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The reaction between 1-aryl-3,4-dihydroisoquinolines and monocyclic anhydrides was studied for the first time. The method is the first one-step route to previously unknown angularly-aryl substituted racemic [1,4]thiazino[3,4-a]isoquinoline derivatives with trans configuration. It was found that electron-withdrawing substituents in the p-position of the aryl group in the starting 3,4-dihydroisoquinoline led to higher yields and shorter reaction times, which is contrary to previous observations for the reactions of homophthalic anhydride and similar acyclic N-arylmethanimines.

The synthetic cannabinoids 5F-QUPIC and MDMB-CHMICA were sprayed on plant material intended for smoking and was seized as a criminal evidence. Their presence was confirmed by gas chromatography – m...

The reaction of homophthalic anhydride with 1H-indol-3-carbaldimines was used for the preparation of trans- and cis-2-alkyl-3-indolyl-1-oxotetrahydroisoquinolin-4-carboxylic acids 3a–d. The stereochemistry of the reaction was investigated by means of 1H NMR spectroscopy. The carboxylic group of trans-3a–d was transformed stereoselectively via 4-hydroxymethyltetrahydroisoquinolin-1-ones into 4-(phthalimidomethyl)-derivatives trans-6a,b and 4-(imidazolylmethyl)-derivatives trans-8b–d. Compounds trans-6a,b and 8b–d were tested for antiaromatase activity, and the preliminary results showed that the phthalimidomethylisoquinolinone trans-6b at 50 μM concentration decreased the aromatase enzyme activity with 40%.

Therapeutically relevant proteins such as GPCRs, antibodies and kinases face clear limitations in NMR studies due to the challenges in site‐specific isotope labeling and deuteration in eukaryotic expression systems. Here we describe an efficient and simple method to observe the methyl groups of leucine residues in proteins expressed in bacterial, eukaryotic or cell‐free expression systems without modification of the expression protocol. The method relies on simple stereo‐selective 13C‐labeling and deuteration of leucine that alleviates the need for additional deuteration of the protein. The spectroscopic benefits of “local” deuteration are examined in detail through Forbidden Coherence Transfer (FCT) experiments and simulations. The utility of this labeling method is demonstrated in the cell‐free synthesis of bacteriorhodopsin and in the insect‐cell expression of the RRM2 domain of human RBM39., Methyl‐based magnetization usage can strongly benefit investigations of large protein systems via NMR spectroscopy. Here, a simple and cost‐effective method to obtain locally deuterated leucine suitable for methyl NMR and to quantify its benefits is presented. The approach substantially expands the applicability of methyl labeling in emerging expression systems including cell‐free and eukaryotic systems.

Tautomerization of 2-phenylimidazolecarbaldehydes has not been studied in detail so far, although this process is a well-known phenomenon for imidazole derivatives. That is why we focus our study on a series of 2-phenylimidazolecarbaldehydes and their parent alcohols that were synthesized and studied by detailed 1H and 13C NMR in solution and in the solid state. The apparent problem is that the fast tautomerization impedes the full structural description of the compounds by conventional 13C NMR measurements. Indeed, the 13C NMR spectra in solution exhibit poor resolution, and in most cases, signals from the imidazole ring are not detectable. To avoid this problem, we used 13C CP-MAS NMR as an alternative spectroscopic method for unambiguous spectroscopic characterization of the studied series of 2-phenylimidazoles. The data were analyzed in combination with quantum chemical DFT-GIAO methods by considering the tautomerization process and the intermolecular interactions. The DFT (B3LYP/6-31G(d,p)) calculations allowed to identify and suggest the preferred tautomer in the gas phase and in DMSO solvent, which for alcohols are (2-phenyl-1H-imidazol-4-yl)methanol and its analogs, and for the aldehydes are the 2-phenyl-1H-imidazole-5-carbaldehydes. The gas-phase calculated energy differences between the two possible tautomeric forms are in the range 0.645&ndash, 1.415 kcal/mol for the alcohols and 2.510&ndash, 3.059 kcal/mol for the aldehydes. In the DMSO solvent, however, for all compounds, the calculated energy differences go below 1.20 kcal/mol. These data suggest that both tautomeric forms of the studied 2-phenylimidazoles can be present in solution at room temperature. Our data from detailed 2D NMR measurements in the solid state (1H-13C HETCOR and 1H-1H double-quantum coherence MAS NMR) suggested that also in the solid state both tautomers coexist in different crystalline domains. This fact does not obscure the 13C CP-MAS NMR spectra of the studied 2-phenyl substituted imidazoles and suggests this spectroscopic method as a powerful tool for a complete structural description of tautomeric systems with aromatic conjugation.

The growing advancement in nuclear medicine challenges researchers from several different fields to integrate imaging and therapeutic modalities in a theranostic radiopharmaceutical, which can be defined as a molecular entity with readily replaceable radioisotope to provide easy switch between diagnostic and therapeutic applications for efficient and patient-friendly treatment of diseases. For such a reason, the diagnostic and therapeutic potential of all five medical radionuclides of copper have thoroughly been investigated as they boost the hope for development of successful radiotheranostics. To facilitate the mutual understanding between all different specialists working on this multidisciplinary field, we summarized the recent updates in copper-based nuclear medicine, with specific attention to the potential theranostic applications. Thereby, this review paper is focused on the current achievements in the copper-related complementary fields, such as synthetic and nuclear chemistry, biological assessment of radiopharmaceuticals, design and development of nanomaterials for multimodal theranostic implications. This work includes: i) description of available copper radionuclide production methods; ii) analyses of the synthetic strategies for development of improved copper radiopharmaceuticals; iii) summary of reported clinical data and recent preclinical studies from the last five years on biological applicability of copper radiopharmaceuticals; and iv) illustration of some sophisticated multimodal nanotheranostic agents that comprise several imaging and therapeutic modalities. Significant advancement can be seen in the synthetic procedures, which enables the broader implication of pretargeting approaches via bioorthogonal click reactions, as well as in the nanotechnology methods for biomimetic construction of biocompatible multimodal copper theranostics. All this gives the hope that personalized treatment of various diseases can be achieved by copper theranostics in the near future.

A novel green method was developed for the preparation of a squaraine dye, on an 8-mmol scale, by microwave irradiation of two equivalents of 1,3,3-trimethyl-2-methyleneindoline with one equivalent squaric acid in the green solvent, ethyl l-lactate. The time required for this green synthesis is only 4 min. The target squaraine dye was isolated in excellent yield (81%) and with high purity.

Atomic-level information about the structure and dynamics of biomolecules is critical for an understanding of their function. Nuclear magnetic resonance (NMR) spectroscopy provides unique insights into the dynamic nature of biomolecules and their interactions, capturing transient conformers and their features. However, relaxation-induced line broadening and signal overlap make it challenging to apply NMR spectroscopy to large biological systems. Here we took advantage of the high sensitivity and broad chemical shift range of 19F nuclei and leveraged the remarkable relaxation properties of the aromatic 19F-13C spin pair to disperse 19F resonances in a two-dimensional transverse relaxation-optimized spectroscopy spectrum. We demonstrate the application of 19F-13C transverse relaxation-optimized spectroscopy to investigate proteins and nucleic acids. This experiment expands the scope of 19F NMR in the study of the structure, dynamics, and function of large and complex biological systems and provides a powerful background-free NMR probe.

Synthetic cannabinoids (SCs) belong to the group of new psychoactive substances (NPS) which appear sprayed on herbal mixtures on the “street” drug market and are intended for smoking like marijuana. In the present report we discuss a fatal case of 18-years-old boy, who had smoked SCs since several months and an overuse of SCs during last 48 h of his life has been apprised. The autopsy findings revealed acute respiratory distress syndrome (ARDS). Both toxicological analysis of deceased blood and urine samples and chemical analysis of the herbal mixture seized revealed presence of two SCs - 5F-ADB and FUB-AMB. The amount of 5F-ADB in blood was found to be 3.7 ng/mL by standard addition method. Severe and irreversible morphology changes in lung specimen, leading to ischemic damage of all internal organs and tissues, were observed during histological examination. The present case can be discussed as an example of both drug-induced and drug-related death resulting from acute intoxication with 5F-ADB and FUB-AMB as well as from systematic use of both synthetic cannabinoids.

Biorelevant dissolution media (BDM) methods are commonly employed to investigate the oral absorption of poorly water-soluble drugs. Despite the significant progress in this area, the effect of commonly employed pharmaceutical excipients, such as surfactants, on the solubility of drugs in BDM has not been characterized in detail. The aim of this study is to clarify the impact of surfactant–bile interactions on drug solubility by using a set of 12 surfactants, 3 model hydrophobic drugs (fenofibrate, danazol, and progesterone) and two types of BDM (porcine bile extract and sodium taurodeoxycholate). Drug precipitation and sharp nonlinear decrease in the solubility of all studied drugs is observed when drug-loaded ionic surfactant micelles are introduced in solutions of both BDM, whereas the drugs remain solubilized in the mixtures of nonionic polysorbate surfactants + BDM. One-dimensional and diffusion-ordered 1H NMR spectroscopy show that mixed bile salt + surfactant micelles with low drug solubilization ca...

The reaction of 1-[ω-(N-acylated amino)alkyl]-3,4-dihydroisoquinolines (7a, 7b, 7c, 7d, 7e) with homophthalic anhydride (1) leads to the formation of 8-oxo-13a-[(N-acylated amino)alkyl]-8H-dibenzo[a,g]quinolizine-13-carboxylic acids (8a–e) with predomination of cis diastereomers, together with small amount of trans-8a. cis-13a-[(N-Cbzaminomethyl)]-8-oxo-dibenzoquinolizine-13-carboxylic acid (cis-8a) cyclized to the unknown dibenzo[a,g]pyrrolo[3,4-i]quinolizinedione (10) upon moderate heating in methanol.

Substituted (±)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-carboxamides (type I) and the acylated derivatives of (±)-trans-5-amino-1-benzyl-6-phenylpiperidin-2-one (type II) were prepared by the reaction of (±)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-carboxylic acid and some common reagents to provide the products in satisfactory yields. Newly synthesized compounds share the same moiety with common SP antagonists and thus similar activities might be expected.

The spectral properties of a tautomeric Schiff base containing aza-15-crown-5 moiety, namely N-((4-methylnaphthalen-1-yl)methylene)-4-(1,4,7,10-tetraoxa-13-azacyclopentadecan-13-yl)aniline on addition of alkali and alkaline earth metal ions were investigated. The newly synthesized ligand exhibited very interesting color changes in presence of metal ions: from yellow (free ligand) via colorlessness (enol tautomer complex) to yellow–orange (keto tautomer complex). These changes result from 2 stepwise processes: complex formation and shift of the tautomeric equilibrium between the tautomers after addition of the metal ions.

The reaction of succinic anhydride and N-benzylidene-benzylamine gave rise to the corresponding substituted trans-5-oxopyrrolidine-3-carboxylic acid, which was transformed stereoselectively into two series of compounds. The first one consists of carboxamides, and the second one includes aminomethyl derivatives. The compounds prepared incorporate both a pyrrolidinone part and other nitrogen containing heterocyclic fragments of pharmacological interest.

Reaction of dihydroisoquinolines (I) with homophthalic anhydride (II) results in the diastereoselective formation of cis-dibenzoquinolizinecarboxylic acids (III).

Avoiding trial and error experiments, the LSChrom software incorporating the Snyder theory was applied successfully to automatic selection of mobile phases for thin‐layer chromatography (TLC) on silica of two libraries of substituted trans‐piperidinones comprising amidolactames 1–15 and aminolactames 16–22. The procedure takes into account the adsorption properties of the mobile phase (parameter ϵ), stationary phase, and sample structure expressed by relevant groups. The recommended software value of ϵ was 0.460 for compounds 1–15 and 0.371 for compounds 16–22. Within about 190 measurements on silica using 13 computer selected mobile phases having these values of ϵ, the retention of any compound fell within a favorable range (0

A series of trans- and cis-3,4-disubstituted 5-oxomorpholine-2-carboxylic acids 5 were prepared by a cyclocondensation between diglycolic anhydride 3 and arylideneamines 4. Transformations of the carboxylic group leading to a peptide bond in the side chain to the morpholinone ring were effected. The relative configurations and the preferred conformations of the substituents at the morpholinone ring in some of the newly prepared derivatives were determined by means of 1H NMR and X-ray analysis.

A novel method for the preparation of 3-(2-hydroxyethyl)-2-methylbenzothiazolium bromide was developed. It consists of heating of 2-methylbenzothiazole, 2-bromoethanol and ethoxyethanol for 2 h. On the next day the precipitate was filtered and air dried.

The reaction between glutaric anhydride (1) and N-benzylidenebenzylamine (3) was studied in detail by 1H NMR spectroscopy under different reaction conditions. The major product was (±)-trans-1-benzyl-6-oxo-2-phenylpiperidine-3-carboxylic acid (2), which was converted into new substituted piperidin-2-ones via transformations of the carboxylic group. The final products are expected to possess pharmaceutical activities, and the relevant screenings are in course.