A facile synthesis of precursor for the σ-1 receptor PET radioligand [18 F]FTC-146 and its radiofluorination.

The σ-1 receptor is a non-opioid transmembrane protein involved in various human pathologies including neurodegenerative diseases, inflammation, and cancer. The previously published ligand [18 F]FTC-146 is among the most promising tools for σ-1 molecular imaging by positron emission tomography (PET), with a potential for application in clinical diagnostics and research. However, the published six- or four-step synthesis of the tosyl ester precursor for its radiosynthesis is complicated and time-consuming. Herein, we present a simple one-step precursor synthesis followed by a one-step fluorine-18 labeling procedure that streamlines the preparation of [18 F]FTC-146. Instead of a tosyl-based precursor, we developed a one-step synthesis of the precursor analog AM-16 containing a chloride leaving group for the SN 2 reaction with 18 F-fluoride. 18 F-fluorination of AM-16 led to a moderate decay-corrected radiochemical yield (RCY = 7.5%) with molar activity (Am ) of 45.9 GBq/µmol. Further optimization of this procedure should enable routine radiopharmaceutical production of this promising PET tracer.

Silicas with Covalently Anchored Fluorosolvatochromic Dyes Suitable for Naked-Eye Detection of Colourless Compounds.

In this work, two stilbene derivatives with different substituents on the phenolic core (phenyl and dimethoxyphenyl) were prepared. The fluorosolvatochromic response of their N-propylated derivatives was studied in a solution of twelve different solvents using UV-Vis absorption and fluorescence emission spectra. Both stilbazolium dyes showed a significant negative solvatochromic effect, with a hypsochromic shift in the visible absorption band of approximately 232 nm and 265 nm for phenyl and the dimethoxyphenyl derivative, respectively, when the solvent was changed from water to pyridine. The stilbene derivatives were subsequently N-alkylated with (3-iodopropyl)trimethoxysilane and covalently anchored to the silica surface. The fluorosolvatochromic response of the prepared silicas compared to N-propylated dyes was then evaluated colorimetrically under daylight and UV illumination. The fluorosolvatochromic behaviour of the anchored dyes was preserved on the silica surface; therefore, the modified silicas could be used for the visual detection of colourless liquids.

Experimental, Spectroscopic, and Computational Insights into the Reactivity of "Methanal" with 2-Naphthylamines.

The reactions of 2-naphthylamine and methyl 6-amino-2-naphthoate with formalin and paraformaldehyde were studied experimentally, spectrally, and by quantum chemical calculations. It was found that neither the corresponding aminals nor imines were formed under the described conditions but could be prepared and spectrally characterized at least in situ under modified conditions. Several of the previously undescribed intermediates and by-products were isolated or at least spectrally characterized. First principle density functional theory (DFT) calculations were performed to shed light on the key aspects of the thermochemistry of decomposition and further condensation of the corresponding aminals and imines. The calculations also revealed that the electrophilicity of methanal was significantly greater than that of ordinary oxo-compounds, except for perfluorinated ones. In summary, methanal was not behaving as the simplest aldehyde but as a very electron-deficient oxo-compound.

Preparation and Characterization of Metalloporphyrin Tröger's and Spiro-Tröger's Base Derivatives.

A series of metalloporphyrin dimers as Tröger's bases 1 or spiro-Tröger's bases 2 was prepared starting from five different C4-symmetry porphyrin derivatives substituted in meso-positions by Ph, 3-MeO-Ph, 4-MeO-Ph, 3,4-(MeO)2-Ph, or 3,5-(MeO)2-Ph. Free-base porphyrins were converted to metalloporphyrins, which were subsequently nitrated with nickel(II), copper(II), or zinc(II) nitrate to give ß-nitrometalloporphyrins. These were further reduced to ß-aminometalloporphyrins and treated with a methanal equivalent under acidic conditions to selectively obtain Tröger's base 1, spiro-Tröger's base 2, or a mixture of both, in yields up to 41% of 1 and 45% of 2 depending on the reaction conditions used. The ratio of 1 to 2 was influenced by the methanal equivalent used, the strength of the acid, and, above all, the solvent. The presence of a metal ion within the porphyrin core and the use of a chlorinated solvent were found to be essential for the formation of spiro-Tröger's base 2. The molecular structure of spiroTB 2a-Ni2 was proven by electron diffraction.

Selectivity of 1-O-Propargyl-d-Mannose Preparations.

Thanks to their ability to bind to specific biological receptors, mannosylated structures are examined in biomedical applications. One of the most common ways of linking a functional moiety to a structure is to use an azide-alkyne click reaction. Therefore, it is necessary to prepare and isolate a propargylated mannose derivative of high purity to maintain its bioactivity. Three known preparations of propargyl-α-mannopyranoside were revisited, and products were analysed by NMR spectroscopy. The preparations were shown to yield by-products that have not been described in the literature yet. Our experiments showed that one-step procedures could not provide pure propargyl-α-mannopyranoside, while a three-step procedure yielded the desired compound of high purity.

Synthesis and biological evaluation of cationic TopFluor cholesterol analogues.

Cholesterol is not only a major component of the cell membrane, but also plays an important role in a wide range of biological processes and pathologies. It is therefore crucial to develop appropriate tools for visualizing intracellular cholesterol transport. Here, we describe new cationic analogues of BODIPY-Cholesterol (TopFluor-Cholesterol, TF-Chol), which combine a positive charge on the sterol side chain and a BODIPY group connected via a C-4 linker. In contrast to TF-Chol, the new analogues TF-1 and TF-3 possessing acetyl groups on the A ring (C-3 position on steroid) internalized much faster and displayed slightly different levels of intracellular localization. Their applicability for cholesterol monitoring was indicated by the fact that they strongly label compartments with accumulated cholesterol in cells carrying a mutation of the Niemann-Pick disease-associated cholesterol transporter, NPC1.

Coumarin Tröger's base derivatives with cyanine substitution as selective and sensitive fluorescent lysosomal probes.

The fluorescent probes based on Tröger's base motive with both coumarin and cyanine substitution 11-13 have been synthesized by multi-step synthesis in high overall yields. Intracellular localization of prepared probes have been tested using four different cell lines (HF-P4, BLM, U-2 OS and A-2058). Prepared probes have intensive green and red fluorescence. Co-localization with commercial lysosome specific marker LysoTracker Blue DND 22 has been confirmed that all prepared fluorescent probes labeled lysosomal compartment with high selectivity and probes show excellent brightness at low concentration.

Synthesis and biological activity evaluation of hydrazone derivatives based on a Tröger's base skeleton.

We report the design and synthesis of novel anticancer agents based on bis-hydrazones separated by a rigid Tröger's base skeleton. This novel approach combines a biologically active moiety (hydrazone) with this scaffold (Tröger's base) to construct DNA intercalators. Evaluation of the anticancer activity of these agents using seven cancer cell lines and two healthy cell lines found that several derivatives had potent anticancer activity and excellent selectivity indexes toward cancer cells. The antimicrobial activities were tested on a set of thirteen bacterial stains, but the prepared compounds were not active. Complexation studies using biologically important metal ions demonstrated that these compounds are able to bind Cu(2+), Fe(3+), Co(2+), Ni(2+) and Zn(2+). DNA intercalation studies showed that the compounds themselves do not interact with DNA, but their metallocomplexes do interact, most likely via intercalation into DNA.

Caffeine-hydrazones as anticancer agents with pronounced selectivity toward T-lymphoblastic leukaemia cells.

We report design and synthesis of set of novel anticancer agents based on caffeine-hydrazones bearing 2-hydroxyaryl- or 2-N-heteroaryl moiety. Anticancer activity evaluation using seven cancer cell lines and two non-malignant cell lines demonstrated that several derivatives display significant anticancer activity and great selectivity index toward T-lymphoblastic leukaemia cells. In general, hydrazones bearing 2-N-heteroaryl moiety are more active and selective than those with 2-hydroxyaryl moiety. Tested compounds exhibit dose-dependent inhibition of both RNA and DNA synthesis, with some exceptions. Antimicrobial activities were tested on set of twelve bacterial and yeast strains, however prepared compounds were not active, suggesting for a molecular target specific for eukaryotic cells.

Preparation and enantioselectivity binding studies of a new chiral cobalt(II)porphyrin-Tröger's base conjugate.

A new bis[cobalt(II)porphyrin]-Tröger's base conjugate was studied as a potential receptor for methyl esters of several amino acids. The conjugate was prepared as racemate, and then resolved via preparative high-performance liquid chromatography (HPLC) on a chiral column. The high affinity to lysine, histidine, and proline methyl esters was found by complexation studies followed by UV-Vis spectroscopy. The studies of pure enantiomers, followed by UV-Vis and electronic circular dichroism spectroscopy, revealed the highest enantioselectivity for lysine methyl ester.

Spectroscopic study on enantiomeric Ni(II) complexes of porphyrin-porphyrin Tröger's base and porphyrin-chlorin spiro-Tröger's base derivatives supported by DFT calculations.

The chiral properties of nickel(II) complexes of porphyrin-porphyrin Tröger's base and porphyrin-chlorin spiro-Tröger's base with phenyl or 3-methoxyphenyl substitutions in their meso-positions were studied. Enantioseparation of racemic mixtures was investigated via high-performance liquid chromatography (HPLC) on an analytical ReproSil Chiral-NR column. The optimal conditions were utilized for a multimilligram scale isolation with a semipreparative column. The purity of the isolated enantiomers was determined by HPLC and UV-Vis spectroscopy. The absolute configurations of the isolated enantiomers were determined by evaluating the Cotton effect in electronic circular dichroism spectra. The determination was supported by TDDFT calculations, in which good agreement was achieved between the experimental and simulated spectra. The maximum molar ellipticity values, [θ]λmax given in deg ∙ cm2 ∙ dmol-1, were [θ]435 = 1.73 ∙ 107 for phenyl spiroTB and [θ]436 = 1.24 ∙ 107 and [θ]436 = 2.15 ∙ 107 for 3-methoxyphenyl TB and spiroTB, respectively.

Oligo Tröger's bases--new molecular scaffolds.

Oligo Tröger's bases are compounds containing two or more Tröger's base subunits (1,5-methanodiareno[b,f][1,5]diazocines) sharing one or more arene parts. Due to their interesting molecular shapes, these compounds are studied as chiral molecular tweezers, clips, cavitands, clefts, calixes, etc. This review includes all available data on oligo Tröger's bases, and introduces their preparation and properties to a wide audience.

Influence of Disinfection Methods on Cinematographic Film.

Microbiological contamination of cinematographic films can cause damage and loss of image information. A large part of the films is made with the base of cellulose triacetate, which has been used from the 1940s until today. Cellulose triacetate is relatively resistant to common organic solvents, but some types of microorganisms can contribute to its faster degradation. In this work, we tested four types of disinfectants suitable for mass disinfection and sufficiently effective against various types of microorganisms. Butanol vapours, a commercial mixture of alcohols (Bacillol® AF), Septonex® (an aqueous solution of [1-(ethoxycarbonyl)pentadecyl] trimethylammonium bromide) and ethylene oxide applied as a gas mixed with carbon dioxide were tested. Samples of a commercial film made of cellulose triacetate were disinfected. The samples were aged for 56 days at 70 °C and 55% RH. Changes in optical, mechanical and chemical properties were studied. None of the disinfectants affected the change in the degree of substitution. For samples disinfected with Bacillol® AF (alcohol mixture), part of the plasticiser (triphenyl phosphate) was extracted and the intrinsic viscosity of the cellulose triacetate solution was reduced after ageing. A slight decrease in intrinsic viscosity also occurred after disinfection with ethylene oxide. Compared to the non-disinfected samples, butanol vapours and Septonex® appear to be the most gentle disinfectants for the cellulose triacetate film base, within the studied parameters.

Binding energies of five molecular pincers calculated by explicit and implicit solvent models.

Molecular pincers or tweezers are designed to hold and release the target molecule. Potential applications involve drug distribution in medicine, environment technologies, or microindustrial techniques. Typically, the binding is dominated by van der Waals forces. Modeling of such complexes can significantly enhance their design; yet obtaining accurate complexation energies by theory is difficult. In this study, density functional theory (DFT) computations combined with dielectric continuum solvent model are compared with the potential of mean force approach using umbrella sampling and the weighted histogram analysis method (WHAM) with molecular dynamics (MD) simulations. For DFT, functional and basis set effects are discussed. The computed results are compared to experimental data based on NMR spectroscopic measurements of five synthesized tweezers based on the Tröger's basis. Whereas the DFT computations correctly provided the observed trends in complex stability, they failed to produce realistic magnitudes of complexation energies. Typically, the binding was overestimated by DFT if compared to experiment. The simpler semiempirical PM6-DH2X scheme proposed lately yielded better magnitudes of the binding energies than DFT but not the right order. The MD-WHAM simulations provided the most realistic Gibbs binding energies, although the approximate MD force fields were not able to reproduce completely the ordering of relative stabilities of model complexes found by NMR. Yet the modeling provides interesting insight into the complex geometry and flexibility and appears as a useful tool in the tweezers' design.

Identification and interconversion of diastereomeric oligo-Tröger bases probed by ion mobility mass spectrometry.

Oligo-Tröger bases are auspicious scaffolds of molecular engineering, which motivates studies on the mechanism of their interconversion and on the facile determination of the relative configuration of their diastereoisomers. Protonated, sodiated, and argentated species of those compounds were therefore studied via ion-mobility mass spectrometry (IM-MS), allowing differentiation on the basis of the shapes of the ions. First, the isomerization was confirmed to be acid-catalyzed as it takes place readily in the case of protonated Tröger bases, whereas the metallated bases are configurationally stable. Second, the corrected arrival times of the various isomers of the cationized bases were found to show distinct differences in IM-MS, and their excellent correlation with the cross sections obtained from quantum chemical calculations paves the way toward the easy identification of diastereoisomers.

Methodology of deconvolution of total solute retention on chemically modified stationary phases to structure specific contributions of bound compounds.

The total solute retention by a chemically modified stationary phase (CMSP) has been shown several times to be a potential tool for studying the binding abilities of the bound compound. In this article, we present a methodology for the deconvolution of the total retention into structure-specific contributions. Three complementary silica-based CMSPs were prepared: 1) non-modified silica, 2) silica modified by syn-bis-Tröger's base (a molecular tweezer) and 3) silica modified by anti-bis-Tröger's base (a non-tweezer molecule). These were characterized by elemental analysis and Raman spectroscopy, and used to assemble liquid chromatography (LC) columns. The total retention factors were estimated for electron-deficient nitro- and cyano-derivatives of benzene in both normal and reverse elution modes. The total retention factor was considered to be the sum of structure-specific retention factors, each related to the affinity (the binding constant) of a specific structure (the binding site), and its content in the modified silica, as defined for weak-affinity chromatography (WAC). The obtained structure-specific contributions are in line with the binding studies of ligands in solution. They reveal details of the retention mechanism, suggesting a more suitable attachment of ligands, and expose the shortcomings of evaluations based solely on the total retentions.

Steroid Glycosides Hyrcanoside and Deglucohyrcanoside: On Isolation, Structural Identification, and Anticancer Activity.

Cardiac glycosides (CGs) represent a group of sundry compounds of natural origin. Most CGs are potent inhibitors of Na+/K+-ATPase, and some are routinely utilized in the treatment of various cardiac conditions. Biological activities of other lesser known CGs have not been fully explored yet. Interestingly, the anticancer potential of some CGs was revealed and thereby, some of these compounds are now being evaluated for drug repositioning. However, high systemic toxicity and low cancer cell selectivity of the clinically used CGs have severely limited their utilization in cancer treatment so far. Therefore, in this study, we have focused on two poorly described CGs: hyrcanoside and deglucohyrcanoside. We elaborated on their isolation, structural identification, and cytotoxicity evaluation in a panel of cancerous and noncancerous cell lines, and on their potential to induce cell cycle arrest in the G2/M phase. The activity of hyrcanoside and deglucohyrcanoside was compared to three other CGs: ouabain, digitoxin, and cymarin. Furthermore, by in silico modeling, interaction of these CGs with Na+/K+-ATPase was also studied. Hopefully, these compounds could serve not only as a research tool for Na+/K+-ATPase inhibition, but also as novel cancer therapeutics.

Trifluoromethylated (tetrahydropyrrolo) quinazolinones by a new three-component reaction and facile assignment of the regio- and stereoisomers formed by NMR spectroscopy.

A new three-component cyclisation reactions of methyl 3,3,3-trifluoropyruvate, 2-aminobenzylamine and oxo compounds afforded tetrahydropyrroloquinazolinones of the types 4 and 5 as mixtures of regio- and stereoisomers. Whereas standard 1D NMR spectroscopy was used for a facile assignment of the cyclization regioisomers, a combination of homo (proton-proton) and heteronuclear (proton-fluorine) NOE experiments allowed the determination of the relative configuration on stereogenic centres. The structure of some compounds was also confirmed by the X-ray diffraction. Adaptation of the 1D double-pulsed field-gradient spin-echo NOE for a heteronuclear case is presented.

Molecular structure study of a heptakis(2,3,6-tri-O-methyl)-ß-cyclodextrin complex of cholesterol.

Heptakis(2,3,6-tri-O-methyl)-ß-cyclodextrin (2) and cholesterol form a water-soluble complex 3. We performed several NMR studies, particularly 1H, 13C, 2D NOESY and DOSY, at various temperatures on 500 and 950 MHz instruments. We discovered that the complex 3 is unstable above 57 °C in heavy water, while it is kinetically stable enough to be studied by NMR in detail at 1 °C. We demonstrated the formation of a face-to-face 2:1 complex with a binding constant of approximately 2.2 × 106 M-2.

Versatile fluorophores for bioimaging applications: π-expanded naphthalimide derivatives with skeletal and appendage diversity.

Four novel fluorescent cores bearing a transformable functional group based on a π-expanded naphthalimide including a fused pyranone or furan ring have been prepared. Fluorescent probes LysoSers 13-16 for lysosomal targeting have been tested. Co-localization with a commercial lysosome specific marker confirmed that the LysoSers labeled the lysosomal compartment with high selectivity. The LysoSers show excellent brightness and low toxicity.