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“There's plenty of room at the bottom” (Richard Feynman, 1959): an invitation for (metalla)carboranes to enter the (new) field of nanomedicine. For two decades, the number of publications on boron cluster compounds designed for potential applications in medicine has been constantly increasing. Hundreds of compounds have been screened in vitro or in vivo for a variety of biological activities (chemotherapeutics, radiotherapeutics, antiviral, etc.), and some have shown rather promising potential for further development. However, until now, no boron cluster compounds have made it to the clinic, and even clinical trials have been very sparse. This review introduces a new perspective in the field of medicinal boron chemistry, namely that boron‐based drugs should be regarded as nanomedicine platforms, due to their peculiar self‐assembly behaviour in aqueous solutions, and treated as such. Examples for boron‐based 12‐ and 11‐vertex clusters and appropriate comparative studies from medicinal (in)organic chemistry and nanomedicine, highlighting similarities, differences and gaps in physicochemical and biological characterisation methods, are provided to encourage medicinal boron chemists to fill in the gaps between chemistry laboratory and real applications in living systems by employing bioanalytical and biophysical methods for characterising and controlling the aggregation behaviour of the clusters in solution., Before we can catch biological systems in their nanometre working dimension, we have to understand them on the physical (bulk and surface), chemical and biological level. Herein, we comprehensively review the current state of research and approaches in the field of boron cluster medicinal chemistry, highlighting successful approaches, exposing challenges and appealing to standardise the heterogeneous nanomedicine field.

Investigations on the antitumor activity of metallacarboranes are sparse in the literature and limited to a handful of ruthena‐ and molybdacarboranes. In this study, the molybdacarborane fragment [3‐(CO)2‐closo‐3,1,2‐MoC2B9H11] was combined with a vector molecule, inspired by the well‐known drug tamoxifen or 4,4′‐dihydroxytamoxifen (TAM‐diOH). The molybdacarborane derivative [3,3‐{4‐[1,1‐bis(4‐hydroxyphenyl)but‐1‐en‐2‐yl]‐2,2′‐bipyridine‐κ2 N,N′}‐3‐(CO)2‐closo‐3,1,2‐MoC2B9H11] (10), as well as the ligand itself 4‐[1,1‐bis(4‐hydroxyphenyl)but‐1‐en‐2‐yl]‐2,2′‐bipyridine (6) showed cytotoxic activities in the low micromolar range against breast adenocarcinoma (MDA‐MB‐231, MDA‐MB‐361 and MCF‐7), human glioblastoma (LN‐229) and human glioma (U‐251) cell lines. In addition, compounds 6 and 10 were found to induce senescence and cytodestructive autophagy, lower ROS/RNS levels, but only the molybdacarborane 10 induced a strong increase of nitric oxide (NO) concentration in the MCF‐7 cells., Privileged structures: Applying this drug design concept on the well‐known anticancer drug tamoxifen leads to its 2,2′‐bipyridine‐modified derivative, which is a vector for molybdacarboranes. The biological activity profile contrasts with those of other organic or inorganic selective estrogen receptor modulators: whereas the ROS/RNS levels are decreased, the NO levels increase. The ability to form nanoparticles with bovine serum albumin opens the way to modern nanomedicine.

Today, medicinal chemistry is still clearly dominated by organic chemistry, and commercially available boron-based drugs are rare. In contrast to hydrocarbons, boranes prefer the formation of polyhedral clusters via delocalized 3c2e bonds, such as polyhedral dicarba-closo-dodecaborane(12) (closo-C2B10H12). These clusters have remarkable biological stability, and the three isomers, 1,2- (ortho), 1,7- (meta), and 1,12-dicarba-closo-dodecaborane(12) (para), have attracted much interest due to their unique structural features. Furthermore, anionic nido clusters ([7,8-C2B9H11]2−), derived from the neutral icosahedral closo cluster 1,2-dicarba-closo-dodecaborane(12) by deboronation followed by deprotonation are suitable ligands for transition metals and offer the possibility to form metallacarboranes, for example via coordination through the upper pentagonal face of the cluster. The isolobal analogy between the cyclopentadienyl(–1) ligand (Cp−) and [C2B9H11]2− clusters (dicarbollide anion, Cb2−) is the motivation in using Cb2− as ligand for coordination to a metal center to design compounds for various applications. This review focuses on potential applications of half- and mixed-sandwich-type transition metal complexes in medicine.

We report on the unique self-assembling properties of one molybdacarborane (1) and two ruthenacarborane complexes (2 and 3) to spontaneously form nanoparticles alone or in combination with bovine serum albumin (BSA) in a 10:1 molar ratio (BSA:metallacarborane). The maverick behaviour of the metallacarboranes in aqueous media was investigated using several spectroscopic techniques, including nanoparticle tracking analysis, UV-Vis, fluorescence, Rayleigh light scattering and NMR spectroscopy, as well as MALDI-TOF mass spectrometry, from which a molecular picture of the nanoparticles was developed. The metallacarborane–albumin nanoparticles showed optimal stability in phosphate buffer (pH 7.4), retaining a mostly monomodal dispersion over 24 h, in contrast to the highly polydispersed nanoparticles of 1–3 alone. The three metallacarboranes were tested in vitro against the MCF-7 (breast carcinoma) cell line, using a BSA-free and a BSA-containing formulation. Surprisingly, the latter induced a significant increase in the cytotoxicity of 1, whereby it did not greatly affect the activity profile of 2 and 3. Finally, label-free confocal Raman imaging was applied to visualise the uptake of the metallacarboranes into single cells. The size of intracellular aggregates in the cytoplasm ranged from 300 nm to 5 μm. The discussed formulation concept is proposed as a new method to increase the bioactivity and the biological stability of poorly water-soluble (metalla)carboranes.

The molybdacarboranes [3-{L-κ2 N,N}-3-(CO)2 -closo-3,1,2-MoC2 B9 H11 ] (L=2,2'-bipyridine (2,2'-bpy, 1 a) or 1,10-phenanthroline (1,10-phen, 1 b)) incorporating well-known potentially non-innocent ligands (CO, 2,2'-bpy, 1,10-phen) and the "non-spectator" nido-carborane ([η5 -C2 B9 H11 ]2- ) ligand were prepared and fully characterised. High-resolution mass spectrometry, single-crystal X-ray diffraction methods, spectroscopy (IR, (resonance) Raman, NMR), cyclic voltammetry and spectroelectrochemistry (electrochemical properties) were supported by theoretical investigations of the electronic structure (DFT, CAS-SCF, TD-DFT).

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.

Carborane-substituted 1,2-diphosphetanes (Ia,b) react with elemental lithium in THF with cleavage of the P-P bond to give a deep red solution from which, in the case of Ia, red crystals of a lithiated intermediate, [{1-Li(THF)PtBu-6-PtBu-4,1,6-closo-Li(THF)C2 B10 H10 }{Li(THF)3 }]2 ⋅2 THF (2 a), are obtained. The compound is dimeric, C2 -symmetric and contains six lithium and four phosphorus atoms. Two lithium atoms cap the six-membered C2 B4 faces, resulting in two 13-vertex closo-clusters (according to Wade's rules) with docosahedral geometry. The addition of methyl iodide resulted in the formation of zwitterionic bis-phosphonium-nido-carborates 7,10-bis(tert-butyldimethylphosphonium)dodecahydro-7,10-dicarba-nido-dodecaborate(2-) (1 a) and 7,10-bis(N,N-diisopropylaminodimethylphosphonium)dodecahydro-7,10-dicarba-nido-dodecaborate(2-) (1 b) in moderate to good yields. Compounds 1 a and 1 b exhibit short Ccluster -P bonds and large Ccluster ⋅⋅⋅Ccluster distances in the solid state. Further insight into the ring opening and reduction potential of the alkyl halide was obtained from methylation reactions of different 1,2-bis-phosphinocarboranes. The reaction of rac-/meso-1,2-bis(tert-butylmethylphosphino)-1,2-dicarba-closo-dodecaborane(12) (3 a) with two equivalents of methyl iodide also resulted in the formation of 1 a (as shown by NMR spectroscopy), whereas the reaction of 1,2-bis(diphenylphosphino)-1,2-dicarba-closo-dodecaborane(12) with methyl triflate afforded the phosphonium salt 1-methyl-diphenylphosphonium-2-diphenylphosphino-1,2-dicarba-closo-dodecaborane(12) triflate (4) without reduction of the cluster.

International audience; This study details the formal hydrogenation of two magnesium(I) dimers {(Nacnac)Mg}2 (Nacnac = [{(C6H3R2-2,6)NCMe}2CH]−; R = Pri (DipNacnac), Et (DepNacnac)) using 1,3-cyclohexadiene. These reactions afford the magnesium(II) hydride complexes, {(Nacnac)Mg(μ-H)}2. Their reactions with excess CO are sterically controlled and lead cleanly to different C–C coupled products, viz. the ethenediolate complex, (DipNacnac)Mg{κ1-O-[(DipNacnac)Mg(κ2-O,O-O2C2H2)]}, and the first cyclopropanetriolate complex of any metal, cis-{(DepNacnac)Mg}3{μ-C3(H3)O3}. Computational studies imply the CO activation processes proceed via very similar mechanisms to those previously reported for related reactions involving f-block metal hydride compounds. This work highlights the potential magnesium compounds hold for use in the “Fischer–Tropsch-like” transformation of CO/H2 mixtures to value added oxygenate products.

The first structurally characterised two-coordinate hydrido-germylenes, :Ge(H)L (L = -N(Ar){Si(OBu)}, Ar = C6H2{C(H)Ph2}2R-2,6,4; R = Pr(i) ((tBuO)L(†)), Me ((tBuO)L*)), have been prepared, and their dimerisation shown to be thermodynamically unfavourable, largely due to the extreme steric bulk of their amide ligands.

Three [(η

Three [(η6-arene)RuC2B9H11] complexes (arene = p-cymene (2), biphenyl (3) and 1-Me-4-COOEt-C6H4 (4)) were synthesised according to modified literature procedures and fully characterised. 2–4 were found to be moderately active against two types of tumour cell lines (HCT116 and MCF7), with IC50 values in the low micromolar range. However, viability of normal, healthy cells (MRC-5 cell line, MLEC and mouse macrophages) was not affected by treatment with 2–4, indicating high selectivity of the metallacarborane complexes towards tumour cell lines, compared to the unselective antitumour agent cisplatin and other potential RuII drugs. Moreover, flow cytometric analysis suggested that 4 induces cell death via a caspase-dependent apoptotic mechanism. DFT calculations of the frontier molecular orbitals showed that the HOMO–LUMO gap in 2–4 is smaller than in the corresponding cyclopentadienyl complexes 2-Cp–4-Cp (e.g. 5.47 (2) vs. 6.31 eV (2-Cp)). In order to assess the stability of 2–4, particularly the ruthenium–dicarbollide bond, energy decomposition analysis (EDA) of 2–4, together with the respective cyclopentadienyl analogues 2-Cp–4-Cp, was performed. EDA suggests that the ruthenium(II)–dicarbollide bond in the three complexes is mostly ionic and far stronger than the ruthenium(II)–arene bond.

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.