Structural Analogues Research Articles

Affinity for Estrogen Receptor α (ERα) in a <i>trans</i>-Stilbene Derivative Containing a Pyridoxine Fragment

Molecular targets for a promising antitumor agent based on trans-stilbene containing a pyridoxine fragment were identified. The lead compound, (E)-6-(3,4-dimethoxystyryl)-2,2,5,8-tetramethyl-4H-[1,3] dioxino[4,5-c]pyridine, was found to selectively induce apoptosis in MCF-7 breast adenocarcinoma cells overexpressing estrogen receptor, but not in MDA-MB-231 cells negative for estrogen receptor. The mechanism by which the novel trans-stilbene derivative acts as a selective estrogen receptor modulator was analyzed, and the affinity for human estrogen receptor α (ERα) was assessed by fluorescence polarization. Unlike its structural analogs—tamoxifen and raloxifene, the lead compound showed no affinity for ERα and did not form complexes with it. Therefore, it was concluded that the selective action of the pyridoxine-containing derivative of trans-stilbene on estrogen-positive breast cancer cells occurs through an alternative mechanism. The EC 50 values for the displacement of the fluorescent ligand from the ERα active site were 22, 120, and 595 nM for estradiol, raloxifene, and tamoxifen, respectively.

Ophthalmic Nanoemulsion Fingolimod Formulation for Topical Application.

Purpose: Fingolimod (FTY720; FT), a structural analog of sphingosine, has potential ocular applications. The goal of this study was to develop an FT-loaded nanoemulsion (NE; FT-NE) formulation for the efficient and prolonged delivery of FT to the posterior segment of the eye through the topical route. Methods: FT-NE formulations were prepared using homogenization followed by the probe sonication method. The lead FT-NE formulations (0.15% and 0.3% w/v loading), comprising soybean oil as oil and Tween® 80 and Poloxamer 188 as surfactants, were further evaluated for in vitro release, surface morphology, filtration sterilization, and stability at refrigerated temperature. Ocular bioavailability following topical application of FT-NE (0.3%) was examined in Sprague-Dawley rats. Results: The formulation, at both dose levels, showed desirable physicochemical characteristics, a nearly spherical shape with homogenous nanometric size distribution, and was stable for 180 days (last time point checked) at refrigerated temperature postfiltration through a polyethersulfone (0.22 µm) membrane. In vitro release studies showed prolonged release over 24 h, compared with the control FT solution (FT-S). In vivo studies revealed that effective concentrations of FT were achieved in the vitreous humor and retina following topical application of FT-NE. Conclusions: The results from these studies demonstrate that the FT-NE formulation can serve as a viable platform for the ocular delivery of FT through the topical route.

Synthesis, crystal and electronic structures of two novel tunnel bismuth oxychlorides Bi18O22Cl8.5(BO3)0.5 and Bi18O22Cl8Se

Single crystals of two new quaternary bismuth oxychlorides, Bi18O22Cl8.5(BO3)0.5(1) and Bi18O22Cl8Se (2), have been serendipitously produced in syntheses starting from bismuth borate or oxyselenide and oxychloride. The crystal structure of 1 represents a high symmetry analog of the PbBi17O22Cl9 type structure, formed by double aliovalent (Pb2+ → Bi3+, 0.5Cl– → 0.5BO33−) substitution at the two respective cationic and anionic sites, while 2 is a full structural analog of PbBi17O22Cl9. Overall, their structures can be described as sequences of thick (16 Å) slabs (2D “host” structure) comprised of litharge–like layers and ribbons formed by edge-sharing oxocentered OBin, polyhedra (n = 4 and 5). The chloride anions fill the 7.6 Å channels with the triangular cross-section inside the slabs as well as the interlayer space wherein they are partially substituted by disordered BO33− groups or Se2− anions. Compound 1 is just the second example of a mixed halide–borate occupancy among bismuth compounds while 2 illustrates much broader perspectives of mixed oxyhalide–oxychalcogenide approach to construction of novel complex bismuth compounds. Both compounds make new contributions to the family of tunnel structures of anion-centered tetrahedra featuring wide trigonal channels filled by halide anions or more complex metal–halide “salt inclusions”.

Exploring the influence of hydrogen bond donor groups on the microstructure and intermolecular interactions of amorphous solid dispersions containing diflunisal structural analogues

Drug-polymer intermolecular interactions, and H-bonds specifically, play an important role in the stabilization process of a compound in an amorphous solid dispersion (ASD). However, it is still difficult to predict whether or not interactions will form and what the strength of those interactions would be, based on the structure of drug and polymer. Therefore, in this study, structural analogues of diflunisal (DIF) were synthesized and incorporated in ASDs with poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) as a stabilizing polymer. The respective DIF derivatives contained different types and numbers of H-bond donor groups, which allowed to assess the influence of these structural differences on the phase behavior and the actual interactions formed in the ASDs. The highest possible drug loading of these derivatives in PVPVA were evaluated through film casting. Subsequently, a lower drug loading of each compound was spray dried. These spray dried ASDs were subjected to an in-depth solid-state nuclear magnetic resonance (ssNMR) study, including 1D spectroscopy and relaxometry, as well as 2D dipolar HETCOR experiments. The drug loading study revealed the highest possible loading of 50 wt% for the native DIF in PVPVA. The methoxy DIF derivative reached the second highest drug loading of 35 wt%, while methylation of the carboxyl group of DIF led to a sharp decrease in the maximum loading, to around 10 wt% only. Unexpectedly, the maximum loading increased again when both the COOH and OH groups of diflunisal were methylated in the dimethyl DIF derivative, to around 30 wt%. The ssNMR study on the spray dried ASD samples confirmed intermolecular H-bonding with PVPVA for native DIF and methoxy DIF. Studies of the proton relaxation decay times and 2D 1H–13C dipolar HETCOR experiments indicated that the ASDs with native DIF and methoxy DIF were homogenously mixed, while the ASDs containing DIF methyl ester and dimethyl DIF were phase separated at the nm level. It was established that, for these systems, the availability of the carboxyl group was imperative in the formation of intermolecular H-bonds with PVPVA and in the generation of homogenously mixed ASDs.

Pressurized Phase Transitions Cascade in BaMn2P2 and BaMn2As2

The structural analogue of iron-based superconductors the BaMn2P2 and BaMn2As2 compounds under hydrostatic pressure upto 140 GPa were studied within the framework of DFT + U. The transition from an antiferromagnetic insulator to an antiferromagnetic metal is observed under pressure of 6.4 GPa for BaMn2P2 and 8.3 GPa for BaMn2As2. This second order phase transition to the AFM metallic state provides an appropriate normal state for possible superconductivity in these materials. Moreover, further increase in pressure leads to a series of first order magnetostructural phase transitions between different antiferromagnetic phases, then to a ferromagnetic metal and finally to a nonmagnetic metal. In case of doping, these compounds could potentially be superconductors under pressure (above 6–8 GPa) with critical temperature growing under pressure.

The Effect of KSK-94, a Dual Histamine H3 and Sigma-2 Receptor Ligand, on Adipose Tissue in a Rat Model of Developing Obesity.

Numerous studies highlight the critical role that neural histamine plays in feeding behavior, which is controlled by central histamine H3 and H1 receptors. This is the fundamental motivation for the increased interest in creating histamine H3 receptor antagonists as anti-obesity medications. On the other hand, multiple other neurotransmitter systems have been identified as pharmacotherapeutic targets for obesity, including sigma-2 receptor systems. Interestingly, in our previous studies in the rat excessive eating model, we demonstrated a significant reduction in the development of obesity using dual histamine H3/sigma-2 receptor ligands. Moreover, we showed that compound KSK-94 (structural analog of Abbott's A-331440) reduced the number of calories consumed, and thus acted as an anorectic compound. Therefore, in this study, we extended the previous research and studied the influence of KSK-94 on adipose tissue collected from animals from our previous experiment. Visceral adipose tissue was collected from four groups of rats (standard diet + vehicle, palatable diet + vehicle, palatable diet + KSK-94, and palatable diet + bupropion/naltrexone) and subjected to biochemical, histopathological, and immunohistochemical studies. The obtained results clearly indicate that compound KSK-94 prevented the hypertrophy and inflammation of visceral adipose tissue, normalized the levels of leptin, resistin and saved the total reduction capacity of adipose tissue, being more effective than bupropion/naltrexon in these aspects. Moreover, KSK-94 may induce browning of visceral white adipose tissue. Our study suggests that dual compounds with a receptor profile like KSK-94, i.e., targeting histamine H3 receptor and, to a lesser extent, sigma-2 receptor, could be attractive therapeutic options for patients at risk of developing obesity or with obesity and some metabolic disorders. However, more studies are required to determine its safety profile and the exact mechanism of action of KSK-94.

Generation of a bloodstream form Trypanosoma brucei double glycosyltransferase null mutant competent in receptor-mediated endocytosis of transferrin.

The bloodstream form of Trypanosoma brucei expresses large poly-N-acetyllactosamine (pNAL) chains on complex N-glycans of a subset of glycoproteins. It has been hypothesised that pNAL may be required for receptor-mediated endocytosis. African trypanosomes contain a unique family of glycosyltransferases, the GT67 family. Two of these, TbGT10 and TbGT8, have been shown to be involved in pNAL biosynthesis in bloodstream form Trypanosoma brucei, raising the possibility that deleting both enzymes simultaneously might abolish pNAL biosynthesis and provide clues to pNAL function and/or essentiality. In this paper, we describe the creation of a TbGT10 null mutant containing a single TbGT8 allele that can be excised upon the addition of rapamycin and, from that, a TbGT10 and TbGT8 double null mutant. These mutants were analysed by lectin blotting, glycopeptide methylation linkage analysis and flow cytometry. The data show that the mutants are defective, but not abrogated, in pNAL synthesis, suggesting that other GT67 family members can compensate to some degree for loss of TbGT10 and TbGT8. Despite there being residual pNAL synthesis in these mutants, certain glycoproteins appear to be particularly affected. These include the lysosomal CBP1B serine carboxypeptidase, cell surface ESAG2 and the ESAG6 subunit of the essential parasite transferrin receptor (TfR). The pNAL deficient TfR in the mutants continued to function normally with respect to protein stability, transferrin binding, receptor mediated endocytosis of transferrin and subcellular localisation. Further the pNAL deficient mutants were as viable as wild type parasites in vitro and in in vivo mouse infection experiments. Although we were able to reproduce the inhibition of transferrin uptake with high concentrations of pNAL structural analogues (N-acetylchito-oligosaccharides), this effect disappeared at lower concentrations that still inhibited tomato lectin uptake, i.e., at concentrations able to outcompete lectin-pNAL binding. Based on these findings, we recommend revision of the pNAL-dependent receptor mediated endocytosis hypothesis.

Gene expression patterns and DNA methylation of neuron and pancreatic β-cell developments in zebrafish embryos treated with bisphenol F and AF

Bisphenol F (BPF) and bisphenol AF (BPAF) are structural analogues of bisphenol A (BPA) that are used in the manufacture of a myriad of BPA-free products; however, there is a paucity of information regarding their developmental effects. The present study investigates the effects of BPF and BPAF on neurodevelopment and pancreatic β-cell differentiation via altering DNA methylation and gene expression patterns using the zebrafish model. BPF and BPAF induced behavioral perturbations: increased average speed, increased maximum acceleration, increased mania time and decreased static time, in 0.3 and 1.0 μM groups in zebrafish embryos. Glucose level was significantly increased in 1.0 μM BPF (28 %); while a monotonic increase of 29 %, 55 %, and 74 % were observed in 0.1, 0.3, and 1.0 μM BPAF, respectively. Consistent with a decreased insulin mRNA level, the expression of two critical transcription factors (pdx-1 and foxa2) essential for the development and functioning of beta-cells decreased following the bisphenols exposure. In addition, embryonic exposure to BPF and BPAF upregulated the transcription of developmental genes (vegfa, wnt8a, and mstn1) and neuron-related genes (mbp, elavl3, gap43, gfap). Also, the expressions of DNA methyltransferases (dnmt1, dnmt3, dnmt4, dnmt5, dnmt6, dnmt7, and dnmt8) were significantly aberrant compared with the control group. The Bisulfite PCR results indicate increased DNA methylation at promoter regions of pdx-1 in BPF (8.2 %) and BPAF (7.6 %); α1-tubulin in BPF (5.3 %) and in BPAF (4.1 %), congruous with the increased dnmt1 and dnmt3 transcription, at early stage of zebrafish development. The present study indicates that zebrafish embryonic exposure to BPF and BPAF elicits islet dysfunction and neuron perturbations resulting in increased DNA methylation levels.

Cd7(SeO3)8]{Cu2Br2}, a host-guest structure derived from β-CdSeO3

Abstract A first cadmium copper selenite–bromide Cd7Cu2(SeO3)8Br2 (1) was obtained via chemical vapor transport reactions. The new compound is triclinic, P 1 ‾ $P\overline{1}$ , a = 5.3280(5) Å, b = 10.6190(12) Å, c = 11.4380(13) Å, α = 100.856(4)°, β = 93.321(4)°, γ = 91.021(4)°, V = 634.22(12) Å3, R 1 = 0.027. 1 has no structural analogs and belongs to a new structure type. The structure of 1 can be described as a host-guest architecture. The host is the [Cd7(SeO3)8]2− interrupted framework, which consists of zigzag layers with a large aperture. The guests are copper bromide species. Thus, the formula can be written as [Cd7(SeO3)8]{Cu2Br2}.

In vitro neuroprotective effects and in silico evaluation of the pharmacological potential of two phenolic acids and a derivative originated from the edible red macroalga (Bangia fuscopurpurea)

Most previous studies on the bioactive substances from the edible red macroalga (Bangia fuscopurpurea) have concentrated on the polysaccharides and proteins. We explored the possible effects of two phenolic acids (HBP2—3) and two derivatives (HBP1 and HBP4) originated from Bangia fuscopurpurea and two structural analogues in an in vitro model of Parkinson’s disease. We also performed in silico evaluation of the pharmacological potential of these six compounds. Our present study showed that HBP1—3 had neuroprotective effects. Moreover, HBP3 (10 nM) could protect SH-SY5Y cells from 6-hydroxydopamine (6-OHDA) damage via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) cascade, and the up-regulation of this pathway could inhibited reactive oxygen species (ROS) production. In addition, we speculated the preliminary structure–activity relationships on the neuroprotective effects of HBP1—3. This study demonstrated that neuroprotective effects of HBP1—3 originated from Bangia fuscopurpurea.

Biotransformation of anabolic drug Dianabol with Rizhopus oryzae

Microbial biotransformation technique is an excellent approach for the synthesis of stereo-, enantio-, chemo-, and regio-selective/specific analogues of existing steroidal and non-steroidal drugs by using bacteria, fungi, algae, actinomycetes, yeast, and plants and animals cell cultures. This technique is effectively used to synthesize compounds whose structures resemble to the substrates (parent drugs) without using protecting/deprotecting steps. In the current study, an anabolic-androgenic steroid (AAS) based drug, methandienone (dianabol) (1) was incubated with the filamentous fungi Rhizopus oryzae ATCC 11145 for twelve days under ambient reaction conditions (at room temperature and neutral pH) by using aqueous media. Therefore, the present study has successfully helped to produce the structural analogues of inert steroidal anabolic drug dianabol (1) without using expensive and toxic chemicals. This yielded five known structural analogues of dianabol (1), i.e., 17β,11β-dihydroxy,17α-methyl-androsta-1,4-diene-3-one (2), 17β-hydroxy,17α-methyl-androsta-1,4-diene-3,11-dione (3), 17β,6β-dihydroxy,17α-methyl-androsta-1,4-diene-3-one (4), 17β,6β-dihydroxy,17α-methyl-androsta-4-ene-3-one (5), and 17β-hydroxy,17α-methyl-androsta-4,6-diene-3-one (6). Structures of transformed products 2-6 were determined through 1H-NMR, and FAB-MS spectroscopic techniques.

Near-infrared nanosensors enable optical imaging of oxytocin with selectivity over vasopressin in acute mouse brain slices

Oxytocin plays a critical role in regulating social behaviors, yet our understanding of its function in both neurological health and disease remains incomplete. Real-time oxytocin imaging probes with spatiotemporal resolution relevant to its endogenous signaling are required to fully elucidate oxytocin's role in the brain. Herein, we describe a near-infrared oxytocin nanosensor (nIROXT), a synthetic probe capable of imaging oxytocin in the brain without interference from its structural analogue, vasopressin. nIROXT leverages the inherent tissue-transparent fluorescence of single-walled carbon nanotubes (SWCNT) and the molecular recognition capacity of an oxytocin receptor peptide fragment to selectively and reversibly image oxytocin. We employ these nanosensors to monitor electrically stimulated oxytocin release in brain tissue, revealing oxytocin release sites with a median size of 3 µm in the paraventricular nucleus of C57BL/6 mice, which putatively represents the spatial diffusion of oxytocin from its point of release. These data demonstrate that covalent SWCNT constructs, such as nIROXT, are powerful optical tools that can be leveraged to measure neuropeptide release in brain tissue.

Bimetallic metal-organic frameworks utilizing AIE for visual detection of glutathione and applications in information encryption

Glutathione (GSH) plays an important role in living organisms and is often added to food as a food additive, so it is of great importance to accurately and conveniently determine GSH in food. In this paper, a terbium and copper bimetallic metal-organic frameworks (Tbx/Cu1-x-BTC) was designed for the visualization and detection of GSH in food. Terbium ions in the Tbx/Cu1-x-BTC provide the background signal and act as an aggregation center. After reduction and aggregation-induced emission (AIE), GSH-modified copper nanoclusters (GSH-Cu NCs) enhance the red fluorescence and keep the green fluorescence unchanged. This results in a color shift of the system from green to orange. Combined with a smartphone, the RGB value of the system color was extracted to realize the visual detection of GSH. Due to the specificity of the reaction, Tbx/Cu1-x-BTC was able to specifically recognize GSH among GSH structural analogs with very good selectivity, anti-interference ability, sensitivity and accuracy. In addition, using the difference in color and excitation wavelength range between the probe and the reaction product, the probe was applied in the field of information encryption, which further expanded the application scenario of the probe. Therefore, this study provides new ideas for the detection of GSH in food and the application of fluorescence probes in the field of information encryption.

Next-generation risk assessment read-across case study: application of a 10-step framework to derive a safe concentration of daidzein in a body lotion.

Introduction: We performed an exposure-based Next Generation Risk Assessment case read-across study using New Approach Methodologies (NAMs) to determine the highest safe concentration of daidzein in a body lotion, based on its similarities with its structural analogue, genistein. Two assumptions were: (1) daidzein is a new chemical and its dietary intake omitted; (2) only in vitro data were used for daidzein, while in vitro and legacy in vivo data for genistein were considered. Methods: The 10-step tiered approach evaluating systemic toxicity included toxicokinetics NAMs: PBPK models and in vitro biokinetics measurements in cells used for toxicogenomics and toxicodynamic NAMs: pharmacology profiling (i.e., interaction with molecular targets), toxicogenomics and EATS assays (endocrine disruption endpoints). Whole body rat and human PBPK models were used to convert external doses of genistein to plasma concentrations and in vitro Points of Departure (PoD) to external doses. The PBPK human dermal module was refined using in vitro human skin metabolism and penetration data. Results: The most relevant endpoint for daidzein was from the ERα assay (Lowest Observed Effective Concentration was 100 ± 0.0nM), which was converted to an in vitro PoD of 33nM. After application of a safety factor of 3.3 for intra-individual variability, the safe concentration of daidzein was estimated to be 10nM. This was extrapolated to an external dose of 0.5μg/cm2 for a body lotion and face cream, equating to a concentration of 0.1%. Discussion: When in vitro PoD of 33nM for daidzein was converted to an external oral dose in rats, the value correlated with the in vivo NOAEL. This increased confidence that the rat oral PBPK model provided accurate estimates of internal and external exposure and that the in vitro PoD was relevant in the safety assessment of both chemicals. When plasma concentrations estimated from applications of 0.1% and 0.02% daidzein were used to calculate bioactivity exposure ratios, values were >1, indicating a good margin between exposure and concentrations causing adverse effects. In conclusion, this case study highlights the use of NAMs in a 10-step tiered workflow to conclude that the highest safe concentration of daidzein in a body lotion is 0.1%.

Enhanced Research Needed on the Structural Analogues of Chlorinated Paraffins as Emerging Contaminants of Concern.

Enhanced Research Needed on the Structural Analogues of Chlorinated Paraffins as Emerging Contaminants of Concern.

Identification of EA-3167, a Structural Analogue of the BZ Incapacitant, in Objects Delivered from the Zone of a Special Military Operation and Detection of Its Metabolites in Urine during Exposure of Rats

Earlier, we found that two alcohol-containing samples delivered from the zone of special military operation contain a rare psychoactive substance EA-3167, which is a structural analogue of the well-known incapacitant BZ, included in the Schedule 1 of the Chemical Weapons Convention. In addition to EA-3167, additives of methadone, α-pyrrolidinovalerophenone and tetrahydrocannabinol were found in liquids.The aim of the work is to establish the analytical characteristics of EA-3167, as well as its metabolites in rat urine. Research methods. Structural identification of the detected substance by nuclear magnetic resonance, gas and liquid chromatomass spectrometry of delivered objects and rat urine obtained by exposing laboratory animals to the detected substance.The results of the study. Concentrations of EA-3167 in liquids were found to be 910 and 3.9 μg/mL, respectively. It has been established that EA-3167 is subject to intensive metabolism in rats. More than 30 metabolites, representing products of mono- and dihydroxylation of aliphatic moieties of the molecule, ketone formation, and hydrolysis, have been tentatively identified in the urine of laboratory animals. Conclusion. The most convenient markers for confirming poisoning of EA-3167 by gas and liquid chromatography-mass spectrometry were the parent substance, the products of its monohydroxylation and the formation of carbonyl group on the cyclopentyl moiety.

High dielectric breakdown strength of antipolar CaTiGeO5 ceramics sintered at optimized temperature

Titanite CaTiSiO5 (CTS) is considered to be a promising dielectric material for preparing high-voltage multilayer ceramic capacitors because it exhibits a positive bias dependence of the dielectric permittivity due to its antipolar crystal structure. In this study, we investigated the dielectric response and breakdown strength of CaTiGeO5 (CTG), a structural analog of CTS, inspired by its higher low-field dielectric permittivity. Particular attention was paid to the sintering temperature to reveal the effect of the microstructure and loss of volatile Ge on the electrical properties of CTG. Dense CTG ceramics with relative densities above 97 % and grain sizes between 1.3 and 3.4 μm were obtained through a conventional solid-state reaction route at sintering temperatures between 1150 and 1250 °C. A secondary phase of CaTiO3 was formed in the ceramics sintered at 1200 and 1250 °C due to Ge loss, but this phase was easily removed by surface polishing alone. The sintering temperature largely affected the dielectric breakdown strength through microstructural development, resulting in the highest breakdown strength of 1190 kV cm−1 for a sample sintered at 1200 °C, while it did not change the low-field dielectric properties of the samples. Furthermore, the sample retained high breakdown strength of >900 kV cm−1 at elevated temperatures up to 150 °C and exhibited a nonlinear polarization response, resulting in the positive electric field dependence of the dielectric permittivity.

Surface-enhanced Raman scattering sensor based on cysteine-mediated nucleophilic addition reaction for detection of patulin

Fruits are susceptible to fungal infection and propagation during storage and transportation, and carry toxic metabolites of fungi. Patulin (PAT) is a primary mycotoxin contaminant in fruits and their products, with neurotoxicity, teratogenicity and carcinogenicity. The current chromatographic methods have limitations such as time-consuming, high-cost and the need for professional training. For rapid and sensitive detection of PAT, a surface-enhanced Raman scattering (SERS) method based on nucleophilic addition reaction was described in this paper. 4-aminothiophenol (4-ATP), silver ion, and cysteine (Cys) were successively attached to the surface of the Au-core-Ag-shell nanoparticles to form SERS sensors. PAT reacted with Cys to form a complex covering the surface of the sensor, attenuating the Raman signal from 4-ATP. Combined with the chemometrics algorithms, the hidden spectral information can be extracted effectively. Among these algorithms, the ant colony optimization partial least squares (ACO-PLS) model demonstrated the best predictive performance (Rc = 0.9985, RMSEC = 0.0494). The recovery rate of PAT was 96.58 ∼ 101.74 % with the RSD ≤ 1.42 %. HPLC was used to verify the applicability of this SERS method, and the results indicated that the SERS method was consistent with the HPLC method (p = 0.283 > 0.05). Furthermore, the SERS sensor was not subject to interference from ochratoxins A, alternariol, and the PAT structural analogues. Consequently, the proposed SERS sensor can realize rapid and highly selective detection of PAT, providing a new strategy for the rational design of SERS sensor based on chemical reaction for indirect detection of harmful substances.

In vitro structure-activity relationships and forensic case series of emerging 2-benzylbenzimidazole 'nitazene' opioids.

2-Benzylbenzimidazole 'nitazene' opioids are presenting a growing threat to public health. Although various nitazenes were previously studied, systematic comparisons of the effects of different structural modifications to the 2-benzylbenzimidazole core structure on μ-opioid receptor (MOR) activity are limited. Here, we assessed in vitro structure-activity relationships of 9 previously uncharacterized nitazenes alongside known structural analogues. Specifically, we focused on MOR activation by 'ring' substituted analogues (i.e., N-pyrrolidino and N-piperidinyl modifications), 'desnitazene' analogues (lacking the 5-nitro group), and N-desethyl analogues. The results from two in vitro MOR activation assays (β-arrestin 2 recruitment and inhibition of cAMP accumulation) showed that 'ring' modifications overall yield highly active drugs. With the exception of 4'-OH analogues (which are metabolites), N-pyrrolidino substitutions were generally more favorable for MOR activation than N-piperidine substitutions. Furthermore, removal of the 5-nitro group on the benzimidazole ring consistently caused a pronounced decrease in potency. The N-desethyl modifications showed important MOR activity, and generally resulted in a slightly lowered potency than comparator nitazenes. Intriguingly, N-desethyl isotonitazene was the exception and was consistently more potent than isotonitazene. Complementing the in vitro findings and demonstrating the high harm potential associated with many of these compounds, we describe 85 forensic cases from North America and the United Kingdom involving etodesnitazene, N-desethyl etonitazene, N-desethyl isotonitazene, N-pyrrolidino metonitazene, and N-pyrrolidino protonitazene. The low-to-sub ng/mL blood concentrations observed in most cases underscore the drugs' high potencies. Taken together, by bridging pharmacology and case data, this study may aid to increase awareness and guide legislative and public health efforts.

Thiazolium salt mimics the non-coenzyme effects of vitamin B1 in rat synaptosomes

Long-term studies have confirmed a causal relationship between the development of neurodegenerative processes and vitamin B1 (thiamine) deficiency. However, the biochemical mechanisms underlying the high neurotropic activity of thiamine are not fully understood. At the same time, there is increasing evidence that vitamin B1, in addition to its coenzyme functions, may have non-coenzyme activities that are particularly important for neurons. To elucidate which effects of vitamin B1 in neurons are due to its coenzyme function and which are due to its non-coenzyme activity, we conducted a comparative study of the effects of thiamine and its derivative, 3-decyloxycarbonylmethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium chloride (DMHT), on selected processes in synaptosomes. The ability of DMHT to effectively compete with thiamine for binding to thiamine-binding sites on the plasma membrane of synaptosomes and to participate as a substrate in the thiamine pyrophosphokinase reaction was demonstrated. In experiments with rat brain synaptosomes, unidirectional effects of DMHT and thiamine on the activity of the pyruvate dehydrogenase complex (PDC) and on the incorporation of radiolabeled [2–14C]pyruvate into acetylcholine were demonstrated. The observed effects of thiamine and DMHT on the modulation of acetylcholine synthesis can be explained by suggesting that both compounds, which interact in cells with enzymes of thiamine metabolism, are phosphorylated and exert an inhibitory/activating effect (concentration-dependent) on PDC activity by affecting the regulatory enzymes of the complex. Such effects were not observed in the presence of structural analogues of thiamine and DMHT without a 2-hydroxyethyl substituent at position 5 of the thiazolium cycle. The effect of DMHT on the plasma membrane Ca-ATPase was similar to that of thiamine. At the same time, DMHT showed high cytostatic activity against neuroblastoma cells.