Unsymmetrical Pd(II) Pincer Complexes with Benzothiazole and Thiocarbamate Flanking Units: Expedient Solvent-Free Synthesis and Anticancer Potential.

Driven by the growing threat of cancer, many research efforts are directed at developing new chemotherapeutic agents, where the central role is played by transition metal complexes. The proper ligand design serves as a key factor to unlock the anticancer potential of a particular metal center. Following a recent trend, we have prepared unsymmetrical pincer ligands that combine benzothiazole and thiocarbamate donor groups. These compounds are shown to readily undergo direct cyclopalladation, affording the target S,C,N-type Pd(II) pincer complexes both in solution and in the absence of a solvent. The solid-phase strategy provided the complexes in an efficient and ecologically friendly manner. The resulting palladacycles are fully characterized using nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy and, in one case, by single-crystal X-ray diffraction (XRD). The solvent-free reactions are additionally analyzed by powder XRD. The pincer complexes exhibit remarkable cytotoxicity against several solid and blood cancer cell lines, including human colorectal carcinoma (HCT116), breast cancer (MCF7), prostate adenocarcinoma (PC3), chronic myelogenous leukemia (K562), multiple plasmacytoma (AMO1), and acute lymphoblastic leukemia (H9), with the dimethylamino-substituted derivative being particularly effective. The latter also induced an appreciable level of apoptosis in both parental and doxorubicin-resistant cells K562 and K562/iS9, vindicating the high anticancer potential of this type of palladacycles.

Cage-like Cu5Cs4-Phenylsilsesquioxanes: Synthesis, Supramolecular Structures, and Catalytic Activity.

A small family of nonanuclear Cu5Cs4-based phenylsilsesquioxanes 1-2 were prepared by a convenient self-assembly approach and characterized by X-ray diffraction studies. The compounds 1 and 2 show some unprecedented structural features such as the presence of a [Ph14Si14O28]14- silsesquioxane ligand and a CuII5CsI4 nuclearity in which the metal cations occupy unusual positions within the cluster. Copper ions are "wrapped" into a silsesquioxane matrix, while cesium ions are located in external positions. This resulted in cesium-involved aggregation of coordination polymer structures. Both compounds 1 and 2 realize specific metallocene (cesium-phenyl) linkage between neighboring cages. Compound 2 is evaluated as a catalyst in the Baeyer-Villiger (B-V) oxidation of cyclohexanone and tandem cyclohexane oxidation/B-V oxidation of cyclohexanone with m-chloroperoxybenzoic acid (mCPBA) as an oxidant, in an aqueous acetonitrile medium, and HNO3 as the promoter. A quantitative yield of ε-caprolactone was achieved under conventional heating at 50 °C for 4 h or MW irradiation for 30 min (for cyclohexanone as substrate); 17 and 19% yields of lactone upon MW irradiation at 80 °C for 30 min and heating at 50 °C for 4 h, respectively (for cyclohexane as a substrate), were achieved. Complex 2 was evaluated as a catalyst for the oxidation of alkanes to alkyl hydroperoxides and alcohols to ketones with peroxides at 60 °C in acetonitrile. The maximum yield of cyclohexane oxidation products was 30%. Complex 2 exhibits high activity in the oxidation of alcohols.

Free Radicals in the Queue: Selective Successive Addition of Azide and N-Oxyl Radicals to Alkenes.

The selective successive addition of azide (•N3) and N-oxyl radicals to alkenes is demonstrated, despite each of the two radicals being known to attack C═C bonds and the mixture of radical adducts possibly being expected. The proposed radical mechanism was supported by density functional theory calculations, electron paramagnetic resonance, and radical trapping experiments. The reaction proceeds at room temperature with the available reagents: NaN3, N-hydroxy compounds, and PhI(OAc)2 as the oxidant. The method can be applied for N-hydroxyimides, N-hydroxyamides, N-hydroxybenzotriazole, and oximes as N-oxyl radical precursors. Vinylarenes, aliphatic alkenes, and even electron-deficient methyl methacrylate were successfully functionalized.

Benzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole) and Its Bromo Derivatives: Molecular Structure and Reactivity.

Benzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole) (isoBBT) is a new electron-withdrawing building block that can be used to obtain potentially interesting compounds for the synthesis of OLEDs and organic solar cells components. The electronic structure and delocalization in benzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole), 4-bromobenzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole), and 4,8-dibromobenzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole) were studied using X-ray diffraction analysis and ab initio calculations by EDDB and GIMIC methods and were compared to the corresponding properties of benzo[1,2-c:4,5-c']bis[1,2,5]thiadiazole (BBT). Calculations at a high level of theory showed that the electron affinity, which determines electron deficiency, of isoBBT was significantly smaller than that of BBT (1.09 vs. 1.90 eV). Incorporation of bromine atoms improves the electrical deficiency of bromobenzo-bis-thiadiazoles nearly without affecting aromaticity, which increases the reactivity of these compounds in aromatic nucleophilic substitution reactions and, on the other hand, does not reduce the ability to undergo cross-coupling reactions. 4-Bromobenzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole) is an attractive object for the synthesis of monosubstituted isoBBT compounds. The goal to find conditions for the selective substitution of hydrogen or bromine atoms at position 4 in order to obtain compounds containing a (het)aryl group in this position and to use the remaining unsubstituted hydrogen or bromine atoms to obtain unsymmetrically substituted isoBBT derivatives, potentially interesting compounds for organic photovoltaic components, was not set before. Nucleophilic aromatic and cross-coupling reactions, along with palladium-catalyzed C-H direct arylation reactions for 4-bromobenzo[1,2-d:4,5-d']bis([1,2,3]thiadiazole), were studied and selective conditions for the synthesis of monoarylated derivatives were found. The observed features of the structure and reactivity of isoBBT derivatives may be useful for building organic semiconductor-based devices.

One-Pot Synthesis of Colloidal Hybrid Au (Ag)/ZnO Nanostructures with the Participation of Maleic Acid Copolymers.

One-pot synthesis of colloidal Au/ZnO and Ag/ZnO nanohybrid structures was carried out. The copolymers of maleic acid-poly(N-vinyl-2-pyrrolidone-alt-maleic acid), poly(ethylene-alt-maleic acid), or poly(styrene-alt-maleic acid) were used as templates for the sorption of cations of metals-precursors and stabilization of the resulting nanoheterostructures. Simultaneous production of two types of nanoparticles has been implemented under mild conditions in an aqueous alkaline medium and without additional reagents. Equimolar ratios of the metal cations and appropriate load on all copolymers were used: molar ratio of maleic acid monomeric units of copolymer/gold (silver)cations/zinc cations was 1/0.15/0.23 (1/0.3/0.15). The process of obtaining the heterostructures was studied using UV-Vis spectroscopy. The kinetics of the formation of heterostructures was influenced by the nature of the maleic acid copolymer and noble metal cations used. A high reaction rate was observed in the case of using zinc and gold cations-precursors and a copolymer of maleic acid with N-vinylpyrrolidone as a stabilizer of nanoparticles. The structure of the synthesized polymer-stabilized heterostructures was studied using instrumental methods of analysis-XPS, FTIR, PXRD, and TEM. Under the conditions used, stable colloidal solutions of heterodimers were obtained, and such structure can be converted to a solid state and back without loss of properties.

Ligand-Receptor Interactions of Lamivudine: A View from Charge Density Study and QM/MM Calculations.

The nature and strength of interactions for an anti-HIV drug, Lamivudine, were studied in a pure crystal form of the drug and the ligand-receptor complexes. High-resolution single-crystal X-ray diffraction studies of the tetragonal polymorph allowed the drug's experimental charge density distribution in the solid state to be obtained. The QM/MM calculations were performed for a simplified model of the Lamivudine complex with deoxycytidine kinase (two complexes with different binding modes) to reconstruct the theoretical charge density distribution. The peculiarities of intramolecular interactions were compared with previously reported data for an isolated molecule. Intermolecular interactions were revealed within the quantum theory of 'Atoms in Molecules', and their contributions to the total crystal energy or ligand-receptor binding energy were evaluated. It was demonstrated that the crystal field effect weakened the intramolecular interactions. Overall, the energies of intermolecular interactions in ligand-receptor complexes (320.1-394.8 kJ/mol) were higher than the energies of interactions in the crystal (276.9 kJ/mol) due to the larger number of hydrophilic interactions. In contrast, the sum of the energies of hydrophobic interactions was found to be unchanged. It was demonstrated by means of the Voronoi tessellation that molecular volume remained constant for different molecular conformations (250(13) Å3) and increased up to 399 Å3 and 521(30) Å3 for the Lamivudine phosphate and triphosphate.

Reaction of Picolinamides with Ketones Producing a New Type of Heterocyclic Salts with an Imidazolidin-4-One Ring.

Reactions of picolinamides with 1,3-propanesultone in methanol followed by the treatment with ketones led to a series of previously unknown chemical transformations, yielding first pyridinium salts (2a-f), with a protonated endocyclic nitrogen atom, and then heterocyclic salts (3a-j) containing an imidazolidin-4-one ring. The structures of intermediate and final products were determined by IR and 1H, 13C NMR spectroscopy, and X-ray study. The effects of the ketone and alcohol structures on the product yield were studied by quantum-chemical calculations. The stability of salts 3a-j towards hydrolysis and alcoholysis makes them excellent candidates for the search for new types of biologically active compounds.

Synthesis and Biological Evaluation of Chalconesulfonamides: En Route to Proapoptotic Agents with Antiestrogenic Potency.

Breast and other estrogen receptor α-positive cancers tend to develop resistance to existing drugs. Chalcone derivatives possess anticancer activity based on their ability to form covalent bonds with targets acting as Michael acceptors. This study aimed to evaluate the anticancer properties of a series of chalcones (7a-l) with a sulfonamide group attached to the vinyl ketone moiety. Chalconesulfonamides showed a potent antiproliferative effect at low micromolar concentrations against several cancer cell lines, including ERα-positive 4-hydroxytamoxifen-resistant MCF7/HT2. Immunoblotting of samples treated with the lead compound 7e revealed its potent antiestrogenic activity (ERα/GREB1 axis) and induction of PARP cleavage (an apoptosis marker) in breast cancer cells. The obtained compounds represent a promising basis for further development of targeted drugs blocking hormone pathways in cancer cells.

Hybrid Silsesquioxane/Benzoate Cu7-Complexes: Synthesis, Unique Cage Structure, and Catalytic Activity.

A series of phenylsilsesquioxane-benzoate heptacopper complexes 1-3 were synthesized and characterized by X-ray crystallography. Two parallel routes of toluene spontaneous oxidation (into benzyl alcohol and benzoate) assisted the formation of the cagelike structure 1. A unique multi-ligation of copper ions (from (i) silsesquioxane, (ii) benzoate, (iii) benzyl alcohol, (iv) pyridine, (v) dimethyl-formamide and (vi) water ligands) was found in 1. Directed self-assembly using benzoic acid as a reactant afforded complexes 2-3 with the same main structural features as for 1, namely heptanuclear core coordinated by (i) two distorted pentameric cyclic silsesquioxane and (ii) four benzoate ligands, but featuring other solvate surroundings. Complex 3 was evaluated as a catalyst for the oxidation of alkanes to alkyl hydroperoxides and alcohols to ketones with hydrogen peroxide and tert-butyl hydroperoxide, respectively, at 50 °C in acetonitrile. The maximum yield of cyclohexane oxidation products as high as 32% was attained. The oxidation reaction results in a mixture of cyclohexyl hydroperoxide, cyclohexanol, and cyclohexanone. Upon the addition of triphenylphosphine, the cyclohexyl hydroperoxide is completely converted to cyclohexanol. The specific regio- and chemoselectivity in the oxidation of n-heptane and methylcyclohexane, respectively, indicate the involvement of of hydroxyl radicals. Complex 3 exhibits a high activity in the oxidation of alcohols.

Pyridine Carboxamides Based on Sulfobetaines: Design, Reactivity, and Biological Activity.

The synthesis of the products of the 1,3-propanesultone ring opening during its interaction with amides of pyridinecarboxylic acids has been carried out. The dependence of the yield of the reaction products on the position (ortho-, meta-, para-) of the substituent in the heteroaromatic fragment and temperature condition was revealed. In contrast to the meta- and para-substituted substrates, the reaction involving ortho-derivatives at the boiling point of methanol unexpectedly led to the formation of a salt. On the basis of spectroscopic, X-Ray, and quantum-chemical calculation data, a model of the transition-state, as well as a mechanism for this alkylation reaction of pyridine carboxamides with sultone were proposed in order to explain the higher yields obtained with the nicotinamide and its N-methyl analog compared to ortho or meta parents. Based on the analysis of ESP maps, the positions of the binding sites of reagents with a potential complexing agent in space were determined. The in silico evaluation of possible biological activity showed that the synthetized compounds revealed some promising pharmacological effects and low acute toxicity.

Non-Covalent Interactions in the Crystal Structures of Perbrominated Sulfonium Derivatives of the closo-Decaborate Anion.

A new series of compounds based on perbrominated disubstituted sulfonium derivatives of the closo-decaborate anion (n-Bu4N)[2-B10Br9SR2] (R = n-Pr, i-Pr, n-Bu, n-C8H17, n-C12H25, n-C18H37) was obtained, characterised by modern physicochemical methods of analysis. According to the results of an X-ray diffraction study, some of the anions and solvate molecules were disordered. The cations (n-Bu4N)+ and anions [2-B10Br9SR2]- were associated via C-H…Br and H…H contacts. In addition, Br…Br interactions between anions were revealed. The role of these contacts was analysed in terms of Hirshfeld surface analysis, QTAIM theory and the NCI method using quantum chemical calculations. An increase in the size of the alkyl R moiety led to significant strengthening of the total energy of H…H interactions. In the case of R = -n-C18H37, a parallel mutual orientation of alkyl moieties was established that was similar to the packing of salts of fatty acids. The nature of C-H…Br and Br…Br interionic interactions was found to be attractive, in contrast to the repulsive nature of intermolecular Br…Br interactions.

A Novel Family of Cage-like (CuLi, CuNa, CuK)-phenylsilsesquioxane Complexes with 8-Hydroxyquinoline Ligands: Synthesis, Structure, and Catalytic Activity.

The first examples of metallasilsesquioxane complexes, including ligands of the 8-hydroxyquinoline family 1-9, were synthesized, and their structures were established by single crystal X-ray diffraction using synchrotron radiation. Compounds 1-9 tend to form a type of sandwich-like cage of Cu4M2 nuclearity (M = Li, Na, K). Each complex includes two cisoid pentameric silsesquioxane ligands and two 8-hydroxyquinoline ligands. The latter coordinates the copper ions and corresponding alkaline metal ions (via the deprotonated oxygen site). A characteristic (size) of the alkaline metal ion and a variation of characteristics of nitrogen ligands (8-hydroxyquinoline vs. 5-chloro-8-hydroxyquinoline vs. 5,7-dibromo-8-hydroxyquinoline vs. 5,7-diiodo-8-hydroxyquinoline) are highly influential for the formation of the supramolecular structure of the complexes 3a, 5, and 7-9. The Cu6Na2-based compound 2 exhibits high catalytic activity towards the oxidation of (i) hydrocarbons by H2O2 activated with HNO3, and (ii) alcohols by tert-butyl hydroperoxide. Studies of kinetics and their selectivity has led us to conclude that it is the hydroxyl radicals that play a crucial role in this process.

Various Approaches to Studying the Phase Transition in an Octamethylcyclotetrasiloxane Crystal: From X-ray Structural Analysis to Metadynamics.

The structure, thermodynamic parameters, and the character of thermal motion in octamethylcyclotetrasiloxane (D4) were investigated using the combination of experimental (single-crystal X-ray diffraction, thermochemistry) and theoretical (density functional theory calculations, ab initio molecular dynamics and metadynamics) methods. Single crystals of D4 were grown in a glass capillary in situ and the structures of high- (238-270 K) and low-temperature (100-230 K) phases were studied in detail. In the temperature interval 230-238 K, a phase transition with rather low enthalpy (-1.04(7) kcal/mol) was detected. It was found that phase transition is accompanied by change of conformation of cyclosiloxane moiety from boat-saddle (cradle) to chair. According to PBE0/6-311G(d,p) calculation of isolated D4, such conformation changes are characterized by a low barrier (0.07 kcal/mol). The character of molecular thermal motion and the path of phase transition were established with combination of periodic DFT calculations, including molecular dynamics and metadynamics. The effect of crystal field led to an increase in the calculated phase transition barrier (4.27 kcal/mol from low- to high-temperature phase and 3.20 kcal/mol in opposite direction).

Inverse α-Effect as the Ariadne's Thread on the Way to Tricyclic Aminoperoxides: Avoiding Thermodynamic Traps in the Labyrinth of Possibilities.

Stable tricyclic aminoperoxides can be selectively assembled via a catalyst-free three-component condensation of ß,δ'-triketones, H2O2, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of tricyclic heterocycles, containing peroxide, nitrogen, and oxygen cycles in one molecule. Amazingly, such complex tricyclic molecules are selectively formed despite the multitude of alternative reaction routes, via equilibration of peroxide, hemiaminal, monoperoxyacetal, and peroxyhemiaminal functionalities! The reaction is initiated by the "stereoelectronic frustration" of H2O2 and combines elements of thermodynamic and kinetic control with a variety of mono-, bi-, and tricyclic structures evolving under the conditions of thermodynamic control until they reach a kinetic wall created by the inverse α-effect, that is, the stereoelectronic penalty for the formation of peroxycarbenium ions and related transition states. Under these conditions, the reaction stops before reaching the most thermodynamically stable products at a stage where three different heterocycles are assembled and fused at the acyclic precursor frame.

Iron(IV) complexes with tetraazaadamantane-based ligands: synthesis, structure, applications in dioxygen activation and labeling of biomolecules.

4,6,10-Trihydroxy-1,4,6,10-tetraazaadamantane (TAAD) has been shown to form a stable Fe(IV) complex having a diamantane cage structure, in which the metal center is coordinated by three oxygen atoms of the deprotonated ligand. The complex was characterized by X-ray diffraction analysis, HRMS, NMR, FT-IR, Mössbauer spectroscopy and DFT calculations, which supported the d4 configuration of iron. The Fe(IV)-TAAD complex showed excellent performance in dioxygen activation under mild conditions serving as a mimetic of the thiol oxidase enzyme. The nucleophilicity of the bridgehead nitrogen atom in TAAD provides a straightforward way for the conjugation of Fe(IV)-TAAD complexes to various functional molecules. Using this approach, steroidal and peptide molecules having an iron(IV) label have been prepared for the first time. In addition, the Fe(IV)-TAAD complex was covalently bound to a polystyrene matrix and the resulting material was shown to serve as a heterogeneous catalyst for aerobic oxidation of thiols to disulfides.

Synthesis, Structure and Electrochemical Properties of Acetamide- and Caprolactam-Containing Silicon Catecholates.

Hexacoordinated heteroligand silicon catecholates, although being prospective as easily soluble compounds with high hydrolytic stability and diverse redox properties, have been insufficiently studied. The transesterification of 1-(trimethoxysilylmethyl)-2-oxohexahydroaze or N-methyl-N-(trimethoxysilylmethyl)acetamide by two equivalents of catechol derivatives in the presence of dicyclohexylamine afforded a series of target compounds in good yield. The complexes were characterized using elemental analysis, FTIR, 1H, 13C and 29Si NMR spectra, X-ray crystallography and cyclic voltammetry. X-ray diffraction confirmed that the silicon atom possesses the octahedral geometry of the SiCO5 polyhedron that remains unchanged in solution as it follows from 29Si NMR data. The compounds demonstrated up to three oxidation waves; and the reduction profile strongly depended on the nature of the substituents on a catecholate anion.

Synthesis of Perchlorinated Sulfonium Derivatives of closo-Decaborate Anion [2-B10Cl9SR2]- (R = i-C3H7, n-C3H7, n-C4H9, n-C8H17, n-C12H25, n-C18H37, CH2Ph, and cyclo-S(CH2)4).

A method for obtaining perchlorinated di-S,S-substituted derivatives of the closo-decaborate anion with various alkyl groups has been developed: [B10Cl9SR2]- (R= i-C3H7, n-C3H7, n-C4H9, n-C8H17, n-C12H25, n-C18H37, CH2Ph, and cyclo-S(CH2)4). The method is based on the preparation of the sulfonium-substituted anion [B10H9SR2]- by alkylation of the anion [B10H9SH]2- with bromoalkanes (i-C3H7Br, n-C3H7Br, n-C4H9Br, n-C8H17Br, n-C12H25Br, n-C18H37Br, PhCH2Br, and BrCH2(CH2)2CH2Br) followed by the cluster chlorination with sulfuryl chloride SO2Cl2 in acetonitrile. The process proceeds until the hydrogen atoms in the boron cluster are completely replaced with chlorine and completes within 60 h. It has been found that the melting point of salts ((C4H9)4N)[B10Cl9SR2] (R= i-C3H7, n-C3H7, n-C4H9, n-C8H17, n-C12H25, and n-C18H37) strongly depends on the length of the hydrocarbon chain of the substituent R.

All-carbon phosphoranes via difluorocarbene trapping.

A reaction of intramolecularly disposed phosphonium and phenoxide (or thiophenoxide) fragments with difluorocarbene affording all-carbon λ5-phosphoranes is described. The presence of electron-withdrawing CHF2-groups at the phosphonium center is important for the phosphorane formation. In a phosphorane, both phenyl groups located in the equatorial positions undergo 1,2-P,C migration under thermal conditions.

Marriage of Peroxides and Nitrogen Heterocycles: Selective Three-Component Assembly, Peroxide-Preserving Rearrangement, and Stereoelectronic Source of Unusual Stability of Bridged Azaozonides.

Stable bridged azaozonides can be selectively assembled via a catalyst-free three-component condensation of 1,5-diketones, hydrogen peroxide, and an NH-group source such as aqueous ammonia or ammonium salts. This procedure is scalable and can produce gram quantities of bicyclic stereochemically rich heterocycles. The new azaozonides are thermally stable and can be stored at room temperature for several months without decomposition and for at least 1 year at -10 °C. The chemical stability of azaozonides was explored for their subsequent selective transformations including the first example of an aminoperoxide rearrangement that preserves the peroxide group. The amino group in aminoperoxides has remarkably low nucleophilicity and does not participate in the usual amine alkylation and acylation reactions. These observations and the 15 pKa units decrease in basicity in comparison with a typical dialkyl amine are attributed to the strong hyperconjugative nN→σ*C-O interaction with the two antiperiplanar C-O bonds. Due to the weakness of the complementary nO→σ*C-N donation from the peroxide oxygens (a consequence of "inverse α-effect"), this interaction depletes electron density from the NH moiety, protects it from oxidation, and makes it similar in properties to an amide.

Novel Polymorph of Favipiravir-An Antiviral Medication.

Various solid forms of pharmaceutically important compounds exhibit different physical properties and bioactivity; thus, knowledge of the structural landscape and prediction of spontaneous polymorph transformations for an active pharmaceutical ingredient is of practical value for the pharmaceutical industry. By recrystallization from ethyl acetate, a novel polymorph of 6-fluoro-3-hydroxypyrazine-2-carboxamide (trademark favipiravir, RNA polymerase inhibitor) was obtained and characterized using differential scanning calorimetry (DSC), infra-red spectroscopy and powder X-ray diffraction (XRD) analysis. The favipiravir molecule in two polymorphs realizes similar H-bonding motifs, but the overall H-bonded networks differ. Based on periodic density functional theory calculations, the novel tetragonal polymorph with two interpenetrated H-bonded networks is slightly less stable than the orthorhombic one with the zst topology of the underlying H-bonded net that is in accord with experimentally observed powder XRD patterns of slow conversion of the tetragonal phase to the orthorhombic one. However, topological analysis of net relations revealed that no transformations can be applied to convert H-bonded networks in the experimental unit cells, and DSC data indicate no solid-state reactions at heating.