Receptor Sites Research Articles

Imino and Benzimidazolinyl Functionalized pyrano[2,3-b] Quinoline as a Dual-Responsive Probe for Detection of Mercury ion and Phosgene.

A dual-responsive probe 8-N, N-diethylamino-3-(1H-benzoimidazol-2-yl)-2H-pyrano[2,3-b]quinoline-2-imino (PQI), pyrano[2,3-b]quinoline as fluorophore, two nitrogen atoms as receptor sites, was developed for the colorimetric and fluorescence detection of Hg2+ and COCl2 in different solvents. PQI showed good recognition ability for Hg2+ via the absorbance decrease, fluorescence quenching by the formation of PQI-Hg2+ complex in MeOH/H2O (4/1, V/V). In addition, PQI could specifically react with COCl2 via intramolecular cyclization to form a cyclic urea product, which exhibited absorption and fluorescence emission changes, and then realized the detection of COCl2. Moreover, the optical responses of PQI to Hg2+ and COCl2 featured high selectivity, fast response (within 30s), and low detection limit (73 nM for Hg2+ and 25 nM for COCl2, respectively). Furthermore, PQI could detect Hg2+ in real water samples with good recoveries and small relative standard deviations, and could be prepared as a PQI-loaded test strip to monitor gaseous COCl2 in an in-site, real-time, highly sensitive manner, demonstrating the practicability of PQI in Hg2+ and gaseous COCl2 detection.

Clioquinol inhibits angiogenesis by promoting VEGFR2 degradation and synergizes with AKT inhibition to suppress triple-negative breast cancer vascularization

Inhibition of angiogenesis, either as monotherapy or in conjunction with other treatments, holds significant promise in cancer treatment. However, the limited efficacy of clinically approved anti-angiogenic agents underscores the urgent need for the development of novel drugs and therapeutic strategies. In this study, we demonstrate the highly selective inhibitory effects of clioquinol, a topical antifungal and antibiotic agent, on the angiogenic activity of endothelial cells (ECs) in a series of in vitro angiogenesis assays. Moreover, clioquinol effectively suppressed blood vessel formation in ex vivo aortic ring and in vivo Matrigel plug assays. Mechanistic studies revealed that clioquinol directly binds to the ATP-binding site of vascular endothelial growth factor receptor 2 (VEGFR2), promoting its degradation through both proteasome and lysosome pathways. This led to the down-regulation of the downstream extracellular signal-regulated kinase (ERK) pathway. In addition, the combination with the AKT inhibitor MK-2206 synergistically boosted the anti-angiogenic efficacy of clioquinol in vitro and in an in vivo dorsal skinfold chamber model of triple-negative breast cancer (TNBC), leading to the suppression of TNBC growth. Accordingly, clioquinol, either alone or in combination with AKT inhibitors, represents a promising therapeutic agent for future anti-angiogenic cancer treatment.

Thiol-maleimide click reaction-driven imprinted polymer for chiral resolution of indoprofen.

Indoprofen (INP) comprises two enantiomers, R- and S-, whose high pharmacological efficacy is realized only in the case of the separated enantiomers. A newly synthesized poly(acrylonitrile-co-divinylbenzene) (PANB)-based sorbent with selective affinity to the S-enantiomer of INP was applied to separate INP racemate. The synthesis was performed by suspension polymerization with low-crosslinked PANB microparticles and by reaction of the inserted nitriles with 1-amino-1H-pyrrole-2,5‑dione (Ma-NH2). The cationic maleimide-hydrazidine was then attached to the polymer particles, followed by its loading with anionic S-INP. In the post-crosslinking, ethane-1,2-dithiol (ETH) was used as a crosslinker through a thiol-maleimide click reaction, which attached the ETH to the maleimide groups in Ma-P. Acidic elution released S-INP enantiomers through specific receptor sites formed in the imprinted polymer particles, S-INP-P. Characterization of the polymers was done by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (13C NMR), and X-ray diffraction (XRD) while the surface morphology of the sorbents was investigated by scanning electron microscope (SEM). Optimum conditions for the enantioselective adsorption indicated that at pH 7, 285 mg/g of S-INP can be extracted. The chiral separation of the INP racemate led to an ee of 85% for R-INP in the first run and 97% for S-INP during elution.

α-Adrenoreceptor blocker phentolamine inhibits voltage-gated sodium channels via the local anaesthetic binding site.

Phentolamine is a non-selective α-adrenoreceptor antagonist used to reverse local anaesthesia, for example, during dental procedures when a vasoconstrictor is co-applied. Phentolamine-mediated vasodilation leads to faster clearance of injected drugs. Previous electrophysiological studies hypothesized that phentolamine acts as a modulator of voltage-gated sodium channels, which could conflict with its indication as local anaesthetic reversal agent. We performed manual and high throughput patch-clamp recordings on HEK and CHO cells expressing NaV1.7 and NaV1.5. We investigated the effects of phentolamine on sodium channel biophysics and the additive impact of phentolamine on cells preconditioned with the local anaesthetic mexiletine. We used site-directed mutagenesis, homology modelling and drug docking to identify phentolamine's binding site. We compared the effect on sodium channels with other clinically established α-adrenoreceptor antagonists. Phentolamine inhibits NaV1.7 in HEK and CHO cells with an IC50 value of 72 and 57 μM and NaV1.5 in CHO cells with an IC50 of 27 μM. Phentolamine enhances the tonic block induced by the local anaesthetic mexiletine. Phentolamine binds to sodium channels at the local anaesthetic receptor site. The α-adrenoreceptor antagonists alfuzosin, urapidil and phenoxybenzamine show lower potency on NaV1.5 and NaV1.7 in patch-clamp recordings. Phentolamine blocks voltage-gated sodium channels via the local anaesthetic receptor site. This may conflict with its current indication as an antidote for local anaesthetics. We propose alternative α-adrenoreceptor antagonists as possible candidates for local anaesthetic reversal because these are less potent inhibitors of both cardiac and neuronal voltage-gated sodium channels.

2-Guanidinobenzimidazole as Ligand in Supramolecular, Coordination and Organometallic Chemistry

Abstract: The benzimidazole core (BI) plays a central role in biologically active molecules. The BI nucleus is widely used as a building block to generate a variety of bioactive heterocyclic compounds to be used as antihelmintics, antiprotozoal, antimalarials, anti-inflammatories, antivirals, antimicrobials, antiparasitics, and antimycobacterials. A versatile BI derivative is the 2-guanidinobenzimidazole (2GBI), which, together with its derivatives, is a very interesting poly-functional planar molecule having a delocalised 10 π electrons system conjugated with the guanidine group. The 2GBI molecule has five nitrogen atoms containing five labile N–H bonds, which interact with the out-ward-facing channel entrance, forming a labile complex with the biological receptor sites. In this work, 2GBI and their derivatives were analyzed as ligands to form host–guest, coordination and organometallic complexes. Synthesis methodology, metal geometries, hydrogen bonding (HB) interactions, and the biological activities of the complexes were discussed.

Defining the Polycystin Pharmacophore Through HTS & Computational Biophysics.

Polycystins (PKD2, PKD2L1) are voltage-gated and Ca2+-modulated members of the transient receptor potential (TRP) family of ion channels. Loss of PKD2L1 expression results in seizure-susceptibility and autism-like features in mice, whereas variants in PKD2 cause autosomal dominant polycystic kidney disease. Despite decades of evidence clearly linking their dysfunction to human disease and demonstrating their physiological importance in the brain and kidneys, the polycystin pharmacophore remains undefined. Contributing to this knowledge gap is their resistance to drug screening campaigns, which are hindered by these channels' unique subcellular trafficking to organelles such as the primary cilium. PKD2L1 is the only member of the polycystin family to form constitutively active ion channels on the plasma membrane when overexpressed. HEK293 cells stably expressing PKD2L1 F514A were pharmacologically screened via high-throughput electrophysiology to identify potent polycystin channel modulators. In-silico docking analysis and mutagenesis were used to define the receptor sites of screen hits. Inhibition by membrane-impermeable QX-314 was used to evaluate PKD2L1's binding site accessibility. Screen results identify potent PKD2L1 antagonists with divergent chemical core structures and highlight striking similarities between the molecular pharmacology of PKD2L1 and voltage-gated sodium channels. Docking analysis, channel mutagenesis, and physiological recordings identify an open-state accessible lateral fenestration receptor within the pore, and a mechanism of inhibition that stabilizes the PKD2L1 inactivated state. Outcomes establish the suitability of our approach to expand our chemical knowledge of polycystins and delineates novel receptor moieties for the development of channel-specific antagonists in TRP channel research.

The role of pallidal substance P and neurokinin receptors in the consolidation of spatial memory of rats.

The tachykinin substance P (SP) facilitates learning and memory processes after its central administration. Activation of its different receptive sites, neurokinin-1 receptors (NK1Rs), as well as NK2Rs and NK3Rs was shown to influence learning and memory. The basal ganglia have been confirmed to play an important role in the control of memory processes and spatial learning mechanisms, and as part of the basal ganglia, the globus pallidus (GP) may also be involved in this regulation. SP-immunoreactive fibers and terminals, as well as NK1Rs and NK3Rs, were shown to be present in the GP. The present study aimed to examine whether the SP administered into the GP can influence spatial memory consolidation in the Morris water maze (MWM). Therefore, male Wistar rats received a post-trial microinjection of 0.4 microliters of 10ng SP, 100ng SP, or vehicle solution. The possible involvement of pallidal NK1Rs and NK3Rs in the SP effects was also studied by applying WIN51708 for NK1R antagonism and SR142801 as a selective NK3R antagonist. Our results showed that the lower dose of SP significantly decreased escape latency on the second day compared to control animals, while the higher dose was ineffective. Prior treatment with the NK1R antagonist WIN51708 could not block, while the NK3R antagonist SR142801 inhibited the effects of SP on memory consolidation in the MWM. Our results are the first to demonstrate that SP improves consolidation of spatial memory in the GP, and this effect is mediated through NK3Rs but not NK1Rs.

Design, synthesis, and evaluation of the pharmacological activity of novel NMDA receptor antagonists based on the germacrone scaffold.

The NMDA receptor has long attracted researchers' attention due to its potential as a drug target and its central role in the central nervous system. The NMDA receptor is a ligand-gated and voltage-dependent ion channel widely distributed in the central nervous system. In this study, we employed a drug design strategy combining "molecular assembly" and "combinatorial chemistry." By reducing the carbonyl group of germacrone to a hydroxyl group and esterifying it with alanine and linarinic acid, we successfully obtained nine novel germacrone derivatives through two rounds of structural optimization. We evaluated the neuroprotective activity of these nine derivatives using the MTT assay. The results revealed that compound C1 exhibited particularly outstanding activity, achieving a cell protection rate of 29.63±1.56% at a concentration of 0.05μM, outperforming the positive control drug, ifenprodil. Further experiments on NMDA-induced Ca2+ influx verified that the action site of compound C1 was the NMDA receptor, and demonstrated its superior antagonistic effect on the NMDA receptor compared to germacrone and ifenprodil. Additionally, molecular docking studies and ADMET property predictions were conducted for compound C1. The results showed that compound C1 tightly bound to the active site of the NMDA receptor and possessed favorable pharmacokinetic properties. In conclusion, compound C1, characterized by a germacrone-linarinic acid structure, not only exhibits strong antagonistic effects on the NMDA receptor but also demonstrates excellent pharmacokinetic properties, indicating its potential for further development as a therapeutic drug for central nervous system diseases.

New derivatives based on zerumbone scaffold as anticancer inhibitors: Synthesis, in vitro anticancer evaluation, docking, and MD simulation studies

A three-step procedure was applied to synthesize seven novel zerumbone ethers 7a–g with N-(4-hydroxybenzyl) benzamide, N-(4-hydroxybenzyl) substituted benzamide, and N-(4-hydroxybenzyl) cinnamamide moieties, including simultaneous O- and N-acylations, ester hydrolysis, and O-alkylation. The structure of intermediates and target compounds was elucidated using one-dimensional and two-dimensional nuclear magnetic resonance, and high-resolution mass spectrometry data. Their cytotoxic activities were screened on three human cancer cell lines HepG2, LU-1, and HeLa. The results showed that ethers 7a–g exhibited activity against all tested cell lines with IC50 values ranging from 1.71 to 6.86 µM and stronger than zerumbone, approximately 10–35 folds. Theoretically, the mode of their anticancer action was studied based on predicting the ability to inhibit Fibroblast Growth Factor Receptor 1 and Vascular Endothelial Growth Factor Receptor 2 proteins using docking and molecular dynamic simulation studies. The interaction of 7a–g with important amino acids in the active binding sites of protein Fibroblast Growth Factor Receptor 1 and Vascular Endothelial Growth Factor Receptor 2, and Umbrella Effect formation explained the significant improvement in their cytotoxic activities compared to the parent compound zerumbone.

Effect of two novel GABAA receptor positive allosteric modulators on neuropathic and inflammatory pain in mice.

Loss of GABAergic inhibition in the spinal dorsal horn (SDH) is implicated in central sensitization and chronic pain. Both agonists and positive allosteric modulators (PAMs) of GABAA receptor are found to be effective in the management of chronic pain. In addition to benzodiazepines, neuroactive steroids (NASs) also act as PAMs through binding to unique sites of GABAA receptors. Thus, it is worth investigating whether these NASs can attenuate chronic pain. This study tested the antinociceptive properties of two novel NAS PAMs, ganaxolone and zuranolone, in segmental spinal nerve ligation (SNL)-induced neuropathic pain and complete Freund's adjuvant (CFA)-induced inflammation pain models. Spinally administered ganaxolone and zuranolone both exhibited dose-dependent analgesic effects but with quite different durations. This antinociceptive effect might be generated from elevated GABAergic inhibition, as the PAMs both enhanced GABA-evoked currents in SDH neurons, and the K+-Cl- cotransporter isoform 2 (KCC2) antagonist reversed the analgesic effect of the PAMs. Different from ganaxolone, zuranolone produced a durable increase in the surface expression of GABAA receptors and of the amplitude of spontaneous inhibitory currents, which may contribute to the long-lasting analgesic effect. Furthermore, the PAMs alleviated SNL-induced mechanical allodynia synergistically with diazepam or GABAA receptor activator muscimol at inactive doses, consistent with the non-competitive activity and distinct binding sites from benzodiazepines. In summary, our findings suggest that NASs may not only acutely modulate GABA receptor activity but also induce sustained metabotropic effects on GABAA receptors and thus exert long-lasting antinociceptive effects.

Serotonin Deficits as a Factor in Suicidal Behavior a Critical Review

Serotonin neurotransmitter levels and receptor site dysfunction have been indicated as a potential factor influencing suicidal behaviors in individuals with major depressive disorder and in individuals with a history of suicide attempts. The serotonin system's abnormal activity is associated with an increased risk of suicide for those with MDD and a history of suicide attempts, however full understanding of the complex relationship between the serotonin system and suicide is still elusive. Despite this lack of firm understanding, progress is being made towards clinically useful tools and models. This paper analyzes scholarly research articles and provides a critical review of the current state of the field of research.

Long-range atmospheric transport of organochlorine pesticides from China to South Korea: Evidence from Deokjeok Island.

The influence of transboundary air pollutants originating from the Asian continent on South Korea has been a major concern. Although organochlorine pesticides (OCPs) have been banned for several decades, they continue to be detected in the Korean environment. However, studies on the long-range atmospheric transport (LRAT) of OCPs in South Korea, particularly in background areas, remain limited. This study investigated the atmospheric levels, sources, and behavior of OCPs at Deokjeok Island, a background site near the west coast of the Korean Peninsula. Total concentrations of 24 OCPs ranged from 53.6 to 325pg/m3, which are lower than those reported by the national POPs monitoring network of South Korea and similar to levels found in other background regions in Northeast Asia. HCB (62.7pg/m3, 45%) and PeCB (46.6pg/m3, 33%) were the most dominant OCPs in the gaseous phase, whereas DDTs were predominant (1.65pg/m3, 44%) in the particulate phase. Gaseous OCPs were strongly influenced by past use and re-emissions, while ongoing emissions and LRAT were the major sources of particulate OCPs. The consistent detection of mirex provides strong evidence of LRAT. In addition, correlation analysis and the Clausius-Clapeyron equation indicated that DDTs were significantly influenced by LRAT. Concentration-weighted trajectory maps identified East, North, and Northeast China as the major source regions for gaseous OCPs, driven by re-emissions, while the primary source areas for particulate OCPs were Beijing, Hebei, Tianjin, and Shandong. Air/soil fugacity fractions showed equilibrium or net deposition for most OCPs (except PeCB), indicating the dynamic environmental behavior of OCPs influenced by past use and LRAT. This study provides evidence of LRAT of OCPs to South Korea, demonstrating the significant impact of transboundary pollution. These results highlight the importance of ongoing monitoring of both historically and currently used pesticides at receptor sites in Northeast Asia.

STATISTICAL PHYSICAL MODELING TO UNVEIL THE ADSORPTION MECHANISM OF MANGANESE ION ON MODIFIED SURFACE OF PORPHYRIN

In this study, the adsorption mechanism of manganese ions onto the 5, 10, 15, 20-Tetrakis(4-tolylphenyl) porphyrin molecule (H2TTPP) was studied and interpreted. Through the spin coating method, a thin film of H2TTPP was deposited and so the adsorption isotherms of Mn2+ ions on a thin H2TTPP layer were measured using quartz crystal microbalance technique (QCM). These isotherms were modeled using the statistical physics approach. The mechanism of the adsorption was elucidated by essentially three physicochemical parameters such as: the quantity of attached ion to each receptor site, the number of accessible receptor sites, and the concentration at half saturations. The simulation results provide that H2TTPP is linked to more than one manganese ion, with an adsorption energy of less than 40kJ/mol which implies a physical adsorption process. The statistical model is useful to characterize the adsorbent-adsorbate system. Hence, three thermodynamic functions are calculated and interpreted. Then, distributions of the pore size (PSD) and the adsorption energy (AED) were also deduced.

In Silico Molecular Docking and In Vitro Antimicrobial Evaluation of Novel 2‐(4‐(3‐(4‐formylphenoxy)propyl)‐1H‐1,2,3‐triazol‐1‐yl)‐N‐Phenylacetamides

AbstractA series of new 2‐(4‐(3‐(4‐formylphenoxy)propyl)‐1H‐1,2,3‐triazol‐1‐yl)‐N‐phenylacetamides was successfully designed and synthesized via the click reaction. The alkyne agent 4‐(pent‐4‐yn‐1‐yloxy) benzaldehyde was prepared from 4‐hydroxybenzaldehyde and 5‐chloropent‐1‐yne. Meanwhile, the 2‐azido‐N‐phenylacetamides were obtained by the azidation of 2‐chloro‐N‐phenylacetamides which were formed from aromatic amine and chloroacetyl chloride. The novel compounds were characterized by FT‐IR, 1H/13C NMR, HRMS, MS, and elemental analysis, and evaluated for their in vitro antimicrobial activity against Acinetobacter baumannii, Carbapenem resistant pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter aerogenes, Vancomycin resistant enterococcus faecium and Methicillin resistant staphylococcus aureus bacterial strains, as well as Candida albicans and Aspergillus niger fungal strains. Some of the compounds revealed significant potential activity compared to the reference drugs. Compound 4 h showed the highest activity (MIC=133 μM, 106 μM, 133 μM, 106 μM) against Ac. Baumannii, Klebsiella pneumoniae, Enterobacter aerogenes, and Methicillin‐resistant Staphylococcus aureus (MRSA), respectively, as antibacterial and against Candida albicans (MIC=534 μM) and Aspergillus niger (MIC=1,068 μM) as antifungal. Using in silico molecular docking and ADMET studies, the compounds with the highest potential activity were examined. The results showed strong receptor site binding affinity and indicated promising antimicrobial potential.

Analytical and Pharmacological Characterization of 1-(Furan-2-Carbonyl)-LSD (1F-LSD) and Comparison With 1-(Thiophene-2-Carbonyl)-LSD (1T-LSD).

The classical psychedelic drug (+)-lysergic acid diethylamide (LSD) continues to attract considerable multidisciplinary interest, and over the last eight decades, many derivatives and analogs of LSD have been synthesized. One site on the ergoline scaffold of LSD that has been frequently modified is the N1-position, with the N1-acylated LSD derivative 1-acetyl-LSD (1A-LSD, ALD-52) being one of the earliest examples. In more recent years, several other alkylcarbonyl- and cycloalkylcarbonyl-substituted LSD derivatives have been evaluated, including several distributed as research chemicals. Although N1-substitution is detrimental for the activity of LSD at the 5-HT2A receptor (the primary site of action of psychedelic drugs), N1-acylated LSD derivatives are rapidly hydrolyzed invivo and are believed to act as prodrugs for LSD. Recently, 1-(thiophene-2-carbonyl)-LSD (1T-LSD, SYN-L-021) was detected as a new recreational drug, signaling a move towards N1-acyl groups with an aromatic character. The present study was conducted to investigate the analytical profile and pharmacology of 1-(2-furoyl)-lysergic acid diethylamide (1F-LSD, SYN-L-005), a novel analog of 1T-LSD. The binding of 1F-LSD to the 5-HT2A receptor and other monoamine sites was assessed using radioligand binding. Furthermore, the invivo activities of 1F-LSD and 1T-LSD were assessed in C57BL/6 J mice by comparing their biotransformation to LSD and effects on the head-twitch response (HTR), a 5-HT2A-mediated behavior. Both 1F-LSD and 1T-LSD induced the HTR in mice and were hydrolyzed to LSD after invivo administration, indicating that both substances exhibit LSD-like properties and may serve as prodrugs for LSD.

Advances in the Pathophysiology and Drug Discovery of Novel Therapeutics for Attention-Deficit/hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity and impulsivity. Psychostimulants such as methylphenidate are first-line treatments, but carry risks of severe side effects and addiction. Therefore, further research and the discovery of non-psychostimulant medications with novel mechanisms are urgently needed. We previously reported that juvenile stroke-prone spontaneously hypertensive rats (SHRSP/Ezo) are a suitable animal model of ADHD, and we identified N-methyl-D-aspartate (NMDA) receptor dysfunction in the prefrontal cortex of SHRSP/Ezo. D-Serine, a co-agonist for the glycine binding site of NMDA receptors, is synthesized from L-serine by serine racemase (SR) and degraded by D-amino acid oxidase (DAAO). Although D-serine dysregulation is implicated in psychiatric disorders, its pathophysiological role in ADHD is unclear. We measured D-serine in the medial prefrontal cortex (mPFC) of SHRSP/Ezo and addressed SR and DAAO expression. Additionally, we assessed cognitive function following DAAO inhibitor microinjection into the mPFC. SHRSP/Ezo showed a reduced D-serine/total serine (DL) ratio in the mPFC compared with the genetic control, Wistar Kyoto rat/Ezo (WKY/Ezo). DAAO expression in the mPFC was higher in SHRSP/Ezo rats compared with WKY/Ezo, however there was no difference in SR expression. The microinjection of a DAAO inhibitor into the mPFC of SHRSP/Ezo rats increased the DL ratio and ameliorated ADHD-like behaviors in the Y-maze test. These results suggest an association between abnormal D-serine metabolism and ADHD-like behaviors based on NMDA receptor dysfunction in the mPFC. Our findings provide insight into ADHD pathogenesis and should advance the development of new therapeutic approaches for the disorder.

Theoretical modeling of experimental isotherms for hydrogen storage in La0.9Ce0.1Ni5 alloy

This research reports the results of an experimental and numerical analysis of the La0.9Ce0.1Ni5 alloy's hydrogen absorption and desorption isotherms at three distinct temperatures (T = 313 K, 333 K, and 353 K). We first determined the morphological and structural properties, as well as the hydrogen storage isotherms, of the intermetallic La0.9Ce0.1Ni5 experimentally. The experimental isotherms were then compared to a mathematical model based on statistical physical theory. Due to the good agreement between the experimental isotherms and the proposed model, the insertion and release of hydrogen atoms (nα, nβ), geometric densities of receptor sites (Nαm, Nβm), and absorption-desorption energies (Pα, Pβ) were determined. Moreover, thermodynamic functions like enthalpy, entropy, Gibbs free energy, and internal energy were calculated using these parameters. The findings demonstrated that the intermetallic compound's CaCu5 structure promotes the formation of stable metal hydrides through attractive interactions, ensuring that hydrogen atoms are securely trapped in the metal lattice, thereby enhancing the material's hydrogen storage capacity.

Synthesis, characterization, cytotoxic activity, and molecular docking of 3,4-diaminobenzophenone-CuhNFs and its major components-based nanoflowers

In this study, organic–inorganic hybrid nanoflower (hNFs) synthesis was realized using 3,4-diaminobenzophenone and Cu(II) metal ions as organic and inorganic ingredients, respectively. The characterization of the synthesized hNFs was carried out using SEM, EDX, FT-IR, XRD, and elemental mapping. The cytotoxic effect of hNFs was investigated against A549 (lung) and MCF-7 (breast) cancer cell lines. Interactions of 3,4-diaminobenzophenone were also investigated via molecular docking studies at the binding site of the human estrogen receptor (PDB ID:3ERT) and epidermal growth factor receptor tyrosine kinase (PDB ID: 1M17). Physicochemical and pharmacokinetic parameters for ligands that could be potential anticancer drug candidates were determined by ADME prediction calculations from in silico approaches. In vitro results showed an increase in cell death when the synthesized hybrid nanoflowers were applied against both cell lines, depending on the concentrations tested. Additionally, it was determined that the synthesized nanoflower was more effective on the MCF-7 cell line.

Vicinal Diol Sesquiterpenes from Cinnamomum migao with Neuroprotective Effects in PC12 Cells.

In the ongoing search for new vicinal diol natural products, four new (Migaones A-D, 1-4) and four known (5-8) vicinal diol sesquiterpenoids were isolated from the branches and leaves of Cinnamomum migao. Their structures were unequivocally determined by comprehensive spectroscopic analyses (HRESIMS, 1D, and 2D NMR), single-crystal X-ray diffraction, electronic circular dichroism calculations, and comparison with existing literature data. All compounds isolated from C. migao possess vicinal diol structural units except compound 2. The newly isolated compounds (1-4) were evaluated for their neuroprotective activity using the PC12 cell injury model induced by N-methyl-daspartate acid (NMDA) and compounds 1-2 showing moderate neuroprotective activity against NMDA-induced neurotoxicity. Furthermore, molecular docking studies indicated that the most active compound 2 binds to the active site of the NMDA receptor via hydrogen bonds and hydrophobic interactions.

Stereospecific Properties and Intracellular Transport of Novel Intrinsically Fluorescent Neurosteroids.

Allopregnanolone (AlloP) is an example of neuroactive steroids (NAS), which is a potent allosteric activator of the γ-aminobutyric acid A (GABAA) receptor. The mechanisms underlying the biological activity of AlloP and other NAS are only partially understood. Here, we present intrinsically fluorescent analogs of AlloP (MQ-323) and its 3β-epimer, epi-allopregnanolone (E-AlloP) (YX-11), and show, by a combination of spectroscopic and computational studies, that these analogs mimic the membrane properties of AlloP and E-AlloP very well. We found stereospecific differences in the orientation and dynamics of the NAS as well as in their impact on membrane permeability. However, all NAS are unable to condense the lipid bilayer, in stark contrast to cholesterol. Using Förster resonance energy transfer (FRET) and electrophysiological measurements, we show that MQ-323 but not YX-11 binds at the intersubunit site of the ELICα1GABAA receptor and potentiates GABA-induced receptor currents. In aqueous solvents, YX-11 forms aggregates at much lower concentrations than MQ-323, and loading both analogs onto cyclodextrin allows for their uptake by human astrocytes, where they become enriched in lipid droplets (LDs), as shown by quantitative fluorescence microscopy. Trafficking of the NAS analogs is stereospecific, as uptake and lipid droplet targeting is more pronounced for YX-11 compared to MQ-323. In summary, we present novel minimally modified analogs of AlloP and E-AlloP, which enable us to reveal stereospecific membrane properties, allosteric receptor activation, and intracellular transport of these neurosteroids. Our fluorescence design strategy will be very useful for the analysis of other NAS in the future.