Silver Complexes of Miconazole and Metronidazole: Potential Candidates for Melanoma Treatment.

Melanoma, arguably the deadliest form of skin cancer, is responsible for the majority of skin-cancer-related fatalities. Innovative strategies concentrate on new therapies that avoid the undesirable effects of pharmacological or medical treatment. This article discusses the chemical structures of [(MTZ)2AgNO3], [(MTZ)2Ag]2SO4, [Ag(MCZ)2NO3], [Ag(MCZ)2BF4], [Ag(MCZ)2SbF6] and [Ag(MCZ)2ClO4] (MTZ-metronidazole; MCZ-miconazole) silver(I) compounds and the possible relationship between the molecules and their cytostatic activity against melanoma cells. Molecular Hirshfeld surface analysis and computational methods were used to examine the possible association between the structure and anticancer activity of the silver(I) complexes and compare the cytotoxicity of the silver(I) complexes of metronidazole and miconazole with that of silver(I) nitrate, cisplatin, metronidazole and miconazole complexes against A375 and BJ cells. Additionally, these preliminary biological studies found the greatest IC50 values against the A375 line were demonstrated by [Ag(MCZ)2NO3] and [(MTZ)2AgNO3]. The compound [(MTZ)2AgNO3] was three-fold more toxic to the A375 cells than the reference (cisplatin) and 15 times more cytotoxic against the A375 cells than the normal BJ cells. Complexes of metronidazole with Ag(I) are considered biocompatible at a concentration below 50 µmol/L.

2,2'-Dithiobispyrazine: about the disulfide bond.

X-ray diffraction studies reveal that pyrazine-2-thiol undergoes condensation to 2,2'-dithiobispyrazine [systematic name: 2-(pyrazin-2-yldisulfanyl)pyrazine], C8H6N4S2 (I), under aerial conditions. In the molecule of I, the pyrazine rings are arranged in an almost perpendicular manner, with an absolute value of the C-S-S-C torsion angle of -91.45 (6)°. A search in the Cambridge Structural Database confirmed that such a conformation is typical for disulfide compounds. Three different rotamers of disulfide I were studied using quantum theoretical studies. The rotamer of lowest energy was observed in the crystalline state in the structure stabilized by hydrogen-bond, chalcogen-bond and stacking interactions. Further quantum chemical computations confirm that 2,2'-dithiobispyrazine can react according to the SN2 mechanism.

Fluoride Anions: Unexploited but Effective Halogen Bond Acceptors.

Due to their high electron density, fluoride anions can be considered the most effective halogen bond (HaB) acceptors among the halides. However, under common experimental conditions, F- uncommonly acts as HaB acceptor, expectedly as it is present in hydrated form. Herein we report that under specific crystallization conditions a hydrogen bond-free F- functioning as donor of electron density can be obtained, with the formed HaBs constituting the driving force of the observed crystal packings. Computations confirm the strength of these HaBs compared to analogous interactions involving other halides.

X-ray studies of three 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine cocrystals: an unexpected molecular conformation stabilized by hydrogen bonds.

The results of the X-ray structure analysis of three novel 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine cocrystals are presented. These are 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine-2,4,6-tribromophenol (1/2), C12H8N6·2C6H3Br3O, 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine-isonicotinic acid N-oxide (1/2), C12H8N6·2C6H5NO3, and 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine-4-nitrobenzenesulfonamide (1/1), C12H8N6·C6H6N2O4S. Special attention is paid to a conformational analysis of the title tetrazine molecule in known crystal structures. Quantum chemistry methods are used to compare the energetic parameters of the investigated conformations. A structural analysis of the hydrogen and halogen bonds with acceptor aromatic tetrazine and pyrazine rings is conducted in order to elucidate factors responsible for conformational stability.

Lack of Cooperativity in the Triangular X3 Halogen-Bonded Synthon?

We have investigated 44 crystal structures, found in the Cambridge Structural Database, containing the X3 synthon (where X = Cl, Br, I) in order to verify whether three type II halogen-halogen contacts forming the synthon exhibit cooperativity. A hypothesis that this triangular halogen-bonded motif is stabilized by cooperative effects is postulated on the basis of structural data. However, theoretical investigations of simplified model systems in which the X3 motif is present demonstrate that weak synergy occurs only in the case of the I3 motif. In the present paper we computationally investigate crystal structures in which the X3 synthon is present, including halomesitylene structures, that are usually described as being additionally stabilized by a synergic interaction. Our computations find no cooperativity for halomesitylene trimers containing the X3 motif. Only in the case of two other structures containing the I3 synthon a very weak or weak synergy, i.e. the cooperative effect being stronger than -0.40 kcal mol-1, is found. The crystal structure of iodoform has the most pronounced cooperativity of all investigated systems, amounting to about 10% of the total interaction energy.

Halogen-bonded haloamine trimers - modelling the X3 synthon.

Halogen-halogen bonded haloamine trimers serve as model systems for the X3 synthon present in numerous crystal structures and in two-dimensional self-assembled nanoarchitectures. Halogen bonds forming the synthon are often considered to display cooperativity. Synergy effects were previously found for halogen-halogen bonded bromoamine and iodoamine tetramers. In the present study comparison between haloamine cyclic trimers and tetramers is made. The cooperativity occurring in bromoamine and iodoamine clusters is significantly weaker in the case of the trimers. The present study demonstrates that the bromoamine and iodoamine trimers display weaker cooperativity due to a smaller number of synergy components in comparison to the corresponding tetramers of stronger cooperativity. Moreover, the halogen-halogen interactions in bromoamine and iodoamine dimers with the geometries of the corresponding trimers and tetramers are examined using energy decomposition analysis methods (supermolecular, canonical EDA and SAPT) and the Kohn-Sham molecular orbital model. The results of the analysis indicate that although the interaction energy values for the dimers of the different spatial arrangement are very close to each other, their origin is substantially different. For pairs with the geometry of the trimers orbital interactions and electrostatic attraction are both weaker than for the corresponding dimers with the geometry of the tetramers. This is especially important because both donor-acceptor interactions and electrostatic attraction were previously proven to be responsible for cooperative effects occurring in the bromoamine and iodoamine tetramers.

Simple Trans-Platinum Complex Bearing 3-Aminoflavone Ligand Could Be a Useful Drug: Structure-Activity Relationship of Platinum Complex in Comparison with Cisplatin.

Following previous studies devoted to trans-Pt(3-af)2Cl2, in this paper, the molecular structure and intermolecular interactions of the title complex are compared with other cisplatin analogues of which the crystal structures are presented in the Cambridge Structural Database (CSD). Molecular Hirshfeld surface analysis and computational methods were used to examine a possible relationship between the structure and anticancer activity of trans-Pt(3-af)2Cl2. The purpose of the article was also to investigate the effect of hyperthermia on the anticancer activity of cisplatin, cytostatics used in the treatment of patients with ovarian cancer and a new analogue of cisplatin-trans-Pt(3-af)2Cl2. The study was conducted on two cell lines of ovarian cancer sensitive to Caov-3 cytostatics and the OVCAR-3 resistant cisplatin line. The study used the MTT (3-(4,5-dimethylthiazol-2,5-diphenyltetrazolium bromide) cell viability assay, LDH (lactate dehydrogenase), and the quantitative evaluation method for measuring gene expression, i.e., qPCR with TagMan probes. Reduced survivability of OVCAR-3 and Caov-3 cells exposed to cytostatics at elevated temperatures (37 °C, 40 °C, 43 °C) was observed. Hyperthermia may increase the sensitivity of cells to platinum-based antineoplastic drugs and paclitaxel, which may be associated with the reduction of gene expression related to apoptotic processes.

Aromaticity of acenes: the model of migrating π-circuits.

In this work we extend the concept of migrating Clar's sextets to explain local aromaticity trends in linear acenes predicted by theoretical calculations and experimental data. To assess the link between resonance and reactivity and to rationalize the constant-height AFM image of pentacene we used the electron density of delocalized bonds and other functions of the one-electron density from conceptual density functional theory. The presented results provide evidence for migration of Clar's π-sextets and larger circuits in these systems, and clearly show that the link between the theoretical concept of aromaticity and the real electronic structure entails the separation of intra- and inter-ring resonance effects, which in the case of [n]acenes (n = 3, 4, 5) comes down to solving a system of simple linear equations.

Tuning Aromaticity of para-Substituted Benzene Derivatives with an External Electric Field.

Substituent effects are phenomena which play an important role in organic chemistry, especially when aromatic species are considered. For this class of systems, the question of the interrelation between substituent effect and aromaticity arises. The relationship between aromaticity and substituent effects appears to be of a competitive nature. This work examines changes in aromaticity in para-substituted benzene derivatives exposed to external electric fields of various intensities. Three systems with different substituent electron-accepting/donating properties are studied, namely p-aminophenol, p-nitrobenzonitrile and p-nitrophenol. In these cases, the competitive character between substituent effects and aromaticity is emphasised. It is also shown that aromaticity (and the substituent effect) can be tuned using an external electric field applied to the system.

The electron density of delocalized bonds (EDDB) applied for quantifying aromaticity.

In this study the recently developed electron density of delocalized bonds (EDDB) is used to define a new measure of aromaticity in molecular rings. The relationships between bond-length alternation, electron delocalization and diatropicity of the induced ring current are investigated for a test set of representative molecular rings by means of correlation and principal component analyses involving the most popular aromaticity descriptors based on structural, electronic, and magnetic criteria. Additionally, a qualitative comparison is made between EDDB and the magnetically induced ring-current density maps from the ipsocentric approach for a series of linear acenes. Special emphasis is given to the comparative study of the description of cyclic delocalization of electrons in a wide range of organic aromatics in terms of the kekulean multicenter index KMCI and the newly proposed EDDBk index.

The role of the long-range exchange corrections in the description of electron delocalization in aromatic species.

In this article, we address the role of the long-range exchange corrections in description of the cyclic delocalization of electrons in aromatic systems at the density functional theory level. A test set of diversified monocyclic and polycyclic aromatics is used in benchmark calculations involving various exchange-correlation functionals. A special emphasis is given to the problem of local aromaticity in acenes, which has been a subject of long-standing debate in the literature. The presented results indicate that the noncorrected exchange-correlation functionals significantly overestimate cyclic delocalization of electrons in heteroaromatics and aromatic systems with fused rings, which in the case of acenes leads to conflicting local aromaticity predictions from different criteria. © 2017 Wiley Periodicals, Inc.

Feynman force components: basis for a solution to the covalent vs. ionic dilemma.

The Hellmann-Feynman theorem, when applied to nuclear coordinates in a molecular system, states that Feynman forces, i.e. forces acting on a nucleus in a molecule, are solely of an electrostatic nature. This theorem is described by Slater as "the most powerful" theorem applicable to molecules. However, its possibilities have hardly been harnessed. This work presents the use of the Hellmann-Feynman theorem in conjunction with the partitioning of the molecular space into atoms in the spirit of the quantum theory of atoms in molecules (QTAIM). Homopolar and heteropolar diatomic molecules of varying polarity are studied in the context of Feynman force components, i.e. the components exerted on each nucleus by the other nucleus and by the electron density distributions of each of the atoms. These results are further related to electronegativity differences used in the differentiation between covalent and ionic bond. The approach based on the directions of Feynman force components gives physical fundamentals for covalent vs. ionic bond distinction without referring to the electronegativity concept.

Source of Cooperativity in Halogen-Bonded Haloamine Tetramers.

Inspired by the isostructural motif in α-bromoacetophenone oxime crystals, we investigated halogen-halogen bonding in haloamine quartets. Our Kohn-Sham molecular orbital and energy decomposition analysis reveal a synergy that can be traced to a charge-transfer interaction in the halogen-bonded tetramers. The halogen lone-pair orbital on one monomer donates electrons into the unoccupied σ*N-X orbital on the perpendicular N-X bond of the neighboring monomer. This interaction has local σ symmetry. Interestingly, we discovered a second, somewhat weaker donor-acceptor interaction of local π symmetry, which partially counteracts the aforementioned regular σ-symmetric halogen-bonding orbital interaction. The halogen-halogen interaction in haloamines is the first known example of a halogen bond in which back donation takes place. We also find that this cooperativity in halogen bonds results from the reduction of the donor-acceptor orbital-energy gap that occurs every time a monomer is added to the aggregate.

Aromaticity Induced by Electric Field: The Case of Polycalicenes.

Local and global π-electron delocalization occurring in planar poly-1,7-[N]calicenes is investigated with use of 10 aromaticity measures based on different physical properties. Systematic change of aromatic character is observed along chains of connected calicene units. Multidimensionality of the aromaticity phenomenon is studied with use of principal component analysis (PCA). The structural characteristics are compared with the properties of the isolated calicene molecule exposed to external electric fields of various intensities. Interrelations between the value of electric field applied and physical properties of the calicene molecule are discussed in the context of calicene unit affected by its surroundings in polycalicene chains. The patterns of global π-electron delocalization are described in graph theory terminology, and interconnections between local and global aromaticity in these systems are established.

The substituent effect on benzene dications.

It was recently postulated that the benzene ring and its 4n + 2 π-electron analogues are resistant to the substituent effect due to the fact that such systems tend to retain their delocalized character. Therefore, the 4n π-electron dicationic form of benzene should appear to be less resistant to the substituent effect, as compared with its parent neutral molecule. For this reason the effect of substitution on the dicationic form of benzene was thoroughly investigated and the consequences of single and double substitution (of para- and meta-type) were assessed by means of several parameters, including various aromaticity indices and the Substituent Effect Stabilization Energy (SESE) parameter. It is shown that, distinct from neutral benzene, its dicationic form is much more sensitive to the substitution. However, the dicationic benzene itself, as a moiety with a significant deficit of electrons, will be considered as a strongly electron-withdrawing centre, thus interacting in a cooperative way with electron-donating substituents and in an anticooperative way with electron-withdrawing substituents. Clear differences between singlet- and triplet-state dicationic forms of benzene were also found. Triplet state structures seem to be significantly more delocalized, and as a consequence less sensitive to the substituent effect than the singlet state structures. Finally, the para- and meta-type substitution was investigated and it was found that the disubstituted dicationic benzene exhibits significantly different behaviour from that of neutral benzene. Although the difference between para- and meta-substitution can be found for dicationic benzene, the mechanism responsible for such an observation is different from that present in neutral benzene. Finally, it is shown how and why double ionization of benzene reduces its aromatic character in the singlet dication whereas aromaticity is essentially conserved in the triplet dication. The above findings highlight that in the case of charged analogues of benzene the aromaticity indices can be misleading and are to be used with great precaution.

UV-vis spectra of singlet state cationic polycyclic aromatic hydrocarbons: time-dependent density functional theory study.

A theoretical study of singlet state cations of polycyclic aromatic hydrocarbons is performed. Appropriate symmetry suitable for further calculations is chosen for each of the systems studied. The excitation states of such species are obtained by the time dependent density functional theory (TD-DFT) method. The computations are performed using both Pople and electronic response properties basis sets. The results obtained with the use of different basis sets are compared. The electronic transitions are described and the relationships for the lowest-lying transitions states of different species are found. The properties of in-plane and out-of-plane transitions are also delineated. The TD-DFT results are compared with the experimental data available.

Does the concept of Clar's aromatic sextet work for dicationic forms of polycyclic aromatic hydrocarbons?--testing the model against charged systems in singlet and triplet states.

The concept of Clar's π-electron aromatic sextet was tested against a set of polycyclic aromatic hydrocarbons in neutral and doubly charged forms. Systems containing different types of rings (in the context of Clar's concept) were chosen, including benzene, naphthalene, anthracene, phenanthrene and triphenylene. In the case of dicationic structures both singlet and triplet states were considered. It was found that for singlet state dicationic structures the concept of aromatic sextet could be applied and the local aromaticity could be discussed in the context of that model, whereas in the case of triplet state dicationic structures Clar's model rather failed. Different aromaticity indices based on various properties of molecular systems were applied for the purpose of the studies. The discussion about the interdependence between the values of different aromaticity indices applied to neutral and charged systems in singlet and triplet states is also included.

Cyclooctatetraene dianion--an artifact?

Cyclooctatetraene in its dianionic form (COT(2-)) is considered to be partially or fully aromatic due to the fact that, unlike its neutral counterpart, it adopts planar structure with CC bonds equalized. However, some authors report that this dianion is neither planar nor aromatic. Thus, we performed a detailed analysis of the COT(2-) case. The influence of several technical parameters on the result of calculations on COT(2-) was investigated. It appears from our analysis that the use of some specific level of approximation may lead to very misleading results in which the COT ring occurs in its neutral structure, in fact being neither planar nor aromatic. Additionally, our results may suggest that COT(2-) dianion is rather an artificial structure (being the result of specific basis set description) and should not occur in experimental conditions.