Dihydrotestosterone-based A-ring-fused pyridines: Microwave-assisted synthesis and biological evaluation in prostate cancer cells compared to structurally related quinolines.

Dysfunction of the androgen receptor (AR) signalling axis plays a pivotal role in the development and progression of prostate cancer (PCa). Steroidal and non-steroidal AR antagonists can significantly improve the survival of PCa patients by blocking the action of the endogenous ligand through binding to the hormone receptor and preventing its activation. Herein, we report two synthetic strategies, each utilizing the advantages of microwave irradiation, to modify the A-ring of natural androgen 5α-dihydrotestosterone (DHT) with pyridine scaffolds. Treatment of DHT with appropriate Mannich salts led to 1,5-diketones, which were then converted with hydroxylamine to A-ring-fused 6'-substituted pyridines. To extend the compound library with 4',6'-disubstituted analogues, 2-arylidene derivatives of DHT were subjected to ring closure reactions according to the Kröhnke's pyridine synthesis. The crystal structure of a monosubstituted pyridine product was determined by single crystal X-ray diffraction. AR transcriptional activity in a reporter cell line was investigated for all novel A-ring-fused pyridines and a number of previously synthesized DHT-based quinolines were included to the biological study to obtain information about the structure-activity relationship. It was shown that several A-ring-fused quinolines acted as AR antagonists, in comparison with the dual or agonist character of the majority of A-ring-fused pyridines. Derivative 1d (A-ring-fused 6'-methoxyquinoline) was studied in detail and showed to be a low-micromolar AR antagonist (IC50 = 10.5 µM), and it suppressed the viability and proliferation of AR-positive PCa cell lines. Moreover, the candidate compound blocked the AR downstream signalling, induced moderate cell-cycle arrest and showed to bind recombinant AR and to target AR in cells. The binding mode and crucial interactions were described using molecular modelling.

Enzymatic route for selective glycerol oxidation using covalently immobilized laccases.

Glycerol is an important starting material for the synthesis of many chemical compounds and its selective oxidation represents an efficient way to produce value-added compounds. Glyceric acid, one of these selective oxidation products, is an important intermediate in the food, medicine, cosmetics, and light industries. In this work, four commercially available native laccases were screened for glycerol oxidation using different initiators, and the two most efficient biocatalysts were covalently immobilized on functionalized magnetic and polymethacrylate (Lifetech™) solid supports. Apart from the mostly employed Fe3O4 magnetic particles, in this work Ni-Zn or Ni-Zn-Co spinel ferrite (MFe2O4) microparticles were used. Particularly, the utilization (for the first time for laccase immobilization) of Ni-Zn ferrite support Ni0.7Zn0.3Fe2O4 functionalized with 3-aminopropyl-trimethoxysilane, via crosslinking by glutaraldehyde and reduction with NaBH4 led to excellent biocatalytic efficiency and stability. These results confirm the feasibility of Trametes versicolor laccase for covalent bonding, as presumed by computational modelling. The resulted enzymatic preparations were characterized in detail in terms of stability and reusability, demonstrating enhanced storage, pH and thermal stability compared to the native enzymes. The most active biocatalysts (790.93 [U/g]) were successfully used for glycerol oxidation and the specific conversion in glyceric acid exceeded 50%.

Poly(dithiophosphate)s, a New Class of Phosphorus- and Sulfur-Containing Functional Polymers by a Catalyst-Free Facile Reaction between Diols and Phosphorus Pentasulfide.

Novel poly(dithiophosphate)s (PDTPs) were successfully synthesized under mild conditions without any additive in the presence of THF or toluene diluents at 60 °C by a direct, catalyst-free reaction between the abundant phosphorus pentasulfide (P4S10) and glycols such as ethylene glycol (EG), 1,6-hexanediol (HD) and poly(ethylene glycol) (PEG). GPC, FTIR, 1H and 31P NMR analyses proved the formation of macromolecules with dithiophosphate coupling groups having P=S and P-SH pendant functionalities. Surprisingly, the ring-opening of THF by the P-SH group and its pendant incorporation as a branching point occur during polymerization. This process is absent with toluene, providing conditions to obtain linear chains. 31P NMR measurements indicate long-time partial hydrolysis and esterification, resulting in the formation of a thiophosphoric acid moiety and branching points. Copolymerization, i.e., using mixtures of EG or HD with PEG, results in polymers with broadly varying viscoelastic properties. TGA shows the lower thermal stability of PDTPs than that of PEG due to the relatively low thermal stability of the P-O-C moieties. The low Tgs of these polymers, from -4 to -50 °C, and a lack of PEG crystallites were found by DSC. This polymerization process and the resulting novel PDTPs enable various new routes for polymer synthesis and application possibilities.

Thermally Induced Solid-Phase Quasi-Intramolecular Redox Reactions of [Hexakis(urea-O)iron(III)] Permanganate: An Easy Reaction Route to Prepare Potential (Fe,Mn)Ox Catalysts for CO2 Hydrogenation.

Research on new reaction routes and precursors to prepare catalysts for CO2 hydrogenation has enormous importance. Here, we report on the preparation of the permanganate salt of the urea-coordinated iron(III), [hexakis(urea-O)iron(III)]permanganate ([Fe(urea-O)6](MnO4)3) via an affordable synthesis route and preliminarily demonstrate the catalytic activity of its (Fe,Mn)Ox thermal decomposition products in CO2 hydrogenation. [Fe(urea-O)6](MnO4)3 contains O-coordinated urea ligands in octahedral propeller-like arrangement around the Fe3+ cation. There are extended hydrogen bond interactions between the permanganate ions and the hydrogen atoms of the urea ligands. These hydrogen bonds serve as reaction centers and have unique roles in the solid-phase quasi-intramolecular redox reaction of the urea ligand and the permanganate anion below the temperature of ligand loss of the complex cation. The decomposition mechanism of the urea ligand (ammonia elimination with the formation of isocyanuric acid and biuret) has been clarified. In an inert atmosphere, the final thermal decomposition product was manganese-containing wuestite, (Fe,Mn)O, at 800 °C, whereas in ambient air, two types of bixbyite (Fe,Mn)2O3 as well as jacobsite (Fe,Mn)T-4(Fe,Mn)OC-62O4), with overall Fe to Mn stoichiometry of 1:3, were formed. These final products were obtained regardless of the different atmospheres applied during thermal treatments up to 350 °C. Disordered bixbyite formed first with inhomogeneous Fe and Mn distribution and double-size supercell and then transformed gradually into common bixbyite with regular structure (and with 1:3 Fe to Mn ratio) upon increasing the temperature and heating time. The (Fe,Mn)Ox intermediates formed under various conditions showed catalytic effect in the CO2 hydrogenation reaction with <57.6% CO2 conversions and <39.3% hydrocarbon yields. As a mild solid-phase oxidant, hexakis(urea-O)iron(III) permanganate, was found to be selective in the transformation of (un)substituted benzylic alcohols into benzaldehydes and benzonitriles.

Estradiol-Based Salicylaldehyde (Thio)Semicarbazones and Their Copper Complexes with Anticancer, Antibacterial and Antioxidant Activities.

A series of novel estradiol-based salicylaldehyde (thio)semicarbazones ((T)SCs) bearing (O,N,S) and (O,N,O) donor sets and their Cu(II) complexes were developed and characterized in detail by 1H and ¹³C nuclear magnetic resonance spectroscopy, UV-visible and electron paramagnetic resonance spectroscopy, electrospray ionization mass spectrometry and elemental analysis. The structure of the Cu(II)-estradiol-semicarbazone complex was revealed by X-ray crystallography. Proton dissociation constants of the ligands and stability constants of the metal complexes were determined in 30% (v/v) DMSO/H2O. Estradiol-(T)SCs form mono-ligand complexes with Cu(II) ions and exhibit high stability with the exception of estradiol-SC. The Cu(II) complexes of estradiol-TSC and its N,N-dimethyl derivative displayed the highest cytotoxicity among the tested compounds in MCF-7, MCF-7 KCR, DU-145, and A549 cancer cells. The complexes do not damage DNA according to both in vitro cell-free and cellular assays. All the Cu(II)-TSC complexes revealed significant activity against the Gram-positive Staphylococcus aureus bacteria strain. Estradiol-TSCs showed efficient antioxidant activity, which was decreased by complexation with Cu(II) ions. The exchange of estrone moiety to estradiol did not result in significant changes to physico-chemical and biological properties.

Crystal structures of zinc(II) complexes with ß-hydroxypyridinecarboxylate ligands: examples of structure-directing effects used in inorganic crystal engineering.

The coordination properties of four hydroxypyridinecarboxylates, designed for the treatment of iron-overloading conditions as bidentate O,O'-donor ligands, have been studied with ZnII in the solid state. The coordination compounds [Zn(A1)2(H2O)2] (1), [Zn(A2)2(H2O)] (2), [Zn(A3)2(H2O)]·2H2O (3) and [Zn2(B1)4(H2O)2]·4H2O (4), where the ligands are 1-methyl-4-oxidopyridinium-3-carboxylate (A1, C7H6NO3), 1,6-dimethyl-4-oxidopyridinium-3-carboxylate (A2, C8H8NO3), 1,5-dimethyl-4-oxido-pyridinium-3-carboxylate (A3, C8H8NO3) and 1-methyl-3-oxidopyridinium-4-carboxylate (B1, C7H6NO3), have been synthesized and analysed by single-crystal X-ray diffraction. The ligands were chosen to probe (i) the electronic effects of inverting the positions of the O-atom donor groups (i.e. A1 versus B1) and (ii) the electronic and steric effects of the addition of a second methyl group in different positions on the pyridine ring. Two axially coordinated water molecules resulting in a six-coordinated symmetrical octahedron complement the bis-ligand complex of A1. Ligands A2 and A3 form five-coordinated trigonal bipyramidal complexes with one additional water molecule in the coordination sphere, which is a rarely reported geometry for ZnII complexes. Ligand B1 shows a dimeric structure, where the two Zn2+ dications have slightly distorted octahedral geometry and the pyridinolate O atom of the neighbouring complex bridges them. The coordination spheres of the Zn2+ dications and the supramolecular structures are discussed in detail. The packing arrangements of 1-3 are similar, having alternating hydrophilic and hydrophobic layers, however the similarity is broken in 4. The obtained coordination geometries are compared with their previously determined CuII analogues. The study of the individual complexes is complemented with a comprehensive analysis of ZnII complexes with oxygen donor ligands with data from the Cambridge Structural Database.

Aqueous Solubility of Organic Compounds for Flow Battery Applications: Symmetry and Counter Ion Design to Avoid Low-Solubility Polymorphs.

Flow batteries can play an important role as energy storage media in future electricity grids. Organic compounds, based on abundant elements, are appealing alternatives as redox couples for redox flow batteries. The straightforward scalability, the independence of material sources, and the potentially attractive price motivate researchers to investigate this technological area. Four different benzyl-morpholino hydroquinone derivatives were synthesized as potential redox active species. Compounds bearing central symmetry were shown to be about an order of magnitude less soluble in water than isomers without central symmetry. Counter ions also affected solubility. Perchlorate, chlorate, sulfate and phosphate anions were investigated as counter ions. The formations of different polymorphs was observed, showing that their solubility is not a function of their structure. The kinetics of the transformation can give misleading solubility values according to Ostwald's rule. The unpredictability of both the kinetics and the thermodynamics of the formation of polymorphs is a danger for new organic compounds designed for flow battery applications.

Solid-Phase Quasi-Intramolecular Redox Reaction of [Ag(NH3)2]MnO4: An Easy Way to Prepare Pure AgMnO2.

Two monoclinic polymorphs of [Ag(NH3)2]MnO4 containing a unique coordination mode of permanganate ions were prepared, and the high-temperature polymorph was used as a precursor to synthesize pure AgMnO2. The hydrogen bonds between the permanganate ions and the hydrogen atoms of ammonia were detected by IR spectroscopy and single-crystal X-ray diffraction. Under thermal decomposition, these hydrogen bonds induced a solid-phase quasi-intramolecular redox reaction between the [Ag(NH3)2]+ cation and MnO4- anion even before losing the ammonia ligand or permanganate oxygen atom. The polymorphs decomposed into finely dispersed elementary silver, amorphous MnOx compounds, and H2O, N2 and NO gases. Annealing the primary decomposition product at 573 K, the metallic silver reacted with the manganese oxides and resulted in the formation of amorphous silver manganese oxides, which started to crystallize only at 773 K and completely transformed into AgMnO2 at 873 K.

(Me2NH2)10[H2-Dodecatungstate] polymorphs: dodecatungstate cages embedded in a variable dimethylammonium cation + water of crystallization matrix.

Two polymorphs and a solvatomorph of a new dimethylammonium polytungstate-decakis(dimethylammonium) dihydrogendodecatungstate, (Me2NH2)10(W12O42)·nH2O (n = 10 or 11)-have been synthesized. Their structures were characterized by single-crystal X-ray diffraction and solid-phase NMR methods. The shape of the dodecatungstate anions is essentially the same in all three structures, their interaction with the cations and water of crystallization, however, is remarkably variable, because the latter forms different hydrogen-bonded networks, and provides a highly versatile matrix. Accordingly, the N-H⋯O and C-H⋯O hydrogen bonds are positioned in each crystal lattice in a variety of environments, characteristic to the structure, which can be distinguished by solid-state 1H-CRAMPS, 13C, 15N CP MAS and 1H-13C heteronuclear correlation NMR. Thermogravimetry of the solvatomorphs also reflect the difference and multiformity of the environment of the water molecules in the different crystal lattices. The major factors behind the variability of the matrix are the ability of ammonium cations to form two hydrogen bonds and the rigidity of the polyoxometalate anion cage. The positions of the oxygen atoms in the latter are favourable for the formation of bifurcated and trifurcated cation-anion hydrogen bonds, some which are so durable that they persist after the crystals are dissolved in water, forming ion associates even in dilute solutions. The H atom involved in furcated hydrogen bonds cannot be exchanged by deuterium when the compound is dissolved in D2O. An obvious consequence of the versatility of the matrix is the propensity of these compounds to form multiple polymorphs.

Diterpenoids from Euphorbia dulcis with Potassium Ion Channel Inhibitory Activity with Selective G Protein-Activated Inwardly Rectifying Ion Channel (GIRK) Blocking Effect.

Nine new (1-9) and two known (10, 11) jatrophane diterpenoids were isolated from the methanol extract of Euphorbia dulcis. The structure elucidation of the compounds was performed by means of extensive spectroscopic analysis, including HRESIMS, 1D (1H, JMOD), and 2D (HSQC, HMBC, 1H-1H-COSY, NOESY) NMR experiments. The absolute configuration of compound 1 was determined by single-crystal X-ray diffraction. The electrophysiological effects of compounds 1-11 and the five diterpenoids (12-16) previously isolated from Euphorbia taurinensis were investigated on stable transfected HEK-GIRK1/4 (Kir3.1/3.4) and HEK-hERG (Kv11.1) cell lines using automated patch-clamp equipment. The majority of the diterpenoids showed significant blocking activity on GIRK channels (60.8-88.7% at 10 µM), while compounds 1, 2, 9-11, 13, and 14 exerted notable inhibitory effects even at 1 µM concentration. None of the jatrophane diterpenoids interfered with the function of hERG proteins; however, compound 14 remarkably hampered K+ flow through hERG channels. These selective activities suggest that jatrophane diterpenoids may represent a group of potential lead compounds for the development of novel therapeutic agents against atrial fibrillation.

Influence of benzylamine on the resolution of ibuprofen with (+)-(R)-phenylethylamine via supercritical fluid extraction.

The resolution of racemic ibuprofen was studied by partial diastereomer salt formation. The resolution was performed via two methods: resolution with (+)-(R)-phenylethylamine as chiral agent and resolution with a mixture of (+)-(R)-phenylethylamine and benzylamine. The diastereomers and unreacted enantiomers were separated by supercritical fluid extraction with carbon dioxide at 15 MPa and 33 degrees C. The influence of the achiral benzylamine on the resolution efficiency was studied by varying the concentrations of the structurally related amines in their mixtures, keeping the sum molar ratio of the amines to racemic ibuprofen constant at 0.55 +/- 0.02. The presence of benzylamine positively influenced the resolution efficiency at certain concentrations. The crystal structure of the salts of (+)-(R)-phenylethylamine with (-)-(R)-ibuprofen and (+)-(S)-ibuprofen, respectively, as well as the cocrystal of the benzylamine-ibuprofen salt with neutral ibuprofen molecules are presented. These structures were determined by single crystal X-ray diffraction, proving the significantly different stoichiometry of the related amines with the chiral acid, in accordance with mass balance calculations.

Optical resolution of 1-(1-naphthyl)ethylamine by its dicarboxylic acid derivatives: Structural features of the oxalic acid derivative diastereomeric salt pair.

Optical resolution methods were established for racemic 1-(1-naphthyl) ethylamine. The resolving agents were synthesized by N-derivatizing (R)-1-(1-naphthyl) ethylamine with dicarboxylic acids. Oxalic, malonic, and succinic acid derivatives were found to be suitable resolving agents. These resolutions are parallel to a series of optical resolutions of 1-phenylethylamine which had been previously performed by our research group using similar derivative resolving agents (Balint et al., Tetrahedron: Asymmetry 2001;12:1511-1518.) The comparison of the results of the enantiomer separations is performed. The diastereomeric salts formed with (R)-N-[1-(1-naphthyl)ethyl]oxalamic acid were investigated by single crystal X-ray diffraction. The crystal structures were compared with the previously published structures of the diastereomers of the phenyl-substituted analogue, namely (R)- and (S)-1-phenylethylammonium (R)-N-(1-phenylethyl)oxalamates (Balint et al., Tetrahedron: Asymmetry 2001;12:1511-1518).

Enhanced efficiency due to the use of achiral additives in the optical resolution of 1-phenylethylamine by its glutaric acid derivative.

Racemic 1-phenylethylamine was optically resolved by its own derivative formed with glutaric acid namely (+)-(R)-N-(1-phenylethyl)glutaramic acid. The amide acid resolving agent was synthesized from (+)-(R)-1-phenylethylamine by N-derivatization. The glutaric acid derivative was the next in a homologous series of dicarboxilic acid derivatized resolving agents of racemic 1-phenylethylamine. Resolution results obtained with the oxalic, malonic, and succinic acid derivatives were previously discussed(1). Each of the above derivative resolving agents could be successfully applied as resolving agents of 1-phenylethylamine. The efficiency of the present optical resolution using (+)-(R)-N-(1-phenylethyl)glutaramic acid resolving agent was remarkably inferior to the results obtained by its shorter chained homologues(1). Use of achiral additives, like urea, thiourea, N-methylurea, and N,N'-dimethylurea caused large increase in the efficiency of the resolution by (+)-(R)-N-(1-phenylethyl)glutaramic acid resolving agent. Precipitated salts obtained in the resolutions performed in the presence of the additives were investigated by thermoanalysis, X-ray powder diffraction, and optical microscopy. Based on the analytical data, the improvement of the resolution results was attributed to the influence of the additives on the crystal nucleation processes of the diasteromeric salts.