A New Structural Motif in Aggregation of Methylalumoxanes: Non-hydrolytic Route by the Alkylation of Dicarboxylic Acids.

Alumoxanes are typically produced via controlled hydrolysis of short-chain alkyl aluminium compounds which leads to oligomeric species that are usually difficult to obtain in crystalline form. Simultaneously, various alternative non-hydrolytic approaches to alumoxanes have also been used. In this work, we report on a new methylalumoxane scaffold derived from the alkylation of a series of dicarboxylic acids: itaconic acid (HO2CCH2C(=CH2)CO2H), succinic acid (HO2CCH2CH2CO2H) and homophthalic acid (HO2CCH2C6H4CO2H). The reactions of AlMe3 with a selected dicarboxylic acid in the molar ratio 4:1 conducted at elevated temperature occur with double methylation of each carboxylic group and provide to the formation of a new methylalumoxane aggregate, Me10Al6O4, flanked by methylaluminium diolate units. We also aimed to obtain dialkylaluminium derivatives of dicarboxylic acids by the controlled reaction of the appropriate acid with AlMe3 in the 1:2 stoichiometry. While the synthesis of organoaluminium derivatives of flexible aliphatic dicarboxylic acids (itaconic and succinic acids) is challenging due to their insolubility, the related homophtalate compound readily forms a molecular tetranuclear cluster, [(homophtalate)(AlMe2)2]2. The molecular and crystal structures of the resulting compounds were determined via NMR spectroscopic analysis and single crystal X-ray diffraction crystallography.

2,3-Dichloroanthracene crystal, a new rigid matrix for single molecule optical investigations.

Absorption and emission spectra of single crystals of 2,3-dichloroathracene (23DCA) and 23DCA dispersed in n-nonane matrix were studied at 5 K. Singlet and triplet excitonic bands in the crystal were estimated to be at about 415 nm and at wavelengths shorter than 700 nm, respectively. Thus, from the spectroscopic point of view, these crystals satisfy all criteria for a transparent and rigid matrix for low temperature optical studies of single molecules of dibenzoterrylene, which have their purely electronic S0→S1 transition at around 785 nm. Quantum-chemistry calculations were used to analyze the spectra.

Towards Anticancer and Antibacterial Agents: Design and Synthesis of 1,2,3-Triazol-quinobenzothiazine Derivatives.

In this paper, we describe a new method for synthesizing hybrid combinations of 1,2,3-triazoles with a tetracyclic quinobenzothiazinium system. The developed approach allowed for the production of a series of new azaphenothiazine derivatives with the 1,2,3-triazole system in different positions of the benzene ring. In practice, the methodology consists of the reaction of triazole aniline derivatives with thioquinanthrenediinium bis-chloride. The structure of the products was determined by 1H-NMR, 13C-NMR spectroscopy, and HR-MS spectrometry, respectively. Moreover, the spatial structure of the molecule and the arrangement of molecules in the crystal (unit cell) were determined by X-ray crystallography. The anticancer activity profiles of the synthesized compounds were tested in vitro against human cancer cells of the A549, SNB-19, and T47D lines and the normal NHDF cell line. Additional tests of antibacterial activity against methicillin-sensitive and methicillin-resistant staphylococci, vancomycin-sensitive and vancomycin-resistant enterococci, and two mycobacterial strains were also performed. In fact, the dependence of anticancer and antibacterial activity on the substituent type and its position in the quinobenzothiazinium system was observed. Furthermore, the distance-guided property evaluation was performed using principal component analysis (PCA) and hierarchical clustering analysis (HCA) on the pool of the calculated descriptors. Finally, the theoretically approximated partition coefficients (clogP) were (inter-)correlated with each other and cross-compared with the empirically specified logPTLC parameters.

Design, Synthesis and Antimicrobial Properties of New Tetracyclic Quinobenzothiazine Derivatives.

A new method for modifying the structure of tetracyclic quinobenzothiazinium derivatives has been developed, allowing introduction of various substituents at different positions of the benzene ring. The method consists of reacting appropriate aniline derivatives with 5,12-(dimethyl)thioquinantrenediinium bis-chloride. A series of new quinobenzothiazine derivatives was obtained with propyl, allyl, propargyl and benzyl substituents in 9, 10 and 11 positions, respectively. The structure of the obtained compounds was analyzed by 1H and 13C NMR (HSQC, HMBC) and X-ray analysis. All the compounds were tested against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212, and representatives of multidrug-resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). In addition, all the compounds were evaluated in vitro against Mycobacterium smegmatis ATCC 700084 and M. marinum CAMP 5644. 9-Benzyloxy-5-methyl-12H-quino [3,4-b][1,4]benzothiazinium chloride (6j), 9-propoxy-5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (6a) and 9-allyloxy-5-methyl-12H-quino[3,4-b][1,4]benzothiazinium chloride (6d) demonstrated high activity against the entire tested microbial spectrum. The activities of the compounds were comparable with oxacillin, tetracycline and ciprofloxacinagainst staphylococcal strains and with rifampicin against both mycobacterial strains. Compound 6j had a significant effect on the inhibition of bacterial respiration as demonstrated by the MTT assay. The compounds showed not only bacteriostatic activity, but also bactericidal activity. Preliminary in vitro cytotoxicity screening of the compounds performed using normal human dermal fibroblasts (NHDF) proved that the tested compounds showed an insignificant cytotoxic effect on human cells (IC50 > 37 µM), making these compounds interesting for further investigation. Moreover, the intermolecular similarity of novel compounds was analyzed in the multidimensional space (mDS) of the structure/property-related in silico descriptors by means of principal component analysis (PCA) and hierarchical clustering analysis (HCA), respectively. The distance-oriented structure/property distribution was related with the experimental lipophilic data.

Towards Property Profiling: SYNTHESIS and SAR Probing of New Tetracyclic Diazaphenothiazine Analogues.

A series of new tertiary phenothiazine derivatives containing a quinoline and a pyridine fragment was synthesized by the reaction of 1-methyl-3-benzoylthio-4-butylthioquinolinium chloride with 3-aminopyridine derivatives bearing various substituents on the pyridine ring. The direction and mechanism of the cyclization reaction of intermediates with the structure of 1-methyl-4-(3-pyridyl)aminoquinolinium-3-thiolate was related to the substituents in the 2- and 4-pyridine position. The structures of the compounds were analyzed using 1H, 13C NMR (COSY, HSQC, HMBC) and X-ray analysis, respectively. Moreover, the antiproliferative activity against tumor cells (A549, T47D, SNB-19) and a normal cell line (NHDF) was tested. The antibacterial screening of all the compounds was conducted against the reference and quality control strain Staphylococcus aureus ATCC 29213, three clinical isolates of methicillin-resistant S. aureus (MRSA). In silico computation of the intermolecular similarity was performed using principal component analysis (PCA) and hierarchical clustering analysis (HCA) on the pool of structure/property-related descriptors calculated for the novel tetracyclic diazaphenothiazine derivatives. The distance-oriented property evaluation was correlated with the experimental anticancer activities and empirical lipophilicity as well. The quantitative shape-based comparison was conducted using the CoMSA method in order to indicate the potentially valid steric, electronic and lipophilic properties. Finally, the numerical sampling of similarity-related activity landscape (SALI) provided a subtle picture of the SAR trends.

Photophysical transformations induced by chemical substitution to salicylaldimines.

A series of different electron-deficient aromatic substituents were used to investigate the role of the electron-acceptor strength on the photophysical properties of salicylaldimine derivatives. These molecules were synthesised and characterised through X-ray diffraction, absorption and emission spectroscopies. Their photochemical reaction mechanisms and properties were explored with the aid of ab initio methods of quantum chemistry. Our results allow us to clarify the dependence of the multiple emission bands on the polarity of the solvent and on the substitution of electron donating and accepting groups to the salicylaldimine core.

Heteroleptic [Os(Cl)(CO)(P

A series of six [Os(Cl)(CO)(P^P)(pbi)] complexes have been synthesized and characterized using FT-IR, 1H NMR, and 31P NMR spectroscopy. Their molecular structures have been confirmed by means of X-ray diffraction studies. For each of the studied bidentate phosphines (P^P = cis-1,2-bis(diphenylphosphino)ethene - dppv, 1,2-bis(diphenylphosphino)ethane - dppe, 1,2-bis(diphenylphosphino)benzene - dppb) the applied synthesis procedure has afforded preparation of two isomers with pseudo-octahedral coordination of the osmium(ii) ion. According to X-ray data, the obtained isomers, green emissive [OC-6-24] and yellow emissive [OC-6-23] species, differ mainly in the arrangement of the 2-(2-pyridyl)benzimidazolate (pbi) anion in their structures. In the [OC-6-24] isomers the benzoimidazole fragment of the pbi ligand is located trans to the coordinated CO molecule, whereas the cis conformation is characteristic of the [OC-6-23] isomers. Each of trans-[Os(Cl)(CO)(P^P)(pbi)] shows intense green emission attributable to the excited triplet state of the pbi ligand, whereas the yellow emission from the excited cis-[Os(Cl)(CO)(P^P)(pbi)] indicates slight metal-to-ligand charge transfer character (from the Os(Cl)(CO)(P^P)+ fragment to the pbi ligand). The investigated complexes are generally well emissive with emission quantum yields up to 0.49 and emission lifetimes in the range of 10-150 µs. Only the yellow emissive cis-[Os(Cl)(CO)(dppv)(pbi)] complex exhibits remarkably different photophysical behaviour despite the fact that all three cis-[Os(Cl)(CO)(P^P)(pbi)] isomers emit in the same spectral region. In the view of DFT/TD-DFT results this has been explained by the presence of an additional excited dark state possessing distinct charge transfer character (from the Os(Cl)(CO)(pbi) fragment to the dppv ligand).

Electron transfer across a spiro link: extreme solvatofluorochromism of a compact spiro-bridged N,N-dimethylaniline-phthalide dyad.

Intramolecular electron transfer over the sp3-C-link in dimethyl-aniline-spiro-phthalide leads to extreme solvatofluorochromism (11 600 cm-1) and a fluorescence maximum shift from 357 (hexane) to 595 nm (acetonitrile). The spiro link enhances π-σ* negative hyperconjugation leading to C-O bond elongation and electron transfer over a longer distance than in a non-spirocyclic analogue.

10H-1,9-diazaphenothiazine and its 10-derivatives: synthesis, characterisation and biological evaluation as potential anticancer agents.

10H-1,9-diazaphenothiazine was obtained in the sulphurisation reaction of diphenylamine with elemental sulphur and transformed into new 10-substituted derivatives, containing alkyl and dialkylaminoalkyl groups at the thiazine nitrogen atom. The 1,9-diazaphenothiazine ring system was identified with advanced 1H and 13C NMR techniques (COSY, NOESY, HSQC and HMBC) and confirmed by X-ray diffraction analysis of the methyl derivative. The compounds exhibited significant anticancer activities against the human glioblastoma SNB-19, melanoma C-32 and breast cancer MDA-MB-231 cell lines. The most active 1,9-diazaphenothiazines were the derivatives with the propynyl and N, N-diethylaminoethyl groups being more potent than cisplatin. For those two compounds, the expression of H3, TP53, CDKN1A, BCL-2 and BAX genes was detected by the RT-QPCR method. The proteome profiling study showed the most probable compound action on SNB-19 cells through the intrinsic mitochondrial pathway of apoptosis. The 1,9-diazaphenotiazine system seems to be more potent than known isomeric ones (1,6-diaza-, 1,8-diaza-, 2,7-diaza- and 3,6-diazaphenothiazine).

Evaluation of angularly condensed diquinothiazines as potential anticancer agents.

We present efficient synthesis of isomeric types of angularly fused diquinothiazines in the reactions of 2,2'-dichloro-3,3'-diquinolinyl disulfide and diquinodithiin with 3-, 5-, 6- and 8-aminoquinolines. The pentacyclic diquinothiazine ring systems were identified as diquino[3,2-b;3',4'-e][1,4]thiazine, diquino[3,2-b;5',6'-e][1,4]thiazine, diquino[3,2-b;6',5'-e][1,4]thiazine and diquino[3,2-b;8',7'-e][1,4]thiazine with advanced two-dimensional 1H and 13C NMR techniques (COSY, ROESY, HSQC and HMBC) of N-methyl derivatives. The identification of pentacyclic ring system was confirmed by X-ray diffraction analysis of selected N-alkyl derivatives. The X-ray analysis revealed different spatial structures of the ring system (planar and folded). NH-diquinothiazines were further transformed into N-alkyl and N-dialkylaminoalkyl derivatives. Most of diquinothiazines exhibited significant cancer cell growth inhibition against the human glioblastoma SNB-19, colorectal carcinoma Caco-2, breast cancer MDA-MB-231 and lung cancer A549 cell lines with the IC50 values < 3 µM. This anti-proliferative activity was found to be more than for cisplatin. The most promising compound, 7-dimethylaminopropyldiquino[3,2-b;6',5'-e]thiazine, was used for gene expression analysis by reverse transcription-quantitative real-time PCR (RT-QPCR) method. The expression of H3, TP53, CDKN1A, BCL-2 and BAX genes revealed that this compound inhibited the proliferation in all cells (H3) and activated mitochondrial events of apoptosis (BAX/BCL-2) in two cancer cell lines (SNB-19 and Caco-2).

Heteroleptic [Os(H)(CO)(N∧N)(tpp)2]+ and [Os(Cl)(CO)(N∧N)(tpp)2]+ complexes - comparative studies of their luminescence properties.

Two series of cationic heteroleptic osmium(ii) complexes with a coordinated CO molecule, a chloride Cl- or hydride H- anion, two monodentate triphenylphosphine (tpp) ligands and one bidentate α-dimine (N∧N) ligand were prepared from an OsCl2(CO)2(tpp)2 precursor. The investigated complexes, available in the form of PF6- salts, have been identified by means of FT-IR, 1H and 31P NMR spectroscopy and X-ray diffraction studies. Their photophysical properties have been investigated in dichloromethane solutions at room temperature and 1 : 1 ethanol-methanol matrices at 77 K. The investigated complexes exhibit metal to ligand charge-transfer (MLCT) phosphorescence with the emission characteristics distinctly affected by the nature of coordinated α-diimine N∧N and Cl- or H- ligands. Franck-Condon emission spectral band shape analyses and DFT/TD-DFT calculations have been applied to obtain more detailed insight into the nature of emissive 3*[Os(H)(CO)(N∧N)(tpp)2]+ and 3*[Os(Cl)(CO)(N∧N)(tpp)2]+ species.

3,6-Diazaphenothiazines as potential lead molecules - synthesis, characterization and anticancer activity.

3,6-Diazaphenothiazines were obtained in cyclization of 3-amino-3'-nitro-2,4'-dipyridinyl sulfide and the reaction of sodium 3-amino-2-pyridinethiolate with 4-chloro-3-nitropyridine followed by alkylation and heteroarylation. The thiazine ring formation ran via the Smiles rearrangement. The structure elucidation was based on 2D NMR and X-ray analysis of N-methylated product. 3,6-Diazaphenothiazines were investigated for antitumor activity using glioblastoma SNB-19, melanoma C-32 and breast cancer MCF-7 cells. 10H-3,6-diazaphenothiazine was 10 times more active (IC50 < 0.72 µg/mL) than cisplatin. Two diazaphenothiazines with the 2-pyrimidinyl and dimethylaminopropyl substituents were selectively active against MCF-7 and C-32 cells. The expressions of H3 (proliferation marker), TP53, CDKN1A (cell cycle regulators), BAX and BCL-2 (proapoptopic and antiapoptopic genes) were detected by RT-QPCR method. The expression analysis suggests the cell cycle arrest and the mitochondrial apoptosis pathway activation in MCF-7 and SNB-19 cells.

Novel imidazolium and imidazolinium salts containing the 9-nickelafluorenyl anion--synthesis, structures and reactivity.

Investigation of the properties of carbene complexes is one of the most important fields of modern coordination chemistry. In this paper, we propose the convenient synthesis of NHC-nickel compounds. The 9-nickelafluorenyllithium complex reacts with imidazolium or imidazolinium salts to afford 9-nickelafluorenyl-NHC salts via ionic metathesis with very good yields (66-92%). These compounds can be isomerised at elevated temperatures to give Ni-NHC complexes with excellent yields (88-91%), probably via nickel mediated hydrogen transfer to the biphenyl moiety. In this reaction, the nickelacyclic ring itself serves as a base in the deprotonation of the carbene precursor. DFT calculations show the thermodynamic instability of the synthesized salts, with Gibbs free energy differences for 1 of -84 kJ mol(-1) at 298 K and -167 kJ mol(-1) at 374 K. The obtained salts and carbene complexes are relatively air and moisture stable in the solid state.

ß-Cyclodextrin as the suitable molecular container for isopulegol enantiomers.

Isopulegol, an insoluble in water and highly volatile compound, due to its neuroactive properties is a potentially important agent for medical applications. Formation of "host-guest" molecular complexes with cyclodextrins would lead to the increase of its water solubility and bioavailability. Interactions between native cyclodextrins (α, ß and γ) and isopulegol enantiomers were studied in solution proving the formation of inclusion complexes for ß- and γ-cyclodextrins. For the more stable complexes with ß-cyclodextrin crystal structures were obtained showing the formation of molecular capsules forming molecular container able to accommodate two guest molecules.

6-[3-(p-Tolyl-sulfonyl-amino)-prop-yl]diquino-thia-zine.

In the title mol-ecule {systematic name: N-[3-(diquino[3,2-b;2',3'-e][1,4]thia-zin-6-yl)prop-yl]-4-methyl-benzene-sulfon-amide}, C28H24N4O2S2, the penta-cyclic system is relatively planar [maximum deviation from the mean plane = 0.242 (1) Å]. The dihedral angle between two quinoline ring systems is 8.23 (2)° and that between the two halves of the 1,4-thia-zine ring is 5.68 (3)°. The conformation adopted by the 3-(p-tolyl-sulfonyl-amino)-propyl substituent allows for the formation of an intra-molecular N-H⋯N hydrogen bond and places the benzene ring of this substituent above one of the quinoline fragments of the penta-cyclic system. In the crystal, mol-ecules are arranged via π-π stacking inter-actions into (0-11) layers [centroid-centroid distances = 3.981 (1)-4.320 (1) Šfor the rings in the penta-cyclic system and 3.645 (1) Šfor the tolyl benzene rings]. In addition, mol-ecules are involved in weak C-H⋯O, which connect the layers, and C-H⋯S hydrogen bonds. The title compound shows promising anti-cancer activity against renal cancer cell line UO-31.

10-(Prop-2-yn-1-yl)-2,7-diaza-phenothia-zine.

In the title mol-ecule [systematic name: 10-(prop-2-yn-1-yl)dipyrido[3,4-b:3',4'-e][1,4]thia-zine], C(13)H(9)N(3)S, the dihedral angle between the two pyridine rings is 146.33 (7)° and the angle between two halves of the thia-zine ring is 138.84 (8)°, resulting in a butterfly shape for the tricyclic system. The central thia-zine ring adopts a boat conformation, with the 2-propynyl substituent at the thia-zine N atom located in a pseudo-equatorial position and oriented to the concave side of the diaza-phenothia-zine system. In the crystal, mol-ecules are arranged via π-π inter-actions between the pyridine rings [centroid-centroid distances = 3.838 (1) and 3.845 (1) Å] into stacks extending along [001]. There are C-H⋯C and C-H⋯N inter-actions between mol-ecules of neighbouring stacks.

Transformations of griseofulvin in strong acidic conditions--crystal structures of 2'-demethylgriseofulvin and dimerized griseofulvin.

The structure of griseofulvic acid, C16H15ClO6, at 100 K has orthorhombic (P2(1)2(1)2) symmetry. It is of interest with respect to biological activity. The structure displays intermolecular O-H...O, C-H...O hydrogen bonding as well as week C-H...pi and pi...pi interactions. In strong acidic conditions the griseofulvin undergoes dimerization. The structure of dimerized griseofulvin, C34H32C12O12 x C2H6O x H2O, at 100 K has monoclinic (P2(1)) symmetry. The molecule crystallized as a solvate with one ethanol and one water molecule. The dimeric molecules form intermolecular O-H...O hydrogen bonds to solvents molecules only but they interact via week C-H...O, C-H...pi, C-Cl...pi and pi...pi interactions with other dimerized molecules.

Monolayers of an amphiphilic para-carboxy-calix[4]arene act as templates for the crystallization of acetaminophen.

The title compound, 5,11,17,23-tetra-carboxy-25,26,27,28-tetradodecyloxy-calix[4]arene, 1, has been studied at the air-water interface, self-assembled as Langmuir monolayers, for its ability to interact with an active pharmaceutical ingredient (API), acetaminophen (APAP), and to initiate its crystallization. The Π/A isotherm study shows that there is a clear interaction between 1 and APAP causing an expansion of the monolayer. In addition to the known phase transition occurring at a surface tension of 38 mN m(-1), an additional kink is observed in the compression isotherm for concentrations of APAP above 40 mM suggesting that this API is causing an additional phase transition of the monolayer. Interface-initiated crystallization studies show that the presence of a monolayer spread on a supersaturated solution of APAP (26 g L(-1)) triggers this API crystal growth from the interface. The transfer of 1-based monolayers on glass surfaces has been carried out using the Langmuir-Blodgett technique. The so-produced monolayers have been shown to template the crystallization of APAP. LB films of 1 have characterized using imaging and spectroscopic ellipsometry. The results suggest that each monolayer has an average thickness of 18 Å, which is consistent with the molecular structure of 1 self-organized parallel to the interface with the alkyl chains pointing out parallel to the axis of the macrocycle and without interdigitation of the alkyl chains. The presence of APAP in the subphase during the LB transfer causes a limited but relevant increase in the layer thickness. The study of the capabilities of the LB films to initiate crystallization of APAP is also demonstrated showing the influence of the monolayer packing on the quantity of formed crystals.

N-[4-(9-Chloro-quino[3,2-b]benzo[1,4]thia-zin-6-yl)but-yl]acetamide.

In the title mol-ecule, C21H20ClN3OS, the tetra-cyclic system is close to planar [r.m.s. deviation = 0.110 (4) Å]. The dihedral angle between the quinoline ring system and the benzene ring is 178.3 (1)° and the angle between two (S-C=C-N) halves of the thia-zine ring is 173.4 (1)°. In the crystal, mol-ecules are arranged via π-π inter-actions [centroid-centroid distances = 3.603 (2)-3.739 (2) Å] into slipped stacks extending along [010]. Inter-molecular N-H⋯O hydrogen bonds link the amide groups of neighbouring mol-ecules along the stack, generating a C(4) motif. The title compound shows promising anti-proliferative and anti-cancer activity.

Amidophenol-modified amphiphilic calixarenes: synthesis, interfacial self-assembly, and acetaminophen crystal nucleation properties.

Three amidophenol-modified calixarenes have been produced reacting the parent 5,11,17,23-tetracarboxy-25,26,27,28-tetradodecyloxycalix[4]arene with o-, m-, and p-aminophenol. The produced amphiphiles have been shown to form stable monomolecular Langmuir layers on water. Working on subphases containing 1 mM acetaminophen (APAP), it has been demonstrated that the produced amphiphiles interact with this active pharmaceutically ingredient (API) with a relevant preference for the para-derivative that possesses in its structure substituents that are analogous to the target. Working at supersaturating concentrations of APAP, it has been demonstrated that the so-produced calixarene Langmuir monolayers do favor crystallization of APAP (polymorph I), with a clear effect of the packing density of the amphiphile at the interface on the quantity of produced crystals. Monolayers of the para-derivative have been transferred on solid substrates using the Langmuir-Blodgett technique; the so-produced ultrathin films have been shown to initiate surface crystal nucleation of APAP. The produced solids have been analyzed by single-crystal X-ray crystallography and shown to preferentially grow in the [010] direction.