Design, Synthesis, and Evaluation of B-(Trifluoromethyl)phenyl Phosphine-Borane Derivatives as Novel Progesterone Receptor Antagonists.

We previously revealed that phosphine-boranes can function as molecular frameworks for biofunctional molecules. In the present study, we exploited the diversity of available phosphines to design and synthesize a series of B-(trifluoromethyl)phenyl phosphine-borane derivatives as novel progesterone receptor (PR) antagonists. We revealed that the synthesized phosphine-borane derivatives exhibited LogP values in a predictable manner and that the P-H group in the phosphine-borane was almost nonpolar. Among the synthesized phosphine-boranes, which exhibited PR antagonistic activity, B-(4-trifluoromethyl)phenyl tricyclopropylphosphine-borane was the most potent with an IC50 value of 0.54 µM. A docking simulation indicated that the tricyclopropylphosphine moiety plays an important role in ligand-receptor interactions. These results support the idea that phosphine-boranes are versatile structural options in drug discovery, and the developed compounds are promising lead compounds for further structural development of next-generation PR antagonists.

The Rise of Boron-Containing Compounds: Advancements in Synthesis, Medicinal Chemistry, and Emerging Pharmacology.

Boron-containing compounds (BCC) have emerged as important pharmacophores. To date, five BCC drugs (including boronic acids and boroles) have been approved by the FDA for the treatment of cancer, infections, and atopic dermatitis, while some natural BCC are included in dietary supplements. Boron's Lewis acidity facilitates a mechanism of action via formation of reversible covalent bonds within the active site of target proteins. Boron has also been employed in the development of fluorophores, such as BODIPY for imaging, and in carboranes that are potential neutron capture therapy agents as well as novel agents in diagnostics and therapy. The utility of natural and synthetic BCC has become multifaceted, and the breadth of their applications continues to expand. This review covers the many uses and targets of boron in medicinal chemistry.

A computational study to determine the role of σ-hole in Br/OH substituted nido-carborane and its binding capabilities.

A detailed investigation of the σ-hole on the halogen atom present in the nido-heteroboranes is made by employing quantum mechanical methods. The bromide and the hydroxyl groups are incorporated in the exo-substituents of the nido-boranes. The potential of the bromide σ-hole was compared to that of electrostatic potential of hydroxyl group counterpart. The presence of a carbon atom vertex, in a different position of a system, influences the σ-hole and hence its binding abilities. Bromide substituted nido-carboranes have less potential and hence weaker binding ability compared to their closo-counterparts. Binding affinity with aliphatic is found to be more compared to that of aromatic system. The presence of solvent dampened the electrostatic interactions. Apart from the neutral system, the binding capabilities of charged nido-heteroboranes were also studied. The results of this study will be further useful for several applications viz., crystal engineering, drug designing (Pharmaceuticals), medicine, material science, energy storage devices, etc.

HER-2-Targeted Boron Neutron Capture Therapy with Carborane-integrated Immunoliposomes Prepared via an Exchanging Reaction.

Boron neutron capture therapy (BNCT) is a promising modality for cancer treatment because of its minimal invasiveness. To maximize the therapeutic benefits of BNCT, the development of efficient platforms for the delivery of boron agents is indispensable. Here, carborane-integrated immunoliposomes were prepared via an exchanging reaction to achieve HER-2-targeted BNCT. The conjugation of an anti-HER-2 antibody to carborane-integrated liposomes successfully endowed these liposomes with targeting properties toward HER-2-overexpressing human ovarian cancer cells (SK-OV3); the resulting BNCT activity toward SK-OV3 cells obtained using the current immunoliposomal system was 14-fold that of the l-BPA/fructose complex, which is a clinically available boron agent. Moreover, the growth of spheroids treated with this system followed by thermal neutron irradiation was significantly suppressed compared with treatment with the l-BPA/fructose complex.

1,2-Diphenyl-o-carborane and Its Chromium Derivatives: Synthesis, Characterization, X-ray Structural Studies, and Biological Evaluations.

The objective of this study is to design and synthesize substituted η6-chromium(0) tricarbonyl metal complexes carrying o-carborane units as potential boron neutron capture therapy (BNCT) agents. In this study, 1,2-diphenyl-o-carborane (1) units were used as starting materials to generate biologically active species. We investigated how the structural changes of 1 substituted with chromium(0) tricarbonyl affect the biological properties, and 1-(Phenyl-η6-chromium(0) tricarbonyl)-2-phenyl-o-carborane (2) and 1,2-bis(phenyl-η6-chromium(0) tricarbonyl)-o-carborane (3) species were produced in moderate yields. The molecular structures of compounds 1-3 were identified and established by infrared (IR); 1H, 11B, and 13C nuclear magnetic resonance (NMR) and X-ray crystallography analyses. Crystal structures of 1,2-diphenyl-o-carborane and the corresponding chromium complexes 1, 2, and 3 were obtained. In an in vitro study using B16 and CT26 cancer cells containing the triphenyl-o-carboranyl chromium(0) complexes Ph3C2BCr2 and Ph3C2BCr3, which we reported previously, compounds 2 and 3 accumulated at higher levels than compounds Ph3C2BCr2 and Ph3C2BCr3. However, the phenylated o-carboranyl chromium complexes have been found to be more cytotoxic than p-boronophenylalanine (BPA).

Plight of CORMs: The unreliability of four commercially available CO-releasing molecules, CORM-2, CORM-3, CORM-A1, and CORM-401, in studying CO biology.

Carbon monoxide (CO) is an endogenously produced gaseous signaling molecule with demonstrated pharmacological effects. In studying CO biology, three delivery forms have been used: CO gas, CO in solution, and CO donors of various types. Among the CO donors, four carbonyl complexes with either a transition metal ion or borane (BH3) (termed CO-releasing molecules or CORMs) have played the most prominent roles appearing in over 650 publications. These are CORM-2, CORM-3, CORM-A1, and CORM-401. Intriguingly, there have been unique biology findings that were only observed with these CORMs, but not CO gas; yet these properties were often attributed to CO, raising puzzling questions as to why CO source would make such a fundamental difference in terms of CO biology. Recent years have seen a large number of reports of chemical reactivity (e.g., catalase-like activity, reaction with thiol, and reduction of NAD(P)+) and demonstrated CO-independent biological activity for these four CORMs. Further, CORM-A1 releases CO in an idiosyncratic fashion; CO release from CORM-401 is strongly influenced or even dependent on reaction with an oxidant and/or a nucleophile; CORM-2 mostly releases CO2, not CO, after a water-gas shift reaction except in the presence of a strong nucleophile; and CORM-3 does not release CO except in the presence of a strong nucleophile. All these beg the question as to what constitutes an appropriate CO donor for studying CO biology. This review critically summarizes literature findings related to these aspects, with the aim of helping result interpretation when using these CORMs and development of essential criteria for an appropriate donor for studying CO biology.

Diastereoselective Synthesis of the Borylated d-Galactose Monosaccharide 3-Boronic-3-Deoxy-d-Galactose and Biological Evaluation in Glycosidase Inhibition and in Cancer for Boron Neutron Capture Therapy (BNCT).

Drug leads with a high Fsp3 index are more likely to possess desirable properties for progression in the drug development pipeline. This paper describes the development of an efficient two-step protocol to completely diastereoselectively access a diethanolamine (DEA) boronate ester derivative of monosaccharide d-galactose from the starting material 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose. This intermediate, in turn, is used to access 3-boronic-3deoxy-d-galactose for boron neutron capture therapy (BNCT) applications. The hydroboration/borane trapping protocol was robustly optimized with BH3.THF in 1,4-dioxane, followed by in-situ conversion of the inorganic borane intermediate to the organic boron product by the addition of DEA. This second step occurs instantaneously, with the immediate formation of a white precipitate. This protocol allows expedited and greener access to a new class of BNCT agents with an Fsp3 index = 1 and a desirable toxicity profile. Furthermore, presented is the first detailed NMR analysis of the borylated free monosaccharide target compound during the processes of mutarotation and borarotation.

Towards the Application of Purely Inorganic Icosahedral Boron Clusters in Emerging Nanomedicine.

Traditionally, drugs were obtained by extraction from medicinal plants, but more recently also by organic synthesis. Today, medicinal chemistry continues to focus on organic compounds and the majority of commercially available drugs are organic molecules, which can incorporate nitrogen, oxygen, and halogens, as well as carbon and hydrogen. Aromatic organic compounds that play important roles in biochemistry find numerous applications ranging from drug delivery to nanotechnology or biomarkers. We achieved a major accomplishment by demonstrating experimentally/theoretically that boranes, carboranes, as well as metallabis(dicarbollides), exhibit global 3D aromaticity. Based on the stability-aromaticity relationship, as well as on the progress made in the synthesis of derivatized clusters, we have opened up new applications of boron icosahedral clusters as key components in the field of novel healthcare materials. In this brief review, we present the results obtained at the Laboratory of Inorganic Materials and Catalysis (LMI) of the Institut de Ciència de Materials de Barcelona (ICMAB-CSIC) with icosahedral boron clusters. These 3D geometric shape clusters, the semi-metallic nature of boron and the presence of exo-cluster hydrogen atoms that can interact with biomolecules through non-covalent hydrogen and dihydrogen bonds, play a key role in endowing these compounds with unique properties in largely unexplored (bio)materials.

Synthesis and In Vitro Biological Evaluation of p-Carborane-Based Di-tert-butylphenol Analogs.

Targeting inflammatory mediators and related signaling pathways may offer a rational strategy for the treatment of cancer. The incorporation of metabolically stable, sterically demanding, and hydrophobic carboranes in dual cycloxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids is a promising approach. The di-tert-butylphenol derivatives R-830, S-2474, KME-4, and E-5110 represent potent dual COX-2/5-LO inhibitors. The incorporation of p-carborane and further substitution of the p-position resulted in four carborane-based di-tert-butylphenol analogs that showed no or weak COX inhibition but high 5-LO inhibitory activities in vitro. Cell viability studies on five human cancer cell lines revealed that the p-carborane analogs R-830-Cb, S-2474-Cb, KME-4-Cb, and E-5110-Cb exhibited lower anticancer activity compared to the related di-tert-butylphenols. Interestingly, R-830-Cb did not affect the viability of primary cells and suppressed HCT116 cell proliferation more potently than its carbon-based R-830 counterpart. Considering all the advantages of boron cluster incorporation for enhancement of drug biostability, selectivity, and availability of drugs, R-830-Cb can be tested in further mechanistic and in vivo studies.

Unveiling the mechanisms behind the chemical vapor generation of plumbane for trace analysis of lead.

The mechanisms controlling the generation of PbH4 by reaction of inorganic Pb(II) with aqueous NaBH4 were investigated both in the presence and in the absence of the additive K3Fe(CN)6. For the first time PbH4 has been identified in analytical chemical vapor generation (CVG) by using gas chromatographic mass spectrometry (GC-MS), which allows the use of deuterium labelled experiments. In the absence of the additive, under reaction conditions typically employed for trace lead determination by CVG, Pb(II) is converted to solid species and no volatile lead species can be detected by either atomic or mass spectrometry for Pb(II) concentration up to 100 mg L-1. In alkaline conditions Pb(II) substrates are unreactive towards NaBH4. In the presence of K3Fe(CN)6, deuterium labelled experiments clearly indicated that the generated PbH4 is formed by the direct transfer of hydride from borane to lead atoms. Kinetic experiments were carried out to evaluate the rate of reduction of K3Fe(CN)6 by NaBH4, the rate of hydrolysis of NaBH4 both in the presence and in the absence of K3Fe(CN)6, and the rate of dihydrogen evolution following NaBH4 hydrolysis. The effect of delayed addition of Pb(II) to NaBH4-HCl- K3Fe(CN)6, and K3Fe(CN)6 to NaBH4-HCl-Pb(II) reaction mixtures on the efficiency of plumbane generation was investigated by continuous flow CVG coupled with atomic fluorescence spectrometry. The collected evidences, complemented with thermodynamic considerations and literature data, have made it possible to clarify long-standing controversial aspects related to the mechanism of plumbane generation and the role of K3Fe(CN)6 additive.

Sweet Battle of the Epimers─Continued Exploration of Monosaccharide-Derived Delivery Agents for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a cancer therapy in which boron delivery agents play a crucial role. In theory, delivery agents with high tumor targeting capabilities can lead to selective eradication of tumor cells without causing harmful side effects. We have been working on a GLUT1-targeting strategy to BNCT for a number of years and found multiple promising hit compounds which outperform the clinically employed boron delivery agents in vitro. Herein, we continue our work in the field by further diversification of the carbohydrate scaffold in order to map the optimal stereochemistry of the carbohydrate core. In the sweet battle of the epimers, carborane-bearing d-galactose, d-mannose, and d-allose are synthesized and subjected to in vitro profiling studies─with earlier work on d-glucose serving as the reference. We find that all of the monosaccharide delivery agents display a significantly improved boron delivery capacity over the delivery agents approved for clinical use in vitro, thus providing a sound foundation for advancing toward in vivo preclinical assessment studies.

Carborane-Based Tebufelone Analogs and Their Biological Evaluation In Vitro.

The presence of inflammatory mediators in the tumor microenvironment, such as cytokines, growth factors or eicosanoids, indicate cancer-related inflammatory processes. Targeting these inflammatory mediators and related signal pathways may offer a rational strategy for the treatment of cancer. This study focuses on the incorporation of metabolically stable, sterically demanding, and hydrophobic dicarba-closo-dodecaboranes (carboranes) into dual cyclooxygenase-2 (COX-2)/5-lipoxygenase (5-LO) inhibitors that are key enzymes in the biosynthesis of eicosanoids. The di-tert-butylphenol derivative tebufelone represents a selective dual COX-2/5-LO inhibitor. The incorporation of meta- or para-carborane into the tebufelone scaffold resulted in eight carborane-based tebufelone analogs that show no COX inhibition but 5-LO inhibitory activity in vitro. Cell viability studies on HT29 colon adenocarcinoma cells revealed that the observed antiproliferative effect of the para-carborane analogs of tebufelone is enhanced by structural modifications that include chain elongation in combination with introduction of a methylene spacer resulting in higher anticancer activity compared to tebufelone. Hence, this strategy proved to be a promising approach to design potent 5-LO inhibitors with potential application as cytostatic agents.

Solid-Phase Synthesis of Glycosyl Phosphate Repeating Units via Glycosyl Boranophosphates as Stable Intermediates.

Solid-phase synthesis of glycosyl phosphate repeating units was investigated using glycosyl boranophosphates as stable precursors. The stable nature of glycosyl boranophosphate enables the elongation of a saccharide chain without remarkable decomposition. After deprotection of the boranophosphotriester linkages to boranophosphodiesters, the intersugar linkages were converted to the phosphate counterparts quantitatively using an oxaziridine derivative. This method significantly improves the synthesis of oligosaccharides containing glycosyl phosphate units.

[Basic Organic and Inorganic Chemistry of Boron Clusters and Its Application to Drug Discovery].

In the past, drug discovery using low-molecular-weight compounds was dominated by structural design based on combinations of non-metallic elements such as carbon, nitrogen, oxygen, and halogens. Recent drug discovery efforts have shown extraordinary progress, an example of which is the adoption of non-universal elements. The approval of boron neutron capture therapy (BNCT) using a neutron accelerator in Japan ahead of other countries is still fresh in our memory. Other small-molecule drugs containing boron atoms have also been developed, and boron is becoming widely recognized as a constituent element for drug discovery. It is known that borane (BH3) is unstable because of its electron-deficient bonds; nevertheless, its stability has been improved by the formation of clusters through multimerization. Carborane (C2B10H12), one of the borane clusters, has an icosahedral structure with two carbon atoms and ten boron atoms and exhibits properties that vastly differ from conventional boron compounds. In this symposium review, we will introduce the basic chemistry of carboranes and their application to drug discovery. Boron is an essential element in plant cell wall formation and has extremely low toxicity to humans. I hope that this symposium review will be an opportunity for us to free ourselves from existing prejudices and constraints in drug discovery, and that new modalities that skillfully utilize the characteristics of boron and boron clusters will be developed one after another.

Synthesis of Sequence-specific Poly(ester-carbonate) Copolymers via Chemoselective Terpolymerization Controlled by the Stoichiometric Ratio of Phosphazene/Triethylborane.

Chemoselective terpolymerization can produce polymer materials with diverse compositions and sequential structures, and thus have attracted considerable attention in the field of polymer synthesis. However, the intrinsic complexity of three-component system also brings great chanllenge, in regard to the reactivity and selectivity of different monomers. Herein, we report the terpolymerization of CO2 /epoxide/anhydride by a binary organocatalytic C3 N3 -Py-P3 /TEB (triethylborane) system. Both the activity and chemoselectivity were highly dependent upon the molar ratio of C3 N3 -Py-P3 to TEB, and sequence-controlled poly(ester-carbonate) copolymers were readily synthesized through one-pot/one-step methodology by tuning the stoichiometric ratio of phosphazene/TEB. In particular, C3 N3 -Py-P3 /TEB with a molar ratio of 1/0.5 exhibited an unprecedentedly high chemoselectivity for ring-opening alternating copolymerization (ROAC) of cyclohexene oxide (CHO) and phthalic anhydride (PA) first and then ROAC of CO2 /CHO. Thus, well-defined triblock polycarbonate-b-polyester-b-polycarbonate copolymers can be produced from the mixture of CO2 , CHO and PA using a bifunctional initiator. With C3 N3 -Py-P3 /TEB=1/1, tapered copolymers were obtained, while random copolymers with high content of polycarbonate (PC) were synthesized with further increasing the amount of TEB. The mechanism of the unexpected chemoselectivity was further investigated by DFT calculations.

Synthesis of Novel Carborane-Containing Derivatives of RGD Peptide.

Short peptides containing the Arg-Gly-Asp (RGD) fragment can selectively bind to integrins on the surface of tumor cells and are attractive transport molecules for the targeted delivery of therapeutic and diagnostic agents to tumors (for example, glioblastoma). We have demonstrated the possibility of obtaining the N- and C-protected RGD peptide containing 3-amino-closo-carborane and a glutaric acid residue as a linker fragment. The resulting carboranyl derivatives of the protected RGD peptide are of interest as starting compounds in the synthesis of unprotected or selectively protected peptides, as well as building blocks for preparation of boron-containing derivatives of the RGD peptide of a more complex structure.

Acridine/Acridone-Carborane Conjugates as Strong DNA-Binding Agents with Anticancer Potential.

Synthesis of acridine derivatives that act as DNA-targeting anticancer agents is an evolving field and has resulted in the introduction of several drugs into clinical trials. Carboranes can be of importance in designing biologically active compounds due to their specific properties. Therefore, a series of novel acridine analogs modified with carborane clusters were synthesized. The DNA-binding ability of these analogs was evaluated on calf thymus DNA (ct-DNA). Results of these analyses showed that 9-[(1,7-dicarba-closo-dodecaborane-1-yl)propylamino]acridine (30) interacted strongly with ct-DNA, indicating its ability to intercalate into DNA, whereas 9-[(1,7-dicarba-closo-dodecaborane-1-yl)propanamido]acridine (29) changed the B-form of ct-DNA to the Z form. Compound 30 demonstrated cytotoxicity, was able to inhibit cell proliferation, arrest the cell cycle in the S phase in the HeLa cancer cell line, and induced the production of reactive oxygen species (ROS). In addition, it was specifically localized in lysosomes and was a weak inhibitor of Topo IIα.

Synergetic effect of Au nanoparticles and transition metal phosphides for enhanced hydrogen evolution from ammonia-borane.

The hydrogen evolution from ammonia borane is intriguing but challenging due to its sluggish kinetics. In this regard, the gold nanoparticles amalgamation with metal phosphides is speculated to be more efficient catalysts. Here, the catalysts Au/Ni2P and Au/CoP with the high synergetic effect of Au nanoparticles and metal phosphides were synthesized for ammonia borane hydrolysis. The activity of Au/Ni2P increases 4.8-fold (i.e., 0.08 to 0.40 L∙h-1) compared to pristine Ni2P, and the activity of Au/CoP increases 1.7-fold (i.e., 0.74 to 1.27 L∙h-1) compared to pristine CoP. This reveals that the synergetic effect of Auδ+ and (Ni2P) δ- is stronger than Auδ+ and (CoP) δ- which is manifested by XPS analysis. The kinetics exposes that the activation energy of Au/Ni2P (45.28 kJ∙mole-1) is greater than Au/CoP (31.45 kJ∙mole-1) and the TOF of Au/Ni2P is less than Au/CoP. This research work presents an effective approach for producing active sites of Auδ+ and (Ni2P & CoP) δ- for ammonia borane hydrolysis to enhance the H2 evolution rate.

Phosphido-borane-supported stannates.

The reactions between SnCl2 and three equivalents of the alkali metal phosphido-borane complexes [R2P(BH3)]M yield the corresponding tris(phosphido-borane)stannate complexes [LnM{R2P(BH3)}3Sn] [R2 = iPr2, LnM = (THF)3Li (2Li), (Et2O)Na (2Na), (Et2O)K (2K); R2 = Ph2, LnM = (THF)Li (3Li), (THF)(Et2O)Na (3Na), (THF)(Et2O)K (3K); R2 = iPrPh, LnM = (THF)4Li (4Li)]. In each case X-ray crystallography reveals an anion consisting of a trigonal pyramidal tin centre coordinated by the P atoms of the phosphido-borane ligands. These tris(phosphido-borane)stannate anions coordinate to the alkali metal cations via their BH3 hydrogen atoms in a variety of modes to give monomers, dimers, and polymers, depending on the alkali metal and the substituents at the phosphorus centres. In contrast, reactions between SnCl2 and three equivalents of [tBu2P(BH3)]M (M = Li, Na) gave the known hydride [M{tBu2P(BH3)}2SnH], according to multinuclear NMR spectroscopy.

The assignment of 11 B and 1 H resonances in the post-reaction mixture from the dry synthesis of Li(BH3 NH2 BH2 NH2 BH3 ).

We report a detailed 1 H NMR and 11 B NMR study of as synthesised Li ( BH 3 NH 2 BH 2 NH 2 BH 3 ) obtained in a novel dry-synthesis method. A combination of 1D and 2D single- and triple-quantum techniques was used for the assignment of all observed signals. Minor side-products and reactants were detected in the product: NH 3 BH 3 , Li ( NH 2 BH 3 ) , Li ( BH 4 ) , and two yet unknown salts containing 7-membered chain anions: ( BH 3 NH 2 BH 2 NH 2 BH 2 NH 2 BH 3 ) - and ( BH ( NH 2 BH 3 ) 3 ) - . We believe the assignment provided within this study might be helpful when analysing the mixtures containing numerous ammonia borane derivatives, which often give overlapping signals that are hard to distinguish.