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Pure and Applied Chemistry

The Scientific Journal of IUPAC

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Volume 87, Issue 2


Carbaboranes – more than just phenyl mimetics

René Frank
  • Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
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/ Verena Ahrens / Solveig Boehnke
  • Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
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/ Sven Hofmann / Martin Kellert
  • Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
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/ Stefan Saretz
  • Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
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/ Souvik Pandey
  • Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
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/ Menyhárt Sárosi
  • Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
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/ Ágota Bartók
  • Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
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/ Annette G. Beck-Sickinger / Evamarie Hey-Hawkins
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  • Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
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Published Online: 2015-01-06 | DOI: https://doi.org/10.1515/pac-2014-1006


Dicarba-closo-dodecaboranes(12) (C2B10H12, carbaboranes) are highly hydrophobic and stable icosahedral carbon-containing boron clusters. The cage framework of these clusters can be modified with a variety of substituents, both at the carbon and at the boron atoms. Substituted carbaboranes are of interest in medicine as boron neutron capture therapy (BNCT) agents or as pharmacophores. High and selective accumulation in tumour cells is an important requirement for a BNCT agent and is achieved by incorporating boron-rich, water-soluble carbaborane derivatives into breast tumour-selective modified neuropeptide Y, [F7, P34]-NPY. Preliminary studies showed that the receptor binding affinity and signal transduction of the boron-modified peptides were very well retained. Use of carbaboranes as pharmacophores was shown by replacement of Bpa32 (Bpa=benzoylphenylalanine) in the reduced-size NPY analogue [Pro30, Nle31, Bpa32, Leu34]-NPY 28–36 by ortho-carbaboranyl propanoic acid. The inclusion of the carbaborane derivative resulted in a short NPY agonist with an interesting hY2R/hY4R preference. This might be a promising approach in the field of anti-obesity drug development.

Keywords: BNCT; carbaboranes; carboranes; IMEBORON XV; NPY–carbaborane conjugates; pharmacophores; tumour selectivity

Article note

A collection of invited papers based on presentations at the 15th International Meeting on Boron Chemistry (IMEBORON-XV), Prague, Czech Republic, 24–28 August 2014.


To date, medicinal chemistry is still dominated by organic chemistry, and most of the known drugs are purely organic compounds. On the other hand, boron is nearly unknown as an element in commercial drugs [1]. In contrast to hydrocarbons, boranes prefer the formation of polyhedral clusters (to overcome the electron deficiency) [2, 3]. Since the discovery of dicarba-closo-dodecaboranes(12) (C2B10H12, carbaboranes) in 1963, various applications [4] have been found in catalysis [5–10], materials design [11–13], and medicine [14]. Dicarba-closo-dodecaboranes(12), in which two BH units of closo-B12H122– are replaced by two CH vertices, have remarkable biological stability and two carbon atoms as well as specific boron atoms as starting point for various organic modifications.

Carbaboranes for medicinal applications are preferably used as boron carriers to design boron neutron capture therapy (BNCT) agents. However, carbaboranes were also found to be very good scaffolds for diagnostics and therapeutics [15]. BNCT has been comprehensively summarised and the medicinal potential of carbaboranes has also been reviewed [14–20]. The first BNCT agents were reported some time ago [17], but the investigation of carbaboranes as pharmacophores [21] is more recent [22–25]. Here, both approaches are presented: the development of selective carbaborane derivatives as potential BNCT agents and the use of carbaboranes as pharmacophores.

Carbaboranes as potential BNCT agents

BNCT is based on the idea of selectively delivering boron compounds to tumour tissue, which is subsequently irradiated with non-hazardous, thermal neutrons. The latter cause a nuclear reaction with the 10B isotope, which has a natural abundance of ca. 19.9 % and a remarkable capability of capturing thermal neutrons with a capture cross section of ca. 3800 barn [26, 27].


The 7Li and 4He nuclei released in the fragmentation of short-lived 11B*, which is formed upon thermal neutron capture of 10B (10B(n,α)7Li), are particles with a high linear energy transfer (high-LET). Thus, they may exert a highly destructive action on cells. Their travel distance is limited to a range of ca. 10 μm, which coincides with the diameter of most cells. Accordingly, there is a good chance to deposit a high radiation dose inside the cell without compromising the integrity of the surrounding tissue [26].

Both the intracellular production of cytotoxic particles and their limited area of action are the major advantages of BNCT compared to classical chemotherapeutic methods [26]. However, targeted delivery of 10B into tumour cells and high and selective accumulation in tumour cells are important requirements for a BNCT agent [14, 26–28]. For successful treatment, a concentration of 30 μg 10B per gram tumour must be achieved.

Up to now, only two boron-containing compounds have been investigated intensively in clinical trials: 4-dihydroxyborylphenylalanine (BPA) and the mercaptoundecahydrododecaborate (BSH) anion. Due to poor targeting (BSH) and low boron loading per molecule (BPA), comparably large quantities of these boron-delivery agents must be applied for reasonable tumour uptake [29]. Therefore, compounds with a high affinity and selectivity to tumour cells represent an interesting option as boron carriers.

In the past two decades, mostly compact, boron-rich moieties, e.g., dodecahydrododecaborate(2–) (B12H122–) and carbaboranes, have been functionalised and investigated as boron-delivering agents. The main problems to date are the availability of boron compounds which exhibit the necessary water solubility and low toxicity in high concentrations and the targeted delivery of 10B into the tumour cells [16].

We have therefore devised efficient syntheses for novel boron compounds which provide a combined tumour-targeting system: carbaborane-containing amino acids and carboxylic acids for incorporation in modified neuropeptide Y to selectively target breast cancer cells.

Carbaborane–peptide conjugates

Recently, peptides have captured much attention as therapeutic compounds [30]. Peptide compounds comprising boron moieties such as boronated starburst dendrimers or BSH, applicable for BNCT, have been described [31–33]. Also, carbaboranes have been integrated into the peptide sequences of well-known therapeutic peptides, especially for the selective delivery of a large amount of boron to tumour cells. Carbaborane-conjugated Tyr3-octreotate derivatives with high internalisation rates were developed to act as tumour-targeting vectors and exhibit nm binding affinities to the somatostatin receptor subtype 2 depending on the spacer length between the carbaborane and the cyclic peptide [34]. These findings demonstrate the suitability of carbaborane–peptide conjugates as potential boron carriers for BNCT. Other peptides which are suggested as carrier systems for the targeted delivery of 10B into the tumour cells are somatostatin (SST), epidermal growth factor (EGF), neurotensin, substance P, gastrin-releasing peptide (GRP), insulin-like growth factor (IGF) [31, 32], alpha-melanocyte stimulating hormone (α-MSH), cholecystokinin (CCK), vascoactive intestinal peptide (VIP), bombesin (BN), and neuropeptide Y (NPY) [35]. As a member of the pancreatic polypeptide family, NPY is composed of 36 amino acid residues and C-terminally amidated. It is one of the most abundant neuropeptides in the brain [36], binds to four Y-receptor subtypes (Y1, Y2, Y4 and Y5) in nanomolar concentration and subsequently triggers receptor-mediated endocytosis [37]. The signal transduction of Y receptors follows a G protein-coupled (GPC) receptor cascade [38, 39]. Beck-Sickinger et al. have developed a modified neuropeptide Y, [F7, P34]-NPY, that was shown to preferentially bind to the human Y1 receptor compared to other Y-receptor subtypes with a high tolerance towards modifications [40]. Since Y1 receptors were found to be over-expressed in 90 % of all types of breast cancer and in 100 % of all metastases, we considered [F7, P34]-NPY as a potent selective carrier for 10B into breast tumour cells.

Fmoc-protected l-lysine was treated with ortho-carbaboranyl propanoic acid to give the carbaborane-modified l-lysine derivative shown in Fig. 1. This artificial amino acid was then incorporated at the 4-position of NPY and [F7, P34]-NPY by an optimised solid-phase peptide synthesis using Fmoc protection. Binding studies and intracellular inositol phosphate (IP) accumulation assays confirmed nanomolar affinity and activity of the modified analogues despite the large carbaborane cluster. Internalisation studies using fluorescence-tagged Y receptors revealed excellent and receptor subtype specific uptake of the conjugates into respective cells [41]. Therefore, these compounds are very promising for future in vivo studies.

Carbaborane-modified l-lysine derivative [41].
Fig. 1

Carbaborane-modified l-lysine derivative [41].

However, the synthesis of ortho-carbaboranyl propanoic acid for peptide coupling proved to be tedious and time-consuming [41]. An alternative building block, 9-(carboxymethylthio)-1,2-dicarba-closo-dodecaborane(12) (2), which retains the steric behaviour and is compatible with the requirements of the Fmoc-based solid-phase peptide synthesis, was therefore employed (Scheme 1). Compound 2 can be prepared with a higher overall yield and in fewer steps compared to ortho-carbaboranyl propanoic acid [41, 42].

Furthermore, as coupling of the carbaborane as a predesigned amino acid building block is a time-consuming process, 2 was employed for coupling to the peptide at lysine in the 4-position in the last step of the synthetic procedure before cleavage from the polymeric support [42].

Synthesis of 1 and 2 [42].
Scheme 1

Synthesis of 1 and 2 [42].

For successful application of BNCT, a high rate of boron uptake is essential. It is assumed that 109 boron atoms per cell are necessary to exert an effective dose in tumour cells [43]. In order to increase the boron content per peptide molecule, a multi-carbaborane peptide was designed. Position 4 in [F7, P34]-NPY is well known not to be sensitive towards various modifications with respect to receptor binding or activation. Different positions in the peptide were screened for their susceptibility for carbaborane modification, and the three positions with the lowest EC50 value in receptor activity studies (positions 4, 18 and 22) were selected for the synthesis of a multi-carbaborane peptide. Therefore, three carbaborane moieties (compound 2) were coupled simultaneously to the peptide sequence [K4, 18, 22, F7, P34]-NPY yielding a peptide with 30 boron atoms, and a threefold increased boron content compared to the previous compounds was achieved [42]. This multi-carbaborane peptide showed an activation and internalisation pattern at the hY1-receptor comparable to that of the native ligand NPY and an improved activation behaviour compared to its respective mono-carbaborane analogues. Boron-uptake studies by inductively coupled plasma mass spectrometry (ICP-MS) revealed successful uptake of the multi-carbaborane peptide into hY1-receptor expressing cells exceeding the required amount of 109 boron atoms per cell. This result demonstrates that the NPY/hY-receptor system can act as an effective transportation system for boron-containing moieties [42].

ortho-Carbaborane [1,2-dicarba-closo-dodecaborane(12), 1,2-closo-C2B10H12] is the most studied carbaborane, and numerous derivatives have been prepared and investigated for potential applications in medicinal chemistry [for boron neutron capture therapy (BNCT) and as a pharmacophore] [14, 15, 24, 44–46] and materials science (in polymers and dendrimers) [47–54]. In most of these tailor-made carbaborane derivatives, only the cluster carbon atoms are substituted, limiting this approach to the introduction of only two substituents [46]. However, for further modifications carbaborane clusters with more than two substituents are required. 1,2-Dicarba-closo-dodecaborane(12)-9-thiol (9-HS-1,2-closo-C2B10H11, 1) can readily be produced in high yield from ortho-carbaborane and sulfur [55] or S2Cl2 [56] in the presence of AlCl3 followed by reduction (Scheme 1). The interest in sulfur-substituted carbaboranes has increased in the past years, as the reactivity of the thiol group can be tuned by means of the vertex of the cluster to which it is attached [57, 58]. However, to date, only a few published methods focus on the introduction of sulfur followed by further functionalisation of other vertices of the cluster [59, 60]. We have shown that 1 is a valuable intermediate in simple routes towards new structures: both cluster carbon atoms can undergo further functionalisation according to common protocols [61–63], and the mercapto group may act as a strong nucleophile [59].

1,2-Dicarba-closo-dodecaborane(12)-9-thiol (1) was shown to be a highly suitable precursor allowing substitution at the carbon atoms after protecting the thiol with a tert-butyl (tBu) group. By employing this tBu protection strategy, the synthesis of bis-galactosyl-substituted ortho-carbaborane carboxylic acid 3 by stepwise introduction of diisopropylidene-protected galactose moieties was achieved (Fig. 2), and the procedure is suggested as a general approach towards carbaboranes with three substituents. Furthermore, the pronounced nucleophilicity of 1 allows the facile synthesis of a tris(ortho-carbaborane) building block 4 (Fig. 2) starting from pentaerythritol [59].

Bis-galactosyl-substituted ortho-carbaborane carboxylic acid 3 and a tris-(ortho-carbaborane) building block 4 obtaind from 1,2-dicarba-closo-dodecaborane(12)-9-thiol (1) [59].
Fig. 2

Bis-galactosyl-substituted ortho-carbaborane carboxylic acid 3 and a tris-(ortho-carbaborane) building block 4 obtaind from 1,2-dicarba-closo-dodecaborane(12)-9-thiol (1) [59].

By employing a similar strategy, 1,2-bis(hydroxymethyl)-9-mercapto-1,2-dicarba-closo-dodecaborane(12) (5) was obtained by treating tert-butyl-protected 9-carbaboranylthiol with tetrabutylammonium fluoride and paraformaldehyde. After deprotection, the thiol group could be further modified without additional protection of the hydroxyl groups to obtain a trifunctionalised o-carbaborane-containing building block, namely, 1,2-bis(hydroxymethyl)-9-(tert-butylcarbonylmethyl-thio)-1,2-dicarba-closo-dodecaborane(12), demonstrating the versatility of this novel building block (Scheme 2) [64].

Synthesis of 5 [64].
Scheme 2

Synthesis of 5 [64].

Building blocks 3, 4 and 5 are currently being incorporated into tumour-selective peptides, and further biochemical assessment will follow.

Carbaboranes as pharmacophores

In medicinal chemistry carbaboranes have been used almost exclusively as boron carriers for BNCT. Recent developments extended the carrier approach and used carbaboranes as scaffolds for radiodiagnostic or therapeutic agents [14–20, 22–24, 44–46]. Carbaboranes occupy a space which is slightly larger than a rotating benzene ring [24]. The phenyl analogy was already applied in the synthesis of carbaborane analogues of tamoxifen [65] and trimethoprim [66]. Carbaborane-modified flufenamic acid and diflunisal, two nonsteroidal anti-inflammatory drugs (NSAID) [67], as well as carbaborane-modified aspirin (asborin) [68–70], indomethacin (indoborin) [71, 72] and other indole derivatives [73, 74] were also reported.

Furthermore, carbaboranes show orthogonal reactivities with weakly acidic CH groups and boron atoms which are easily functionalised by electrophiles [15], and hence carbaboranes are optimal structures for chemical modification and integration into peptides. Furthermore, they express high stability and low toxicity towards cells, making them interesting compounds for therapeutic applications [14].

Manipulating Y-receptor selectivity

The NPY/hYR system plays a crucial role in a variety of physiological functions, which are mediated by ligand binding, signal transduction through inhibitory Gαi proteins, and subsequent receptor internalisation [37, 75]. It is involved in food intake stimulation and inducing satiety. hYRs have recently been shown to be involved in a variety of pathophysiological conditions such as cancer and obesity. The hY1R subtype has been shown to be over-expressed in gastrointestinal stromal tumours, renal cell carcinoma and in breast carcinoma and derived metastases [76–79]. In contrast, hY4Rs have been addressed for the treatment of obesity based on their strong anorexigenic potential [80–82]. Thus, selective hYR agonists and antagonists provide important tools to unveil distinct physiological functions of single hYR subtypes and are emerging as promising lead structures for targeted diagnostic and therapeutic interventions [83].

The hY1R and hY4R subtypes are activated by different endogenous ligands with different affinities and potencies and are contrarily involved in food-intake regulation. Nonetheless, they show the highest sequence homology among all hYR subtypes and share a similar ligand binding mode [84, 85], which limits the development of selective ligands.

The incorporation of carbaboranes into peptides und their biological characterisation has already been described in the literature. Especially tumour-targeting peptides like octeotride, neurotensin and full-length NPY were efficiently modified with an ortho-carbaborane moiety without affecting their biological affinity [33, 34, 41, 86].

Short selective neuropeptide Y (NPY) analogues are most valuable because of facile synthesis and modification routes. Based on the reduced-size NPY analogue [Pro30, Nle31, Bpa32, Leu34]-NPY 28–36, position 32 was uncovered as the crucial position to redirect hYR subtype selectivity [87]. Interestingly, substitution of Bpa32 (bpa=benzoylphenylalanine) by a strongly hydrophobic moiety, i.e., Nε-ortho-carbaboranyl propanoic acid-modified lysine (Fig. 3), influenced the subtype selectivity of the analogue. Whereas the parent compound is able to preferentially activate the hY1R and hY4R subtypes, the introduction of an Nε-ortho-carbaboranyl propanoic acid-modified lysine decreased the hY1R activity and increased the activity at both hY2R and hY4R. Structural investigations by 1H NMR spectroscopy in solution revealed significant structural changes of the important side-chain residues Pro30 and Leu34 which nicely correlated with the different hYR selectivity pattern. As possible explanations, steric hindrance by the three-dimensional bulkiness and the in situ generated hydrate shell, which may enlarge the side chain considerably, were considered. Thus, position 32 has been identified to influence the bioactive conformation of short NPY analogue and thereby modulates receptor subtype selectivity [88].

Carbaborane-modified [Pro30, Nle31, Lys(Cpa)32, Leu34]-NPY 28–36.
Fig. 3

Carbaborane-modified [Pro30, Nle31, Lys(Cpa)32, Leu34]-NPY 28–36.

While the hY1R and hY5R subtype have been described as orexigenic receptors because of their appetite-stimulating effects, hY2R and hY4R have been described as anorexigenic receptors which mediate satiety [80, 81, 89]. Therefore, the gain in hY2R/hY4R preference of the Nε-ortho-carbaboranyl propanoic acid-modified analogue is regarded as a promising approach in the field of anti-obesity drug development.


Our studies revealed that the combination of selective peptides and carbaboranes covalently linked to the peptide represents a most efficient shuttle system to transport large amounts of boron into respective target cells expressing Y receptors. This system certainly can be transferred to other therapeutic molecules, such as cytotoxic compounds, in the future.

Furthermore, we could show that replacement of Bpa32 in the reduced-size NPY analogue [Pro30, Nle31, Bpa32, Leu34]-NPY 28–36 by ortho-carbaboranyl propanoic acid changed the subtype selectivity, resulting in a short NPY agonist with an interesting hY2R/hY4R preference. This might be a promising approach in the field of anti-obesity drug development.


Financial support from the European Union and the Free State of Saxony [Landesinnovationspromotion (S.B. and S.H.); the Saxonian Ministry for Science and Art (project number 4-7531.60/30/14, A.G.B.-S. and E.H.-H.); EFRE; ESF-NFG 100148830 (S.P.); ESF-NFG 100148835 (M.S.)], the Free State of Saxony [project number 4-7531.60/30/14 (A.B.)], the Fonds der Chemischen Industrie (VCI, doctoral grant R.F.) and the Graduate School “Leipzig School of Natural Sciences – Building with Molecules and Nano-objects” (BuildMoNa), funded by the Deutsche Forschungsgemeinschaft, is gratefully acknowledged. We thank Chemetall GmbH for a generous donation of n-BuLi.


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About the article

Corresponding author: Evamarie Hey-Hawkins, Institute of Inorganic Chemistry, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany, Phone: +49-341-9736151, Fax: +49-341-9739319, E-mail: hey@uni-leipzig.de

Published Online: 2015-01-06

Published in Print: 2015-02-01

Citation Information: Pure and Applied Chemistry, Volume 87, Issue 2, Pages 163–171, ISSN (Online) 1365-3075, ISSN (Print) 0033-4545, DOI: https://doi.org/10.1515/pac-2014-1006.

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