Lipid membranes are notorious for their ability to maintain ionic concentration gradients, acting as efficient barriers to ions. However, the validity of this statement for nano-ions (ions of nanometric size which are in fact small charged molecules) is not obvious. Experimental results show that the presence of a concentration gradient of certain nano- ions (most notably cobaltabisdicarbollide ([o-COSAN] − an- ions), induce a current across intact artificial phospholipid bilayers. The mechanism underlying this observed translo- cation of nano-anions across membranes is unknown. Here we show, using molecular dynamics simulations, that the permeation of [o-COSAN] − anions across a lipid bilayer pro- ceeds in a cooperative manner. Single nano-ions can enter the bilayer but they cannot cross it due to a free energy barrier of about 8k B T . The interaction between these nano- ions inside a leaflet induces a flip-flop translocation mech- anism with the formation of transient, elongated structure inside the membrane. This cooperative flip-flop allows an efficient distribution of [o-COSAN] − anions in both bilay- ers of the membrane. These results suggest the existence of a new mechanism for permeation of nano-ions across lipid membranes, relevant for those that have the appropriate self-assembly character.

A new series of o-carborane-fused pyrazoles has been recently successfully synthesized. This fusion was expected to create a hybrid 3D/2D aromatic system, combining the 3D aromaticity of o-carborane with the 2D aromaticity of pyrazole. However, while the boron cage retains its aromatic character, the pyrazole’s aromaticity is lost. As a result, rather than forming o-carborane-fused pyrazoles, the synthesis yielded o-carborane-fused pyrazolines, which are non-aromatic. The limited overlap between the π molecular orbitals (MOs) of the planar heterocycle and the n + 1 MOs of the carborane prevents significant electronic delocalization between the two fused components. This contrasts with the fusion of pyrazole and benzene to form indazole, where both rings maintain their 2D aromaticity. Our findings demonstrate that the peripheral σ-aromaticity of carborane and the π-aromaticity of the heterocycle are orthogonal, making a true 3D/2D aromatic system unachievable. The carborane is highly aromatic, generating highly negative NICS values (−25 to −30 ppm). We have observed that these high NICS values extend to fused rings, leading to incorrect estimations of aromaticity. Therefore, relying solely on NICS can be misleading, and other computational indicators, along with experimental or structural data, should be used to accurately assess aromaticity.

Abstract Background Protons, which are considered low-LET (Linear Energy Transfer) radiation, have an average RBE (relative biological effectiveness) of 1.1, with a range from 0.7 to 1.6. Thus, increasing biological effectiveness is of high interest in radiation oncology, and one way to enhance this is by using radiosensitizers. The present work investigates the effectiveness of the proton boron fusion reaction (PBFR) at the cellular level, using the sodium salt of metallacarborane [3,3’-Co(C2B9H11)2]− (Na[o-COSAN]) as the boron source, aiming to explore the potential of this type of boron clusters as a radiosensitizer for proton therapy. Therefore, the main goal was to test the hypothesis that loading the cells with boron will favour the PBFR at energies close to the Bragg peak. This would enhance the radiation-induced biological effects through the production of alpha-particles. Results MDA-MB-231 breast cancer cells were used. Nuclear microscopy assessed [o-COSAN] uptake and distribution in single cells, while biodistribution was studied in tumor-bearing Balb/cSlc-nu/nu mice (MDA-MB-231 xenograft), with boron accumulation in target organs and tumor measured by ICP-OES. The cells were irradiated with a proton beam tuned to reach the PBFR resonance energy of 675 keV at the cell layer. DNA damage was assessed with the g-H2AX assay and cell survival with the clonogenic assay. Beam parameters and dose calibration curves using radiochromic films validated Monte Carlo dosimetry simulations. As expected, we observed higher biological damage in irradiated cells and the presence of [o-COSAN]− potentiated the damage. These results translate into a lower cellular viability, indicating that DNA damage imposed colonies smaller than their non-irradiated counterparts. This suggests that these damages either took longer time to be repaired or made the cells undergo less efficient survival mechanisms. Conclusions The radiosensitizing effect of [o-COSAN]− by strategic cellular 11B placement and proton irradiation intensifies the DNA damage, making the nucleus particularly susceptible and thus increasing the destructive capability of alpha-particles, generated in the nuclear fusion reaction, which may lead to increased cell mortality.

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.

Background: Boron neutron capture therapy (BNCT) is a tumor-selective particle radiotherapy that combines preferential boron accumulation in tumors and neutron irradiation. Based on previous studies in tumor-bearing mice, this study evaluated the biodistribution of the sodium salt of cobaltabis(dicarbollide) (Na[3,3′-Co(C2B9H11)2], abbreviated as Na[o-COSAN]) in the hamster cheek pouch oral cancer model and the Na[o-COSAN]/BNCT therapeutic effect on tumors and induced radiotoxicity. The synthesis and comprehensive characterization of 10B-enriched trimethylammonium salt of nido-[7,8-C210B9H12]−o-carborane, along with the cesium and sodium salts of [o-10COSAN] cobaltabis(dicarbollide) are reported here for the first time. Methods: Hamsters bearing tumors were injected with Na[o-COSAN] (7.5 mg B/kg) and euthanized at different time-points after injection (30 min, 2, 3, 5, and 18 h post-administration) to evaluate boron uptake in different tissues/organs. Based on these results, tumor-bearing animals were treated with Na[10B-o-COSAN]/BNCT (7.5 mg B/kg b.w., 3 h), prescribing 5 Gy total in absorbed dose to the precancerous tissue surrounding tumors, i.e., the dose-limiting tissue. Results: Na[o-10COSAN] exhibited no toxicity. Although biodistribution studies employing Na[o-COSAN] have shown low absolute boron concentration in the tumor (approx. 11 ppm), Na[o-10COSAN]/BNCT induced a high and significant therapeutic effect on tumors versus the control group (cancerized, untreated animals). Moreover, only half of the animals exhibited severe mucositis in the precancerous dose-limiting tissue after BNCT, which resolved completely at 21 days after irradiation. Conclusions: Na[o-10COSAN] would be potentially useful to treat head and neck cancer with BNCT.

A new cooperative photoredox catalytic system, [RuII(trpy)(bpy)(H2O)][3,3′-Co(8,9,12-Cl3-1,2-C2B9H8)2]2, 5, has been synthesized and fully characterized for the first time. In this system, the photoredox catalyst [3,3′-Co(8,9,12-Cl3-1,2-C2B9H8)2]− [Cl6-1]−, a metallacarborane, and the oxidation catalyst [RuII(trpy)(bpy)(H2O)]2+, 2 are linked by non-covalent interactions. This compound, along with the one previously synthesized by us, [RuII(trpy)(bpy)(H2O)][(3,3′-Co(1,2-C2B9H11)2]2, 4, are the only examples of cooperative molecular photocatalysts in which the catalyst and photosensitizer are not linked by covalent bonds. Both cooperative systems have proven to be efficient photocatalysts for the oxidation of alkenes in water through Proton Coupled Electron Transfer processes (PCETs). Using 0.05 mol% of catalyst 4, total conversion values were achieved after 15 min with moderate selectivity for the corresponding epoxides, which decreases with reaction time, along with the TON values. However, with 0.005 mol% of catalyst, the conversion values are lower, but the selectivity and TON values are higher. This occurs simultaneously with an increase in the amount of the corresponding diol for most of the substrates studied. Photocatalyst 4 acts as a photocatalyst in both the epoxidation of alkenes and their hydroxylation in aqueous medium. The hybrid system 5 shows generally higher conversion values at low loads compared to those obtained with 4 for most of the substrates studied. However, the selectivity values for the corresponding epoxides are lower even after 15 min of reaction. This is likely due to the enhanced oxidizing capacity of CoIV in catalyst 5, resulting from the presence of more electron-withdrawing substituents on the metallacarborane platform.

Replacement of a phenyl moiety with a 3D-carborane cluster induces a more effective energy transfer on lanthanide ions.

Anticancer drugs inhibit DNA replication by intercalating between DNA base pairs, forming covalent bonds with nucleotide bases, or binding to the DNA groove. To develop safer drugs, novel molecular structures with alternative binding mechanisms are essential. Stable boron hydrides offer a promising alternative for cancer therapy, opening up additional options like boron neutron capture therapy based on 10B and thermal neutron beams or proton boron fusion therapy using 11B and proton beams. These therapies are more efficient when the boron compound is ideally located inside cancer cells, particularly in the nucleus. Current cancer treatments often utilize small, polycyclic, aromatic, planar molecules that intercalate between ds-DNA base pairs, requiring only a spacing of approximately 0.34 nm. In this paper, we demonstrate another type of intercalation. Notably, [3,3 '-Fe(1,2-C2B9H11)2]-, ([o-FESAN]-), a compact 3D molecule measuring 1.1 nm x 0.6 nm, can as well intercalate by strong non-bonding interactions preferentially with guanine. Unlike known intercalators, which are positive or neutral, [o-FESAN]- is a negative species and when an [o-FESAN]- molecule approaches the negatively charged DNA phosphate chain an anion-anion interaction consistently anti-electrostatic via Ccluster-H & ctdot;O-P bonds occurs. Then, when more molecules approach, an elongated outstandingly self-assembled structure of [o-FESAN]--[o-FESAN]- forms moving anions towards the interthread region to interact with base pairs and form aggregates of four [o-FESAN]- anions per base pair. These aggregates, in this environment, are generated by Ccluster-H & ctdot;O-C, N-H & ctdot;H-B and Ccluster-H & ctdot;H-B interactions. The ferrabis(dicarbollide) boron-rich small molecules not only effectively penetrate the nucleus but also intercalate with ds-DNA, making them promising for cancer treatment. This amphiphilic anionic molecule, used as a carrier-free drug, can enhance radiotherapy in a multimodal perspective, providing healthcare professionals with improved tools for cancer treatment. This work demonstrates these findings with a plethora of techniques. The amphiphilic anionic ferrabis(dicarbollide) boron-rich small molecule effectively penetrates the nucleus as a carrier-free drug and intercalates with ds-DNA base pairs, making it a promising candidate for multimodal cancer radiotherapy.

Cobaltabis(dicarbollides), ferrabis(dicarbollide), and their halogenated derivatives are the most studied metallacarboranes with great medical potential. These versatile compounds and their iodinated derivatives can be used in chemotherapy, radiotherapy, particle therapy, and bioimaging when isotopes are used. These metallacarboranes have been evaluated in vitro and recently in vivo with complex animal models. Lately, these studies have been complemented using the invertebrate Caenorhabditis elegans (C. elegans), a nematode largely used in toxicology. When evaluated at the L4 stage, cobaltabis(dicarbollides), ([o-COSAN]- and [8,8'-I-2-o-COSAN]-), exhibited a higher mean lethal dose (LD50) than ferrabis(dicarbollides) ([o-FESAN]- and [8,8'-I-2-o-FESAN]-). In this work, we used the C. elegans embryos since they are a complex biological barrier with concentric layers of polysaccharides and proteins that protect them from the environment. We assessed if the metal atom changes their biointeraction with the C. elegans embryos. First, we assessed the effects on embryo development for metallacarboranes and their di-iodinated derivatives. We observed changes in color and in their surface structure. An exhaustive physicochemical characterization was performed to understand better this interaction, revealing a stronger interaction of ferrabis(dicarbollide) compounds with C. elegans embryos than the cobaltabis(dicarbollide) molecules. Unveiling the biological interaction of these compounds is of great interest for their future biomedical applications.

3D-aromatic molecules with (distorted) tetrahedral, octahedral, or spherical structures are much less common than typical 2D-aromatic species or even 2D-aromatic-in-3D systems. Closo boranes, [BnHn]2- (5 ≤ n ≤ 14) and carboranes are examples of compounds that are singly 3D-aromatic, and we now explore if there are species that are doubly 3D-aromatic. The most widely known example of a species with double 2D-aromaticity is the hexaiodobenzene dication, [C6I6]2+. This species shows π-aromaticity in the benzene ring and σ-aromaticity in the outer ring formed by the iodine substituents. Inspired by the hexaiodobenzene dication example, in this work, we explore the potential for double 3D-aromaticity in [B12I12]0/2+. Our results based on magnetic and electronic descriptors of aromaticity together with 11B{1H} NMR experimental spectra of boron-iodinated o-carboranes suggest that these two oxidized forms of a closo icosahedral dodecaiodo-dodecaborate cluster, [B12I12] and [B12I12]2+, behave as doubly 3D-aromatic compounds. However, an evaluation of the energetic contribution of the potential double 3D-aromaticity through homodesmotic reactions shows that delocalization in the I12 shell, in contrast to the 10σ-electron I62+ ring in the hexaiodobenzene dication, does not contribute to any stabilization of the system. Therefore, the [B12I12]0/2+ species cannot be considered as doubly 3D-aromatic.

Multi‐metallic multivariate (MTV) rare earth (RE) metal−organic frameworks (MOFs) are of interest for the development of multifunctional materials, however examples with more than three RE cations are rare and obstructed by compositional segregation during synthesis. Herein, this work demonstrates the synthesis of a multi‐metallic MTV RE MOF incorporating two, four, six, or eight different RE ions with different sizes and in nearly equimolar amounts and no compositional segregation. The MOFs are formed by a combination of RE cations (La, Ce, Eu, Gd, Tb, Dy, Y, and Yb) and a 1,7‐di(4‐carboxyphenyl)‐1,7‐dicarba‐ closo ‐dodecaborane ( m CB‐L) linker. The steric bulkiness and acidity of m CB‐L is crucial for the incorporation of different size RE ions into the MOF structure. Demonstration of the incorporation of all RE cations is performed via compositional and structural characterization. The more complex MTV MOF, including all eight RE ions ( m CB‐8RE), are also characterized using optical, thermal, and magnetic techniques. Element‐selective X‐ray absorption spectroscopy and X‐ray Magnetic Circular Dichroism measurements allow us to characterize spectroscopically each of the eight RE ions and determine their magnetic moments. This work paves the way for the investigation of MTV MOFs with the possibility to combine RE ions à la carte for diverse applications.

A ruthenium aqua photoredox catalyst has been successfully heterogeneneized on graphene oxide (GO@trans-fac-3) and graphite rods (GR@trans-fac-3) for the first time and have proven to be sustainable and easily reusable systems for the photooxidation of alcohols in water, in mild and green conditions. We report here the synthesis and total characterization of two Ru(II)-polypyridyl complexes, the chlorido trans-fac-[RuCl(bpea-pyrene)(bpy)](PF6) (trans-fac-2) and the aqua trans-fac-[Ru(bpea-pyrene)(bpy)OH2](PF6)(2) (trans-fac-3), both containing the N-tridentate, 1-[bis(pyridine-2-ylmethyl)amino]methylpyrene (bpea-pyrene), and 2,2 '-bipyridine (bpy) ligands. In both complexes, only a single isomer, the trans-fac, has been detected in solution and in the solid state. The aqua complex trans-fac-3 displays bielectronic redox processes in water, assigned to the Ru(IV/II) couple. The trans-fac-3 complex has been heterogenized on different types of supports, (i) on graphene oxide (GO) through pi-stacking interactions between the pyrene group of the bpea-pyrene ligand and the GO and (ii) both on glassy carbon electrodes (GC) and on graphite rods (GR) through oxidative electropolymerization of the pyrene group, which yield stable heterogeneous photoredox catalysts. GO@trans-fac-3- and GR/poly trans-fac-3-modified electrodes were fully characterized by spectroscopic and electrochemical methods. Trans-fac-3 and GO@trans-fac-3 photocatalysts (without a photosensitizer) showed good catalytic efficiency in the photooxidation of alcohols in water under mild conditions and using visible light. Both photocatalysts display high selectivity values (>99%) even for primary alcohols in accordance with the presence of two-electron transfer processes (2e(-)/2H(+)). GO@trans-fac-3 keeps intact its homogeneous catalytic properties but shows an enhancement in yields. GO@trans-fac-3 can be easily recycled by filtration and reused for up to five runs without any significant loss of catalytic activity. Graphite rods (GR@trans-fac-3) were also evaluated as heterogeneous photoredox catalysts showing high turnover numbers (TON) and selectivity values.

As an antibody-free sensing membrane for the detection of the antibiotic tetracycline (TC), a liquid PVC membrane doped with the ion-pair tetracycline/θ-shaped anion [3,3′-Co(1,2-C2B9H11)2]− ([o-COSAN]−) was formulated and deposited on a SWCNT modified gold microelectrode. The chosen transduction technique was electrochemical impedance spectroscopy (EIS). The PVC membrane was composed of: the tetracycline/[o-COSAN]− ion-pair, a plasticizer. A detection limit of 0.3 pg/L was obtained with this membrane, using bis(2-ethylhexyl) sebacate as a plasticizer. The sensitivity of detection of tetracycline was five times higher than that of oxytetracycline and of terramycin, and 22 times higher than that of demeclocycline. A shelf-life of the prepared sensor was more than six months and was used for detection in spiked honey samples. These results open the way to having continuous monitoring sensors with a high detection capacity, are easy to clean, avoid the use of antibodies, and produce a direct measurement.

The feasibility of using an external beam microprobe facility to explore the biological effects generated by proton irradiation in cultured cells is demonstrated. An in-air irradiation set-up was developed that allows energy tuning and enables estimating the flux and dose deposition in cells. A pilot study on the effect of boron-rich metallacarboranes as radiosensitizers towards human glioblastoma cells was carried out. This served as a proof of concept for the enhancement effect of proton irradiation induced by the presence of boron, which undergoes a nuclear 11 B(p, α ) αα reaction. Details of the experimental set-up and physical parameters measured are presented. Also, preliminary results of cell’s irradiation and uncertainties are discussed anticipating the advances that have been achieved by our group in this field.

The homolytic elimination of two H atoms from two adjacent carbons in benzene results in the aromatic product o-benzyne. In a similar way, the homolytic elimination of two H atoms from the two adjacent carbons in 1,2-C2B10H12 results in the aromatic product o-carboryne. In this work, we provide experimental and computational evidences that despite the similarity of o-carboryne and o-benzyne, the nature of the C-C bond generated between two adjacent carbons that lose H atoms is different. While in o-benzyne the C-C bond behaves as a triple bond, in o-carboryne the C-C bond is a double bond. Therefore, we must stop naming 1,2-dehydro-o-carboryne as o-carboryne but instead call it o-carborene.

This proceeding article compiles current research on the development of boron delivery drugs for boron neutron capture therapy that was presented and discussed at the National Cancer Institute (NCI) Workshop on Neutron Capture Therapy that took place on April 20-22, 2022. The most used boron sources are icosahedral boron clusters attached to peptides, proteins (such as albumin), porphyrin derivatives, dendrimers, polymers, and nanoparticles, or encapsulated into liposomes. These boron clusters and/or carriers can be labeled with contrast agents allowing for the use of imaging techniques, such as PET, SPECT, and fluorescence, that enable quantification of tumor-localized boron and their use as theranostic agents.

The removal of organophosphorus (OP) herbicides from water has been studied using adsorptive removal, chemical oxidation, electrooxidation, enzymatic degradation, and photodegradation. The OP herbicide glyphosate (GP) is one of the most used herbicides worldwide, leading to excess GP in wastewater and soil. GP is commonly broken down in environmental conditions to compounds such as aminomethylphosphonic acid (AMPA) or sarcosine, with AMPA having a longer half-life and similar toxicity to GP. Metal-organic frameworks (MOFs) are excellent materials for purifying OP herbicides from water due to their ability to combine adsorption and photoactivity within one material. Herein, we report the use of a robust Zr-based MOF with a meta-carborane carboxylate ligand (mCB-MOF-2) to examine the adsorption and photodegradation of GP. The maximum adsorption capacity of mCB-MOF-2 for GP was determined to be 11.4 mmol/g. Non-covalent intermolecular forces between the carborane-based ligand and GP within the micropores of mCB-MOF-2 are thought to be responsible for strong binding affinity and capture of GP. After 24 h of irradiation with ultraviolet-visible (UV-vis) light, mCB-MOF-2 selectively converts 69% of GP to sarcosine and orthophosphate, following the C-P lyase enzymatic pathway and biomimetically photodegrading GP. Circumventing the production of AMPA is desirable, as it has a longer half-life and similar toxicity to GP. The exceptional adsorption capacity of GP by mCB-MOF-2 and its biomimetic photodegradation to non-toxic sarcosine make it a promising material for removing OP herbicides from water.

Glioblastoma (GBM), as the most central nervous system (CNS) intractable disease, has spoiled millions of lives due to its high mortality. Even though several efforts have been made, the existing treatments have had limited success. In this sense, we studied a lead compound, the boron-rich selective epidermal growth factor receptor (EGFR)-inhibitor hybrid 1, as a potential drug for GBM treatment. For this end, we analyzed the in vitro activity of hybrid 1 in a glioma/primary astrocytes coculture, studying cellular death types triggered by treatment with this compound and its cellular localizations. Additionally, hybrid 1 concentrated boron in glioma cells selectively and more effectively than the boron neutron capture therapy (BNCT)-clinical agent 10B-l-boronophenylalanine and thus displayed a better in vitro-BNCT effect. This encouraged us to analyze hybrid 1 in vivo. Therefore, immunosuppressed mice bearing U87 MG human GBM were treated with both 1 and 1 encapsulated in a modified liposome (recognized by brain–blood barrier peptide transporters), and we observed a potent in vivo per se antitumor activity (tumor size decrease and animal survival increase). These data demonstrate that 1 could be a promising new targeted therapy for GBM.

Visualization of a protein in its native form and environment without any interference has always been a challenging task. Contrary to the assumption that protein surfaces are smooth, they are in fact highly irregular with undulating surfaces. Hence, in this study, we have tackled this ambiguous nature of the 'surface' of a protein by considering the 'effective' protein surface (EPS) with respect to its interaction with the geometrically well-defined and structurally inert anionic molecule [3,3'-Co(1,2-C2B9H11)2]-, abbreviated as [o-COSAN]-, whose stability, propensity for amine residues, and self-assembling abilities are well reported. This study demonstrates the intricacies of protein surfaces exploiting simple electrochemical measurements using a 'small molecule' redox-active probe. This technique offers the advantage of not utilizing any harsh experimental conditions that could alter the native structure of the protein and hence the protein integrity is retained. Identification of the amino acid residues which are most involved in the interactions with [3,3'-Co(1,2-C2B9H11)2]- and how a protein's environment affects these interactions can help in gaining insights into how to modify proteins to optimize their interactions particularly in the fields of drug design and biotechnology. In this research, we have demonstrated that [3,3'-Co(1,2-C2B9H11)2]- anionic small molecules are excellent candidates for studying and visualizing protein surfaces in their natural environment and allow proteins to be classified according to the surface composition, which imparts their properties. [3,3'-Co(1,2-C2B9H11)2]- 'viewed' each protein surface differently and hence has the potential to act as a simple and easy to handle cantilever for measuring and picturing protein surfaces.