carboranes
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Halogen bonds are a subset of noncovalent interactions with rapidly expanding applications in materials and medicinal chemistry. While halogen bonding is well known in organic compounds, it is new in the field of boron cluster chemistry. We have synthesized and crystallized carboranes containing Br atoms in two different positions, namely, bound to C- and B-vertices. The Br atoms bound to the C-vertices have been found to form halogen bonds in the crystal structures. In contrast, Br atoms bound to B-vertices formed hydrogen bonds. Quantum chemical calculations have revealed that halogen bonding in carboranes can be much stronger than in organic architectures. These findings open new possibilities for applications of carboranes, both in materials and medicinal chemistry.
- Klíčová slova
- X-ray crystal structure, bromine, carboranes, halogen bonds, sigma holes,
- Publikační typ
- časopisecké články MeSH
Polyhedral carboxymethyl carborane (C2 B10 H12 ) derivatives, including mono- and disubstituted o-, m-, and p-isomers, have been synthesized. Supramolecular host-guest complexation of these derivatives with cyclodextrins (CDs; namely, α-, β-, and γ-CD) has been investigated in water. The globular structure of the carborane binding moiety and its hydrophobic character qualify it as an ideal recognition site to form stable inclusion complexes with macrocyclic host molecules in aqueous solution. The measured binding affinities for the carborane derivatives were in the millimolar range (Ka =103 -104 m-1 ) with differently sized CDs, and preferential binding to β-CD.
- Klíčová slova
- boron, carboranes, cluster compounds, host-guest systems, hydrophobic effect,
- Publikační typ
- časopisecké články MeSH
Modern computational protocols based on the density functional theory (DFT) infer that polyhedral closo ten-vertex carboranes are key starting stationary states in obtaining ten-vertex cationic carboranes. The rearrangement of the bicapped square polyhedra into decaborane-like shapes with open hexagons in boat conformations is caused by attacks of N-heterocyclic carbenes (NHCs) on the closo motifs. Single-point computations on the stationary points found during computational examinations of the reaction pathways have clearly shown that taking the "experimental" NHCs into account requires the use of dispersion correction. Further examination has revealed that for the purposes of the description of reaction pathways in their entirety, i.e., together with all transition states and intermediates, a simplified model of NHCs is sufficient. Many of such transition states resemble in their shapes those that dictate Z-rearrangement among various isomers of closo ten-vertex carboranes. Computational results are in very good agreement with the experimental findings obtained earlier.
- Klíčová slova
- DFT, N-heterocyclic carbenes, carboranes, cations, reaction pathways,
- Publikační typ
- časopisecké články MeSH
Noncovalent interactions of the polyhedral carborane 1-carba-closo-dodecaborane (CB(11)H(12))(-) with building blocks of biomolecules, modelled by glycine (GLY), serine (SER), phenylalanine (PHE), glutamic acid (GLU), lysine (LYS) and arginine (ARG), were investigated in vacuo by molecular dynamics simulations with the UFF empirical potential. Selected structures were further studied by accurate ab initio quantum chemical procedures. Interactions with a peptide bond (GLY-SER dipeptide) and a nucleic acid building block (guanine) were also considered. The RESP and NPA charges of carboranes and small model systems are compared and their use is discussed. The dominant interaction between carboranes and biomolecules is the formation of unconventional proton-hydride hydrogen bonds (dihydrogen bonds) characterized by a short distance between hydrogen atoms (as close as 1.8 A) and an average strength in the range of 4.2-5.8 kcal mol(-1). The total stabilization energy of complexes investigated is rather large, and the largest value (approximately 15 kcal mol(-1)) was found for the carborane complexes with ARG and the GLY-SER dipeptide. These interactions are ubiquitous under geometrical constraints influencing the strength of the interaction. The carborane forms dihydrogen bonds with biomolecules preferably with the hydrogen atoms of its lower hemisphere (i.e. the part of the cage opposite to the carbon atom). These two geometrical factors can be used to explain the specificity of inhibition of HIV protease by carboranes.
- MeSH
- biofyzika metody MeSH
- borany chemie MeSH
- chemické modely MeSH
- fenylalanin chemie MeSH
- fyzikální chemie metody MeSH
- glycin chemie MeSH
- HIV-proteasa chemie MeSH
- inhibitory HIV-proteasy chemie farmakologie MeSH
- kvantová teorie MeSH
- molekulární konformace MeSH
- serin chemie MeSH
- termodynamika MeSH
- uhlík chemie MeSH
- vodík chemie MeSH
- vodíková vazba MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- borany MeSH
- fenylalanin MeSH
- glycin MeSH
- HIV-proteasa MeSH
- inhibitory HIV-proteasy MeSH
- serin MeSH
- uhlík MeSH
- vodík MeSH
Carbonic anhydrase IX (CA IX) is a transmembrane enzyme overexpressed in hypoxic tumors, where it plays an important role in tumor progression. Specific CA IX inhibitors potentially could serve as anti-cancer drugs. We designed a series of sulfonamide inhibitors containing carborane clusters based on prior structural knowledge of carborane binding into the enzyme active site. Two types of carborane clusters, 12-vertex dicarba-closo-dodecaborane and 11-vertex 7,8-dicarba-nido-undecaborate (dicarbollide), were connected to a sulfonamide moiety via aliphatic linkers of varying lengths (1-4 carbon atoms; n = 1-4). In vitro testing of CA inhibitory potencies revealed that the optimal linker length for selective inhibition of CA IX was n = 3. A 1-sulfamidopropyl-1,2-dicarba-closo-dodecaborane (3) emerged as the strongest CA IX inhibitor from this series, with a Ki value of 0.5 nM and roughly 1230-fold selectivity towards CA IX over CA II. X-ray studies of 3 yielded structural insights into their binding modes within the CA IX active site. Compound 3 exhibited moderate cytotoxicity against cancer cell lines and primary cell lines in 2D cultures. Cytotoxicity towards multicellular spheroids was also observed. Moreover, 3 significantly lowered the amount of CA IX on the cell surface both in 2D cultures and spheroids and facilitated penetration of doxorubicin. Although 3 had only a moderate effect on tumor size in mice, we observed favorable ADME properties and pharmacokinetics in mice, and preferential presence in brain over serum.
- Klíčová slova
- Anti-tumor agents, Carbonic anhydrase IX, Carboranes, Dicarbollide, Drug penetration, Enzyme inhibitors, Multicellular spheroids,
- MeSH
- antigeny nádorové metabolismus MeSH
- experimentální nádory farmakoterapie metabolismus MeSH
- inhibitory karboanhydras chemická syntéza chemie farmakologie MeSH
- karboanhydrasa IX antagonisté a inhibitory metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- molekulární struktura MeSH
- myši inbrední BALB C MeSH
- myši SCID MeSH
- myši MeSH
- nádory prsu farmakoterapie metabolismus MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky chemická syntéza chemie farmakologie MeSH
- psi MeSH
- rekombinantní proteiny metabolismus MeSH
- screeningové testy protinádorových léčiv MeSH
- sulfonamidy chemická syntéza chemie farmakologie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antigeny nádorové MeSH
- CA9 protein, human MeSH Prohlížeč
- inhibitory karboanhydras MeSH
- karboanhydrasa IX MeSH
- protinádorové látky MeSH
- rekombinantní proteiny MeSH
- sulfonamidy MeSH
The calculated properties of substituted carboranes such as dipole moment, polarisability, the magnitude of the σ-hole and the desolvation free energy are compared with these properties in comparable aromatic and cyclic aliphatic organic compounds. Dispersion and charge transfer energies are similar. However, the predicted strength of the halogen bonds with the same electron donor (based on the magnitude of the σ-hole) is larger for neutral C-vertex halogen-substituted carboranes than for their organic counterparts. Furthermore, the desolvation penalties of substituted carboranes are smaller than those of the corresponding organic compounds, which should further strengthen the halogen bonds of the former in the solvent. It is predicted that substituted carboranes have the potential to form stronger halogen bonds than comparable aromatic hydrocarbons, which will be even more pronounced in the medium. This theoretical study thus lays ground for the rational engineering of halogen bonding in inorganic crystals as well as in biomolecular complexes.
- Publikační typ
- časopisecké články MeSH
The continuous expansion of research in the field of stable carboranes and their wide potential in the drug design require carrying out fundamental studies regarding their chiral separations. Although supercritical fluid chromatography (SFC) is a viable technique for fast enantioseparations, no investigation concerning boron cluster compounds has been done yet. We aimed at the development of a straightforward method enabling chiral separations of racemic mixtures of anionic cluster carboranes and metallacarboranes that represent an analytical challenge. The fast gradient screening testing nine polysaccharide-based columns was used. The key parameters affecting the selectivity were the type of chiral selector, the type of alcohol, and the base in cosolvent. Moreover, the addition of acetonitrile or water to the cosolvent was identified as an effective tool for decreasing the analysis time while preserving the resolution. After the optimization, the chiral separations of 19 out of 20 selected compounds were achieved in less than 10 min. These results demonstrate the clear advantage of SFC over chiral separations using HPLC in terms of both analysis time and structural variety of successfully separated compounds.
The aspect of the different spatial arrangement of anionic cobalt bis(dicarbollides) and dicarba-nido-undecaboranes remains grossly overlooked despite increased scientific interest. Regarding their growing potential, which does not limit only to medicinal chemistry, suitable enantioseparation methods are needed. The presented paper explores the possibilities of chiral separations of anionic cobalt bis(dicarbollide) and dicarba-7,8-nido-undecaborane derivatives on four polysaccharide-based columns under reversed-phase conditions. The chromatographic behavior of anionic derivatives was evaluated and compared with that of zwitterionic clusters. The isocratic procedure for HPLC method development was suggested. The main parameters for the optimization of separations were described. Successful chiral separations were critically compared to previously reported results in normal phase and polar-organic mode. Reversed-phase separations are superior in resolution, lower consumption of organic solvents, and flexibility during the method development. Moreover, the first chiral discrimination of some hydroxyalkyl derivatives of anionic cobalt bis(dicarbollides) is reported. The outcomes of this work may be used for method development in any area, where the chirality of these interesting molecules is of concern.
- Klíčová slova
- Boron clusters, Carboranes, Chiral separation, HPLC, Polysaccharides, Reversed-phase,
- MeSH
- anionty MeSH
- chromatografie s reverzní fází * MeSH
- kobalt MeSH
- polysacharidy * chemie MeSH
- stereoizomerie MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- anionty MeSH
- kobalt MeSH
- polysacharidy * MeSH
(11)B and (13)C NMR spectra of so-far experimentally unknown carbon-rich cationic closo-carboranes C(3)B(n-3)H(n)(+) (n = 5, 6, 7, 10, 12) have been calculated at the GIAO-MP2 level and subsequently analyzed to reveal the nature of bonding in these potentially weakly coordinating cations. All previous rules derived for understanding (11)B NMR spectra of borane derivatives can be applied to realistically account for the corresponding shieldings. The correlated wavefunction for n = 5 and, to a lesser extent, for n = 10 seems to be decisive when trying to compute realistic shielding tensors, which is in agreement with the corresponding known dicarbaboranes. For other cluster dimensions noncorrelated wavefunctions also work well, in particular in relation to the corresponding dicarbaboranes. All these observations strongly support the fact that experimental availability of these unique clusters is possible.
- Publikační typ
- časopisecké články MeSH
CA inhibitors: Human carbonic anhydrases (CAs) are diagnostic and therapeutic targets. Various carborane cages are shown to act as active-site-directed inhibitors, and substitution with a sulfamide group and other substituents leads to compounds with high selectivity towards the cancer-specific isozyme IX. Crystal structures of the carboranes in the active site provide information that can be applied to the structure-based design of specific inhibitors.
- Klíčová slova
- carbonic anhydrases, carboranes, drug discovery, inhibitors, structure elucidation,
- MeSH
- inhibitory karboanhydras farmakologie MeSH
- lidé MeSH
- objevování léků MeSH
- racionální návrh léčiv MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- inhibitory karboanhydras MeSH
