Search

Schistosomiasis, caused by a parasitic blood fluke of the genus Schistosoma, is a global health problem for which new chemotherapeutic options are needed. We explored the scaffold of gallinamide A, a natural peptidic metabolite of marine cyanobacteria that has previously been shown to inhibit cathepsin L-type proteases. We screened a library of 19 synthetic gallinamide A analogs and identified nanomolar inhibitors of the cathepsin B-type protease SmCB1, which is a drug target for the treatment of schistosomiasis mansoni. Against cultured S. mansoni schistosomula and adult worms, many of the gallinamides generated a range of deleterious phenotypic responses. Imaging with a fluorescent-activity-based probe derived from gallinamide A demonstrated that SmCB1 is the primary target for gallinamides in the parasite. Furthermore, we solved the high-resolution crystal structures of SmCB1 in complex with gallinamide A and its two analogs and describe the acrylamide covalent warhead and binding mode in the active site. Quantum chemical calculations evaluated the contribution of individual positions in the peptidomimetic scaffold to the inhibition of the target and demonstrated the importance of the P1 and P2 positions. Our study introduces gallinamides as a powerful chemotype that can be exploited for the development of novel antischistosomal chemotherapeutics.

Co-pyrolysis reactions of B2Br4 with S2Br2 at 350 °C in vacuo yielded the brominated thiaboranes closo-SB5Br5 (1), closo-1-SB9Br9 (2) and closo-SB11Br11 (3), confirmed by high-resolution mass spectrometry, experimental and computational 11B NMR spectroscopy. The strong Brδ+(σ-hole)⋯Brδ−(ring) attraction has been the decisive energy contribution in the crystal of 1. [ABSTRACT FROM AUTHOR]

The objective of this study is to evaluate the effectiveness of various computational methods in reproducing the experimental heats of formation of boron hydrides using the atomization energy approach. The results have demonstrated that the empirical dispersion combined with the BJ damping function provided too large intramolecular dispersion energies, thereby compromising the accuracy of the outcomes produced by the DFT-D3 methods. Additionally, the CCSD(T) method has reproduced the experimental values only when combined with a basis set optimized for an accurate description of the core-valence correlation effect. Furthermore, the number of multicenter bonds present in the molecules under examination has also reflected their stability, as indicated by the heats of formation. Finally, a five-center two electron (5c–2e) bond has emerged in B5H9, by applying the intrinsic bond orbital (IBO) method. [ABSTRACT FROM AUTHOR]

Herein, we report on the synthesis and stereochemistry of mono- and isomeric dinitrile derivatives of [(1,2-C2B9H11)2-3,3′-Co]− ions. The shape and electronic properties of CN groups can apparently surmount the strain associated with the substitution of two vicinal carbon positions. Owing to electron donation to the cage, this results in a substituent-induced rearrangement of one of the carbon atoms to the upper pentagonal ring. The molecular structure of this isomer was confirmed using sc-XRD and DFT chemical computations. [ABSTRACT FROM AUTHOR]

Six‐vertex closo‐SB5Cl5 (1) and ten‐vertex closo‐1‐SB9Cl9 (2) thiaboranes have been prepared, besides the already known 12‐vertex closo‐SB11Cl11 (3), from the co‐pyrolysis reaction of B2Cl4 with S2Cl2 at 280 °C in vacuo. The compounds are sublimable, off‐white solids. Their elemental composition has been determined by high‐resolution mass spectrometry. They were further characterized by one‐ and two‐dimensional 11B NMR spectroscopy and X‐ray structure determination for 1 and 3. Ab initio/GIAO/NMR computations support octahedral, bicapped square‐antiprismatic, and icosahedral geometries for 1, 2 and 3, respectively, as expected based on their closo‐electron counts. 1 is the first isolated example of a neutral polyhedral closo‐thiaborane with a cluster size smaller than ten vertices. The solid‐state structure of 3 is one of the rare examples of a single‐crystal X‐ray structure determination of an icosahedral heteroborane reported. The corresponding crystal‐packing forces show the different role of chalcogen bonding in these octahedral and icosahedral crystals. In addition, there is a mass‐spectrometry evidence for the recurrent formation of further thiaborane homologs of closo‐SBnCln with n=4, 6, 10, and supra‐icosahedral 12. [ABSTRACT FROM AUTHOR]

Octahedral closo‐1,2‐Pn2B4Br4 (Pn=P, As) molecules react with tetrahydrothiophene (THT), regarded as a soft base, much slower than with tetrahydrofuran (THF), considered a hard base. Namely, the reaction begins with only Pn=P at temperatures above 140 °C; 4‐Br(CH2)4S‐closo‐1,2‐P2B4Br3 has been detected as the first product resulting from the cleavage and insertion of a thiobutylate group into the B−Br bond. Unlike in the reaction with THF, the addition of a second THT moiety has not been observed. Conversely, also starting from 140 °C, conjuncto‐3,3'‐(1,2‐Pn2B4Br3)2 has been found as the final product of the reaction, which indicates the presence of 3‐Br(CH2)4S‐closo‐1,2‐P2B4Br3 as another intermediate during the conversion. A computational examination has revealed that it occurs through a pentagonal pyramidal stationary point as an additional intermediate, the latter of which serves as the crucial structural assembly for the thermal conversion that produces the conjuncto motif. Computations of the energy balance and 11B and 31P NMR chemical shifts are in agreement with experimental observations. This reaction is made possible by the presence of σ‐holes on the bromine atoms. In addition, the presence of the σ‐holes on the pnictogens has enabled ESI‐MS to detect various anions appearing during earlier and current syntheses. [ABSTRACT FROM AUTHOR]

The recent success in the formation of chlorinated telluraboranes and the reactivities of pnictogenaboranes prompted us to re-examine the vacuum co-pyrolysis of B2Cl4 with Se2Cl2 at various molar ratios and temperatures in order to search for the generation of other polyhedral selenaboranes than closo-SeB5Cl5 (1a) and closo-SeB11Cl11 (1b), the latter being observed earlier. Interestingly, a new compound with the elemental composition SeB9Cl9 (2) was detected, this time by high- and low-resolution mass spectrometry. Further characterization by 1- and 2-D 11B-NMR spectroscopy suggests that 2 should adopt a closed bicapped square-antiprismatic geometry with selenium at the apical position. Moreover, vacuum sublimation gave suitable crystals of 1b, which were subjected to single-crystal X-ray structure determination. Crystallographic data analysis confirmed that 1b, consistent with its 26 skeletal electron count, adopts a distorted icosahedral structure close to the symmetry of C5v. Computations at the DFT-D3 level have revealed that 33% of the total computed binding motifs in the grown 1b crystals are due to the very strong chalcogen bonding. Moreover, SAPT decomposition has shown that the bonding motifs in the crystals are stabilized mainly by dispersion and electrostatic terms. Homodecoupling and high resolution 11B NMR and 77Se NMR experiments have resolved both coupling constants ¹J(11B11B) and ¹J(77Se11B) as well as the 77Se chemical shift of 1a and 1b, which are in reasonable agreement with the corresponding computed values. The computed 11B chemical shifts of 2 were determined by the well-established DFT/GIAO/NMR structural tool based on its B3LYP/6-311+G** internal coordinates. They agree well with the experimental values and provide a good representation of the molecular structure of 2 in solution. The extraordinary downfield 11B NMR chemical shift of B(10) in 2 has been ascribed to the intensive paramagnetic contribution to the shielding tensor in this bicapped square-antiprismatic motif. Calculations of the synproportionation free energies of smaller (n – 1) closo-selenaboranes with larger-sized (n + 1) ones support the extraordinary stability of octahedral, bicapped square-antiprismatic and icosahedral closo motifs in the SeBnCln family (n = 4–12). [ABSTRACT FROM AUTHOR]

Six‐vertex closo‐TeB5Cl5 (1) and twelve‐vertex closo‐TeB11Cl11 (2) telluraboranes have been prepared via co‐pyrolysis of B2Cl4 with TeCl4 in vacuo at temperatures between 360 °C and 400 °C. Both compounds are sublimable, off‐white solids, and they have been characterized by one‐ and two‐dimensional 11B NMR and high‐resolution mass spectroscopy. Both ab initio/GIAO/NMR and DFT/ZORA/NMR computations support octahedral and icosahedral geometries for 1 and 2, respectively, as expected due to their closo‐electron counts. The octahedral structure of 1 has been confirmed by single‐crystal X‐ray diffraction on an incommensurately modulated crystal. The corresponding bonding properties have been analyzed in terms of the intrinsic bond orbital (IBO) approach. 1 is the first example of a polyhedral telluraborane with a cluster size smaller than 10 vertices. [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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. [ABSTRACT FROM AUTHOR]

Among non-covalent interactions, B–H⋯π and C–H⋯π hydrogen bonding is rather weak and less studied. Nevertheless, since both can affect the energetics of protein–ligand binding, their understanding is an important prerequisite for reliable predictions of affinities. Through a combination of high-resolution X-ray crystallography and quantum-chemical calculations on carbonic anhydrase II/carborane-based inhibitor systems, this paper provides the first example of B–H⋯π hydrogen bonding in a protein–ligand complex. It shows that the B–H⋯π interaction is stabilized by dispersion, followed by electrostatics. Furthermore, it demonstrates that the similar C–H⋯π interaction is twice as strong, with a slightly smaller contribution of dispersion and a slightly higher contribution of electrostatics. Such a detailed insight will facilitate the rational design of future protein ligands, controlling these types of non-covalent interactions. [ABSTRACT FROM AUTHOR]

Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile GÜ1303 and a 3-cyano-3-aza-β-amino acid GÜ2602. Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of GÜ2602 is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs. [ABSTRACT FROM AUTHOR]

Reported herein are mutual rearrangements in the whole series of seven bicapped-square antiprismatic closo-C2B8H10 by means of high-quality computations that disprove the earlier postulated dsd (diamond-square-diamond) scheme for these isomerizations. The experimentally existing closo-1,2-C2B8H10 was able to be converted to 1,6-, and 1,10-isomers by pyrolysis, and the dsd (diamond-square-diamond) mechanism was offered as an explanation of these processes. However, these computations disprove the postulated dsd scheme for these isomerizations that take place in the ten-vertex closo series. Experimentally observed thermal rearrangements, both in the parent and substituted closo-1,2-C2B8H10, closo-1-CB9H10−, and closo-B10H102−, indirectly support these refined computations. All these processes are based on the new concept of the so-called Z-mechanism, being consistent with a transition state of a boat shape with an open hexagonal belt that results from the initial breakage of three bonds. Such bond breakings and the consequent bond formations bring to mind the shape of the letter Z. In effect, the pattern of multicenter bonding shifts from reactant through a transition state to product. The molecular rearrangements that are available experimentally favour either the axial or equatorial isomers, and this ratio depends on temperature and the type of cluster and its substitution. [ABSTRACT FROM AUTHOR]

9‐Br‐closo‐1,2‐C2B10H11 has been prepared and its gas‐phase structure has been examined by means of gas electron diffraction. The structure of the carbaborane core is similar to the structure of the parent compound, which is of C2v symmetry. A DFT‐based search for the corresponding reaction pathway of the bromination of closo‐1,2‐C2B10H12 revealed that the catalytic amount of aluminum reduces the barrier of the initial attack of the bromination agent toward the negatively charged part of the icosahedral carbaborane, i. e., the first transition state, from about 40 to about 27 kcalmol‐1. The Br−Br bond is weakened by an intermediate binding to the large π‐hole on the aluminum atom of AlBr3, which is the driving force for the AlBr3‐catalyzed bromination. [ABSTRACT FROM AUTHOR]

Quantum mechanical (QM) methods have been gaining importance in structure‐based drug design where a reliable description of protein‐ligand interactions is of utmost significance. However, strategies i. e. QM/MM, fragmentation or semiempirical (SQM) methods had to be pursued to overcome the unfavorable scaling of QM methods. Various SQM‐based approaches have significantly contributed to the accuracy of docking and improvement of lead compounds. Parametrizations of SQM and implicit solvent methods in our laboratory have been instrumental to obtain a reliable SQM‐based scoring function. The experience gained in its application for activity ranking of ligands binding to tens of protein targets resulted in setting up a faster SQM/COSMO scoring approach, which outperforms standard scoring methods in native pose identification for two dozen protein targets with ten thousand poses. Recently, SQM/COSMO was effectively applied in a proof‐of‐concept study of enrichment in virtual screening. Due to its superior performance, feasibility and chemical generality, we propose the SQM/COSMO approach as an efficient tool in structure‐based drug design. [ABSTRACT FROM AUTHOR]

We report on the discovery of norbornyl moiety as a novel structural motif for cyclin‐dependent kinase 2 (CDK2) inhibitors which was identified by screening a carbocyclic nucleoside analogue library. Three micromolar hits were expanded by the use of medicinal chemistry methods into a series of 16 novel compounds. They had prevailingly micromolar activities against CDK2 and the best compound of the series attained IC50 of 190 nM. The binding modes were explored in molecular details by modeling and docking. Quantum mechanics‐based scoring was used to rationalize the affinities. In conclusion, the discovered 9‐hydroxymethylnorbornyl moiety was shown by joint experimental‐theoretical efforts to be able to serve as a novel substituent for CDK2 inhibitors. This finding opens door to the exploration of chemical space towards more effective derivatives targeting this important class of protein kinases. [ABSTRACT FROM AUTHOR]

Rationale: For the risk assessment of penconazole in the environment and the evaluation of the possible consequences of its use, it is important to determine how its reactivity and degradation are influenced by metals commonly found in nature, such as copper and zinc. Methods: Changes in the reactivity of penconazole in the presence of zinc/copper ions were studied using electrospray ionisation mass spectrometry and density functional theory calculations. Results: Many penconazole complexes with copper and zinc ions were created; a comparison of the elements showed that a few complexes were formed analogously (doubly charged complexes with four penconazole molecules, singly charged complexes with chlorine as a counterion and singly charged complexes with deprotonated penconazole as a counterion). The metal complexes with different structures indicated different reactivity of penconazole with copper and zinc. Conclusions: The experimental and computational approaches have revealed different changes in the structure of penconazole. In the Zn(II) complex, penconazole deprotonated to stabilise the bond to Zn(II). In the Cu(II) complex, it loses one chlorine atom, creates an additional ring between the triazole ring and the phenyl ring, and/or creates a double bond in the short aliphatic chain. [ABSTRACT FROM AUTHOR]

The concept of icosahedral barrier has been expanded from the chemistry of carbaboranes to the area of thiaboranes. Both representatives of this barrier, i. e., closo-1,2-C2B10H12 and closo-1-SB11H11, are similar in their electron distribution, which is dominated by positive charge in the midpoint of the C-C vector and on the sulfur atom with experimentally determined dipole moments of 4.50 D and 3.64 D, respectively. This is a driving force for their reactivity as exemplified by their reactions with different carbon functionalities. Icosahedral closo-1-SB11H11 reacts both with an electron sextet containing carbon (in the form of N-heterocyclic carbenes), reported earlier, and with methyl iodide with an electron octet on the carbon. The latter reaction provides hexamethylated thiaborane on the basis of methylation so far unknown in this area of heteroborane chemistry. The computations of the heat of formation (ΔHf 298) make it possible to estimate the height of the barrier as well as to propose closo-thiaboranes beyond the barrier. Eleven and twelve vertex thiaboranes with nido electron count are known experimentally for breaking the barrier. These computations also suggest that the larger nido-thiaboranes are promising candidates for the corresponding experimental availability, i. e., the ΔHf 298 of a 13-vertex nido-thiaborane cluster has been computed to be more negative than that of the well-known nido-SB10H11 - cluster (- 6.7 and - 5.6 kcalmol-1 per vertex, respectively). [ABSTRACT FROM AUTHOR]

Decaborane(14), nido-B10H14, is the major commercially available molecular building block in boron cluster chemistry. The condensation of two such {nido-B10} blocks gives the known isomers of B18H22– a molecule used in the fabrication of p-type semiconductors and capable of blue laser emission. Here, we computationally determine the structures and thermodynamic stabilities of 20 possible B26H30 regioisomers constructed from the fusion of three {nido-B10} blocks with the three subclusters conjoined by two-boron atom shared edges. In addition, density functional theory, time-dependent (TD)-DFT and multiconfigurational CASPT2 methods have been used to model and investigate the physical and photophysical properties of the three most stable of these isomers. Our findings predict these isomers to be potentially useful materials for the semiconductor industry, as high boron-content doping agents, and in the fabrication of new optical materials. [ABSTRACT FROM AUTHOR]

Superconductivity in polycrystalline and thin-film MgB2 is strongly affected by the termination of its surface, but a reliable determination of the surface termination is still a challenging task of surface chemistry. Here, the surface properties of superconducting MgB2 were investigated using a combination of inverse gas chromatography and van der Waals corrected density functional theory calculations. The dispersive surface energy was measured as a function of the surface coverage and its value (58 mJ m−2 to 48 mJ m−2) was verified by high-level non-local EXX + RPA calculations, which predicted that the dispersive contribution to the cleavage energy was 56 mJ m−2. The isosteric adsorption enthalpies of cyclohexane, dioxane, acetone and acetonitrile molecules were measured on an MgB2 sample and compared to the DFT calculated enthalpies for the Mg-terminated MgB2, B-terminated MgB2 and MgO(001) surfaces. The close agreement between theory and experiment for the Mg-terminated surface suggested that the magnesium termination is the dominant surface phase of MgB2. Thus, combining inverse gas chromatography experiments with theoretical calculations may provide information about the surface termination. [ABSTRACT FROM AUTHOR]

The thiaboranes closo-1-SB11H11 (1a) and 12-I-closo-1-SB11H10 (1b) react with 4-(dimethylamino)pyridine under inert conditions upon the formation of the nido-type thiaboranes 9-B{(4-Me2N)C5NH4}2(H)-7-SB10H11 and 9-B{(4-Me2N)C5NH4}2(H)-5-I-7-SB10H10 containing an exoskeletal B–H group. The same type of B–H moiety is also stabilised by one bipyridine molecule in a chelating fashion. These complexes are unstable in solution, and in air and hydrolyse to monodeboronated ionic compounds having [nido-7-SB10H11]− or [5-I-nido-7-SB10H10]− anions which are also products of the reactions of 1a and 1b with other N-bases such as pyridine, ammonia and DABCO. The extrusion of one boron and one sulphur atom takes place when 1a reacts with 2,6-di-tert-butylpyridine to yield decaborane. [ABSTRACT FROM AUTHOR]

Carbaboranes 1,2‐(EH)2‐closo‐1,2‐C2B10H10 (E=S, Se) were prepared, in the case of E=Se for the first time. Their semi‐experimental equilibrium molecular structures were established by the concerted use of quantum‐chemical calculations and gas electron diffraction. A method was developed and implemented to quantify the contribution of experimental data to each refined structural parameter. The accuracy of the experimental structures and those calculated at the MP2 level of theory were gauged by comparison of experimental 11B NMR chemical shifts with quantum‐chemically computed values; the inclusion of electron correlation (GIAO‐MP2) provided superior results. For the purpose of geometrical prediction, the remaining group 16 elements were considered, and the icosahedral structures for E=O and Te were also computed; for E=O the same theoretical approach was used as for E=S, and for E=Te a description similar to that for E=Se was employed. Hydrochalcogeno carbaboranes: Icosahedral carbaboranes with thiol and selenol groups were prepared and their structures determined by gas electron diffraction augmented by ab initio calculated data (see figure). A method for quantifying the experimental contribution to the structural parameters was developed and tested. Comparison of NMR chemical shifts in solution with quantum‐chemically calculated values allowed further structural information to be retrieved. [ABSTRACT FROM AUTHOR]

Two binary boron hydrides (NH4)2B10H10 and Na2B12H12 and mono- and dicarboxy p- and m-carboranes (namely, 1-(COOH)-closo-1,7-C2B10H11, 1,12-(COOH)2-closo-1,12-C2B10H10 and 1,7-(COOH)2-closo-1,7-C2B10H10) were intercalated into ZnAl-layered double hydroxides (ZnAl-LDH) and into Zn5(OH)8(NO3)2·2H2O. The formed compounds were characterized using elemental analysis, thermogravimetry analysis, X-ray powder diffraction, infrared spectroscopy and solid state NMR. All the intercalated boron compounds are present in the interlayer space of the layered hosts as anions. It is presumed that in the case of B10H102−, B12H122− and 1,12-(COO)2-closo-1,12-C2B10H102−, the guest molecules form a monolayer, whereas in the case of 1-(COO)-closo-1,7-C2B10H111− and 1,7-(COO)2-closo-1,7-C2B10H102− a bilayer arrangement is more probable. In the case of 1,7-(COO)2-closo-1,7-C2B10H102−, the guest molecules are strongly interdigitated resulting in lowering of the interlayer distance. Two different modes of binding were found. Whereas the carboxylate derivatives of p- and m-carboranes are bonded through classical hydrogen bonds, the corresponding parent borane anions interact with the host structures by mainly dihydrogen bonding. In effect, both kinds of hydrogen bonding are mainly of an electrostatic nature. The dihydrogen bond is detected, e.g. in crystal engineering, and represents a driving force for interactions of boranes with biomolecules. Since the latter dicarboxylic acids were found to be superacids, their interactions with the host structures should be stronger than in the case of the benzoic and terephthalic acid intercalates. [ABSTRACT FROM AUTHOR]

Reported are procedures leading to the first types of methyl camouflaged dicarbadecaboranes with fewer than eleven vertices. The compounds contain the closo-1,6-C2B8 scaffolding inside the egg-shaped hepta – decamethyl sheath, which imparts unusually high air and solvolytic stability to all of these compounds. [ABSTRACT FROM AUTHOR]