na2 (thf)4 (P4 Mes4 )] (Mes=2,4,6-Me3 C6 H2 ) with cyclohexyl isocyanide (2:5) resulted in the formation of the heterocyclic N-(tetramesityltetraphosphacyclopentylidene)cyclohexylamine [cyclo-{P4 Mes4 C(NCy)}] (2) (30-35 %), the unusual 1,3,5-triphospha-1,4-pentadiene (3) (40-45 %), and small amounts of the dimeric iminomethylidenephosphane cyclo-{PMesC(NCy)}2 (4). With catalytic amounts of AgBF4 , 2 was the major product. The reaction of 2 with [CuBr(SMe2 )] (1:1) produced bromido-bridged dimeric CuI complex 5. Molecular structures of compounds 3, 4, and 5 were obtained.

Ordered Layered Dendrimers Constructed from Two Known Dendrimer Families: Inheritance and Emergence of Properties.

A new concept is presented, namely the synthesis of dendrimers intrinsically composed in alternation of building blocks pertaining to two known families of dendrimers: phosphorhydrazone dendrimers and triazine-piperazine dendrimers. These mixed dendrimers with layered controlled architecture inherit their easy (31) P NMR characterization and their thermal stability from the phosphorhydrazone family, and their decreased solubility from the triazine-piperazine family. However, they have also their own and original characteristics. Both parent families are white powders, whereas the mixed dendrimers are yellow, orange, or red powders, depending on the generation. DFT calculations were carried out on model dendrons to understand these special color features. Remarkably, these dendrimers incorporating redox-active organic entities allow for the first time the monitoring of the growth of an organic dendrimer by electrochemistry while highlighting an even-odd generation behavior.

Acetylation of C/EBPα inhibits its granulopoietic function.

CCAAT/enhancer-binding protein alpha (C/EBPα) is an essential transcription factor for myeloid lineage commitment. Here we demonstrate that acetylation of C/EBPα at lysine residues K298 and K302, mediated at least in part by general control non-derepressible 5 (GCN5), impairs C/EBPα DNA-binding ability and modulates C/EBPα transcriptional activity. Acetylated C/EBPα is enriched in human myeloid leukaemia cell lines and acute myeloid leukaemia (AML) samples, and downregulated upon granulocyte-colony stimulating factor (G-CSF)- mediated granulocytic differentiation of 32Dcl3 cells. C/EBPα mutants that mimic acetylation failed to induce granulocytic differentiation in C/EBPα-dependent assays, in both cell lines and in primary hematopoietic cells. Our data uncover GCN5 as a negative regulator of C/EBPα and demonstrate the importance of C/EBPα acetylation in myeloid differentiation.