High-purity butoxydibutylborane catalysts enable the low-exothermic polymerization of PMMA bone cement with enhanced biocompatibility and osseointegration.

Polymethyl methacrylate (PMMA) based biomaterials have been widely utilized in clinics. However, currently, PMMA catalyzed by benzoyl peroxide (BPO) exhibits disquieting disadvantages including an exothermic polymerization reaction and a lack of bioactivity. Here, we first designed three industrial-scale synthesis methods for high-purity butoxydibutylborane (BODBB), achieving purity levels greater than 95% (maximum: 97.6%) and ensuring excellent fire safety. By utilizing BODBB as a catalyst, the highest polymerization temperature of PMMA bone cement (PMMA-BODBB) reached only 36.05 °C, ensuring that no thermal damage occurred after implantation. Compared to PMMA catalyzed by BPO and partially oxidized tributylborane (TBBO, catalyst of Super Bond C&B), PMMA-BODBB exhibited superior cell adhesion, proliferation, and osteogenesis, attributed to the reduced release of free radicals and toxic monomer, and moderate bioactive boron release. After injection into a 5 mm defect in the rat cranial bone, PMMA-BODBB demonstrated the highest level of osteointegration. This work not only presents an industrial-scale synthesis of high-purity BODBB, but also offers an innovative PMMA biomaterial system with intrinsic biocompatibility and osseointegration, paving the way for the next generation of PMMA-based biomaterials with broader applications.

Extracellular Vesicles Comprising Carborane Prepared by a Host Exchanging Reaction as a Boron Carrier for Boron Neutron Capture Therapy.

With their low immunogenicity and excellent deliverability, extracellular vesicles (EVs) are promising platforms for drug delivery systems. In this study, hydrophobic molecule loading techniques were developed via an exchange reaction based on supramolecular chemistry without using organic solvents that can induce EV disruption and harmful side effects. To demonstrate the availability of an exchanging reaction to prepare drug-loading EVs, hydrophobic boron cluster carborane (CB) was introduced to EVs (CB@EVs), which is expected as a boron agent for boron neutron capture therapy (BNCT). The exchange reaction enabled the encapsulation of CB to EVs without disrupting their structure and forming aggregates. Single-particle analysis revealed that an exchanging reaction can uniformly introduce cargo molecules to EVs, which is advantageous in formulating pharmaceuticals. The performance of CB@EVs as boron agents for BNCT was demonstrated in vitro and in vivo. Compared to L-BPA, a clinically available boron agent, and CB delivered with liposomes, CB@EV systems exhibited the highest BNCT activity in vitro due to their excellent deliverability of cargo molecules via an endocytosis-independent pathway. The system can deeply penetrate 3D cultured spheroids even in the presence of extracellular matrices. The EV-based system could efficiently accumulate in tumor tissues in tumor xenograft model mice with high selectivity, mainly via the enhanced permeation and retention effect, and the deliverability of cargo molecules to tumor tissues in vivo enhanced the therapeutic benefits of BNCT compared to the L-BPA/fructose complex. All of the features of EVs are also advantageous in establishing anticancer agent delivery platforms.

A novel BN aromatic module modified near-infrared fluorescent probe for monitoring carbon monoxide-releasing molecule CORM-3 in living cells and animals.

Carbon monoxide (CO), a significant gas transmitter, plays a vital role in the intricate functioning of living systems and is intimately linked to a variety of physiological and pathological processes. To comprehensively investigate CO within biological system, researchers have widely adopted CORM-3, a compound capable of releasing CO, which serves as a surrogate for CO. It aids in elucidating the physiological and pathological effects of CO within living organisms and can be employed as a therapeutic drug molecule. Therefore, the pivotal role of CORM-3 necessitates the development of effective probes that can facilitate the visualization and tracking of CORM-3 in living systems. However, creating fluorescent probes for real-time imaging of CORM-3 in living species has proven to be a persisting challenge that arises from factors such as background interference, light scattering and photoactivation. Herein, the BNDN fluorescent probe, a brand-new near-infrared is proposed. Remarkably, the BNDN probe offers several noteworthy advantages, including a substantial Stokes shift (201 nm), heightened sensitivity, exceptional selectivity, and an exceedingly low CORM-3 detection limit (0.7 ppb). Furthermore, the underlying sensing mechanism has been meticulously examined, revealing a process that revives the fluorophore by reducing the complex Cu2+ to Cu+. This distinctive NIR fluorescence "turn-on" character, coupled with its larger Stokes shift, holds great promise for achieving high resolution imaging. Most impressively, this innovative probe has demonstrated its efficacy in detecting exogenous CORM-3 in living animal. It is important to underscore that these endeavors mark a rare instance of a near-infrared probes successfully detecting exogenous CORM-3 in vivo. These exceptional outcomes highlighted the potential of BNDN as a highly promising new tool for in vivo detection of CORM-3. Considering the impressive imaging capabilities demonstrated by BNDN presented in this study, we anticipate that this tool may offer a compelling avenue for shedding light on the roles of CO in future research endeavors.

Development of a Novel System Consisting of a Reductase-Like Nanozyme and the Reaction of Resazurin and Ammonia Borane for Sensitive Fluorometric Sensing.

We report a novel system consisting of a redox reaction and a highly efficient reductase-like nanozyme, silica-palladium nanoparticles (Pd@SiO2 NPs), as a novel detection platform for fluorometric sensing. In a proof-of-concept demonstration using an oligonucleotide as the detection target, a glass fiber-based sensor is fabricated by covalently conjugating two oligo probes, which are complementary to the adjacent segments of the target oligonucleotide, on Pd@SiO2 NPs and glass fiber, respectively. In the presence of the target oligonucleotide, the two probes are drawn together by the target through sequence-specific hybridization, bringing the Pd@SiO2 NPs to the glass fiber. When the glass fiber is subsequently immersed in a mixture of resazurin and ammonia borane solution, the Pd@SiO2 NPs on the glass fiber trigger the catalytic conversion of resazurin (blue, slightly fluorescent) to resorufin (pink, highly fluorescent) with massive signal amplification, indirectly signaling the presence of the target oligonucleotide. We show that the glass fiber-based fluorometric sensor can detect a target oligonucleotide associated with the BRAF mutation linearly in the concentration range of 20 to 400 pM with a detection limit (LOD) of 15 pM and the specificity to differentiate targets with single-base difference. These results demonstrate a new frontier for the development of a sensitive, specific, and inexpensive nonenzyme-based fluorometric sensing platform as an alternative to conventional enzyme-based assays.

Quantum Chemical and Biological Insights into Redox Activity of Metallacarborane Complexes in Cancer Cells.

A relationship between the electronic properties of metal ions in metallacarboranes and their ability to modulate mitochondrial oxidase activity and membrane hyperpolarization in cancer cells was demonstrated. Quantum chemistry methods, including DFT and molecular dynamics simulations, were used to understand the oxidized and reduced forms of metallacarboranes and their intramolecular rotatory behavior. According to the low-spin assumption for metal ions, the intramolecular oscillations of cluster ligands in metallacarboranes are significantly influenced by the type of metal and correspond to the cellular uptake of these complexes in vitro. In particular, the low-spin iron compound may be a new xenogeneic booster of redox homeostasis in cancer cells resistant to cisplatin, which induces metabolic 'exhaustion' of cancer cells and their death.

Cobalt-Catalyzed Reduction of Aldehydes to Alcohols via the Hydroboration Reaction.

A method for the reduction of aldehydes with pinacolborane catalyzed by pincer cobalt complexes based on a triazine backbone is developed in this paper. The presented methodology allows for the transformation of several aldehydes bearing a wide range of electron-withdrawing and electron-donating groups under mild conditions. The presented procedure allows for the direct one-step hydrolysis of the obtained intermediates to the corresponding primary alcohols. A plausible reaction mechanism is proposed.

Metallacarboranes in Medicinal Chemistry: Current Advances and Future Perspectives.

Metallacarboranes, exemplified by cobalt bis(dicarbollide) ([COSAN]-), have excelled their historical metallocene analogue label to become promising in drug design, medical studies, and fundamental biological research. Serving as a unique platform for conjugation with biomolecules, they also constitute an auspicious building block for biologically active derivatives and a carrier for cellular transport of membrane-impermeable cargos. Modified [COSAN]- exhibits specific antimicrobial, antiviral, and anticancer actions showing promise for preclinical trials. Contributing to the ongoing development in medicinal chemistry, metallacarboranes offer desirable physicochemical properties and low acute toxicity. This article presents a critical look at metallacarboranes in the context of their application in medicinal chemistry, emphasizing [COSAN]- as a potential game-changer in drug design and biomedical sciences. As medicinal chemistry seeks innovative building blocks, metallacarboranes emerge as an important novelty with versatile solutions and promising implications.

In-silico-assisted derivatization of triarylboranes for the catalytic reductive functionalization of aniline-derived amino acids and peptides with H2.

Cheminformatics-based machine learning (ML) has been employed to determine optimal reaction conditions, including catalyst structures, in the field of synthetic chemistry. However, such ML-focused strategies have remained largely unexplored in the context of catalytic molecular transformations using Lewis-acidic main-group elements, probably due to the absence of a candidate library and effective guidelines (parameters) for the prediction of the activity of main-group elements. Here, the construction of a triarylborane library and its application to an ML-assisted approach for the catalytic reductive alkylation of aniline-derived amino acids and C-terminal-protected peptides with aldehydes and H2 is reported. A combined theoretical and experimental approach identified the optimal borane, i.e., B(2,3,5,6-Cl4-C6H)(2,6-F2-3,5-(CF3)2-C6H)2, which exhibits remarkable functional-group compatibility toward aniline derivatives in the presence of 4-methyltetrahydropyran. The present catalytic system generates H2O as the sole byproduct.

One-step synthesis of amphiphilic copolymers PDMS-b-PEG using tris(pentafluorophenyl)borane and subsequent study of encapsulation and release of curcumin.

A series of amphiphilic block copolymer (BCP) micelles based on poly(dimethylsiloxane) (PDMS) and poly(ethylene glycol) (PEG) were synthesized by a one-step reaction in the presence of tris(pentafluorophenyl)borane (BCF) as a catalyst. The structural composition of PDMS-b-PEG (PR11) and PEG-b-PDMS-b-PEG (PR12) was corroborated by FTIR, 29Si NMR, and TGA. The BCPs were assembled in an aqueous solution, obtaining micelles between 57 and 87 nm in size. PR11 exhibited a higher (2.0 g L-1) critical micelle concentration (CMC) than PR12 (1.5 g L-1) due to the short chain length. The synthesized nano micelles were used to encapsulate curcumin, which is one of three compounds of turmeric plant 'Curcuma longa' with significant biological activities, including antioxidant, chemoprotective, antibacterial, anti-inflammatory, antiviral, and anti-depressant properties. The encapsulation efficiency of curcumin was 60% for PR11 and 45% for PR12. Regarding the release study, PR11 delivered 53% curcumin after five days under acidic conditions (pH of 1.2) compared to 43% at a pH of 7.4. The degradation products of curcumin were observed under basic conditions and were more stable at acidic pH. In both situations, the release process is carried out by breaking the silyl-ether bond, allowing the release of curcumin. PR11 showed prolonged release times, so it could be used to reduce ingestion times and simultaneously work as a nanocarrier for other hydrophobic drugs.

Carborane-FAPI conjugate: A potential FAP-targeted boron agent with improved boron content.

Boron neutron capture therapy (BNCT) has received extensive attention as an advanced binary radiotherapy method. However, BNCT still faces poor selectivity of boron agent and is insufficient boron content in tumor tissues. To improve the tumor-targeted ability and boron content, this research aims to design, synthesize and preliminary evaluate a new borane agent Carborane-FAPI, which coupling the o-carborane to the compound skeleton of a mature fibroblast activating protein (FAP) inhibitor (FAPI). FAP is a tumor-associated antigen. FAP expressed lowly in normal organs and highly expressed in tumors, so it is a potential target for diagnosis and treatment. Boronophenylalanine (BPA) is the most widely investigated BNCT drug in present. Compared with BPA, the boron content of a single molecule is increased and drug targeting is enhanced. The results show that Carboaren-FAPI has low toxicity to normal cells, and selective enrichment in tumor tissues. It is a promising boron drug that has the potential to be used in BNCT.

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.

Transfer Hydrogenation of Vinyl Arenes and Aryl Acetylenes with Ammonia Borane Catalyzed by Schiff Base Cobalt(II) Complexes.

A series of bench-stable Co(II) complexes containing hydrazone Schiff base ligands were evaluated in terms of their activity and selectivity in carbon-carbon multiple bond transfer hydrogenation. These cobalt complexes, especially a Co(II) precatalyst bearing pyridine-2-yl-N(Me)N=C-(1-methyl)imidazole-2-yl ligand, activated by LiHBEt3, were successfully used in the transfer hydrogenation of substituted styrenes and phenylacetylenes with ammonia borane as a hydrogen source. Key advantages of the reported catalytic system include mild reaction conditions, high selectivity and tolerance to functional groups of substrates.

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.

Fusing Bismuth and Mercaptocarboranes: Design and Biological Evaluation of Low-Toxicity Antimicrobial Thiolato Complexes.

This study proposes an innovative strategy to enhance the pharmacophore model of antimicrobial bismuth thiolato complex drugs by substituting hydrocarbon ligand structures with boron clusters, particularly icosahedral closo-dicarbadodecaborane (C2B10H12, carboranes). The hetero- and homoleptic mercaptocarborane complexes BiPh2L (1) and BiL3 (2) (L=9-S-1,2-C2B10H11) were prepared from 9-mercaptocarborane (HL) and triphenylbismuth. Comprehensive characterization using NMR, IR, MS, and XRD techniques confirmed their successful synthesis. Evaluation of antimicrobial activity in a liquid broth microdilution assay demonstrated micromolar to submicromolar minimum inhibitory concentrations (MIC) suggesting high effectiveness against S. aureus and limited efficacy against E. coli. This study highlights the potential of boron-containing bismuth complexes as promising antimicrobial agents, especially targeting Gram-positive bacteria, thus contributing to the advancement of novel therapeutic approaches.

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.

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.

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.