Enhancing Surface Hydroxyl Group Modulation on Carbon Nitride Boosts the Effectiveness of Photodynamic Treatment for Brain Glioma.

The effectiveness of photodynamic therapy (PDT) in treating brain gliomas is limited by the solubility of photosensitizers and the production of reactive oxygen species (ROS), both of which are influenced by the concentration of photosensitizers and catalyst active sites. In this study, we developed a controllable surface hydroxyl concentration for the photosensitizer CN11 to address its poor water solubility issue and enhance PDT efficacy in tumor treatment. Compared to pure g-C3N4 (CN), CN11 exhibited 4.6 times higher hydrogen peroxide production under visible light, increased incidence of the n → π* electron transition, and provided more available reaction sites for cytotoxic ROS generation. These findings resulted in a 2.43-fold increase in photodynamic treatment efficacy against brain glioma cells. Furthermore, in vivo experiments conducted on mice demonstrated that CN11 could be excreted through normal cell metabolism with low cytotoxicity and high biosafety, effectively achieving complete eradication of tumor cells.

Controllable ion design in flexible metal organic framework film for performance regulation of electrochemical biosensing.

The limitations of solvent residues, unmanageable film growth regions, and substandard performance impede the extensive utilization of metal-organic framework (MOF) films for biosensing devices. Here, we report a strategy for ion design in gas-phase synthesized flexible MOF porous film to attain universal regulation of biosensing performances. The key fabrication process involves atomic layer deposition of induced layer coupled with lithography-assisted patterning and area-selective gas-phase synthesis of MOF film within a chemical vapor deposition system. Sensing platforms are subsequently formed to achieve specific detection of H2O2, dopamine, and glucose molecules by respectively implanting Co, Fe, and Ni ions into the network structure of MOF films. Furthermore, we showcase a practical device constructed from Co ions-implanted ZIF-4 film to accomplish real-time surveillance of H2O2 concentration at mouse wound. This study specifically elucidates the electronic structure and coordination mode of ion design in MOF film, and the obtained knowledge aids in tuning the electrochemical property of MOF film for advantageous sensing devices.

[The functional differences of macrophages derived from murine bone marrow and peritoneal cavity].

Objective To compare the functional differences between bone marrow derived macrophages and peritoneal macrophages, which may provide the basis for the selection of macrophages in immunological research and immunoregulatory drug evaluation. Methods Marophage colony-stimulating factor (M-CSF) was used to induce the differentiation of bone marrow monocytes into macrophages, and thioglycolate medium was used to induce peritonitis to obtain peritoneal macrophages. After both macrophages being stimulated by zymosan, LPS, R848 and CpG respectively, mRNA levels of tumor necrosis factor α(TNF-α), interleukin 6(IL-6), macrophage inflammatory protein 1α(MIP-1α), monocyte chemoattractant protein 1(MCP-1) were measured by Real-time fluorescent quantitative PCR and the concentrations of secreted TNF-α, IL-6, MIP-1α and MCP-1 were detected by ELISA. In addition, the expression of costimulatory molecules CD80, CD86, CD40 and histocompatibility complex II (MHC II) on the cell surface was analyzed by flow cytometry. Results After inducing by different TLR ligands, mRNA expression levels of inflammatory cytokines and chemokines were increased in both macrophages. The secretion of TNF-α, IL-6, MIP-1α and MCP-1 in peritoneal macrophages and the expression of CD86 and MHC II on the surface of peritoneal macrophages were significantly higher than those of bone marrow derived macrophages. Conclusion There are significant differences in the expression of inflammatory factors, chemokines, costimulatory molecules, and histocompatibility complex between bone marrow derived macrophages and peritoneal macrophages. Peritoneal macrophages have more complete macrophage function and is more suitable for immunological research and immunomodulatory drug evaluation.

Fabrication of NiCo Bimetallic MOF Films on 3D Foam with Assistance of Atomic Layer Deposition for Non-Invasive Lactic Acid Sensing.

Lactic acid (LA) is an important downstream product of glycolysis in living cells and is abundant in our body fluids, which are strongly associated with diseases. The development of enzyme-free LA sensors with high sensitivity and low consumption remains a challenge. 2D metal-organic frameworks (MOFs) are considered to be promising electrochemical sensing materials and have attracted much attention in recent years. Compared to monometallic MOFs, the construction of bimetallic MOFs (BMOFs) can obtain a larger specific surface area, thereby increasing the exposed active site. 3D petal-like NixCoy MOF films on nickel foams (NixCoy BMOF@Ni foams) are successfully prepared by combining atomic layer deposition-assisted technology and hydrothermal strategy. The established NixCoy BMOF@Ni foams demonstrate noticeable LA sensing activity, and the study is carried out on behalf of the Ni1Co5 BMOF@Ni foam, which has a sensitivity of up to 9030 µA mM-1 cm-2 with a linear range of 0.01-2.2 mM and the detection limit is as low as 0.16 µM. Additionally, the composite has excellent stability and repeatability for the detection of LA under a natural air environment with high accuracy and reliability. Density functional theory calculation is applied to study the reaction process between composites and LA, and the result suggests that the active site in the NiCo BMOF film favors the adsorption of LA relative to the active site of monometallic MOF film, resulting in improved performance. The developed composite has a great potential for the application of noninvasive LA biosensors.

Bacteroid cerium oxide particles promote macrophage polarization to achieve early vascularization and subsequent osseointegration around implants.

The establishment of an osseointegration is crucial for the long-term stability and functionality of implant materials, and early angiogenesis is the key to successful osseointegration. However, the bioinertness of titanium implants affects osseointegration, limiting their clinical application. In this study, inspired by the rapid polarization of macrophages following the phagocytosis of bacteria, we developed bacteroid cerium oxide particles; these particles were composed of CeO2 and had a size similar to that of Bacillus (0.5 µ m). These particles were constructed on the implant surfaces using a hydrothermal method. In vitro experiments demonstrated that the particles effectively decreased the reactive oxygen species (ROS) levels in macrophages (RAW264.7). Furthermore, these particles exerted effects on M1 macrophage polarization, enhanced nitric oxide (NO) secretion to promote vascular regeneration, and facilitated rapid macrophage transition to the M2 phenotype. Subsequently, the particles facilitated human umbilical vein endothelial cell (HUVEC) migration. In vivo studies showed that these particles rapidly stimulated innate immune responses in animal models, leading to enhanced angiogenesis around the implant and improved osseointegration. In summary, the presence of bacteroid cerium oxide particles on the implant surface regulated and accelerated macrophage polarization, thereby enhancing angiogenesis during the immune response and improving peri-implant osseointegration.

Icaritin Sensitizes Thrombin- and TxA2-Induced Platelet Activation and Promotes Hemostasis via Enhancing PLCγ2-PKC Signaling Pathways.

BACKGROUND: Vascular injury results in uncontrollable hemorrhage in hemorrhagic diseases and excessive antithrombotic therapy. Safe and efficient hemostatic agents which can be orally administered are urgently needed. Platelets play indispensable roles in hemostasis, but there is no drug exerting hemostatic effects through enhancing platelet function. METHODS: The regulatory effects of icaritin, a natural compound isolated from Herba Epimedii, on the dense granule release, thromboxane A2 (TxA2) synthesis, α-granule release, activation of integrin αIIbß3, and aggregation of platelets induced by multiple agonists were investigated. The effects of icaritin on tail vein bleeding times of warfarin-treated mice were also evaluated. Furthermore, we investigated the underlying mechanisms by which icaritin exerted its pharmacological effects. RESULTS: Icaritin alone did not activate platelets, but significantly potentiated the dense granule release, α-granule release, activation of integrin αIIbß3, and aggregation of platelets induced by thrombin and U46619. Icaritin also shortened tail vein bleeding times of mice treated with warfarin. In addition, phosphorylated proteome analysis, immunoblotting analysis, and pharmacological research revealed that icaritin sensitized the activation of phospholipase Cγ2 (PLCγ2)-protein kinase C (PKC) signaling pathways, which play important roles in platelet activation. CONCLUSION: Icaritin can sensitize platelet activation induced by thrombin and TxA2 through enhancing the activation of PLCγ2-PKC signaling pathways and promote hemostasis, and has potential to be developed into a novel orally deliverable therapeutic agent for hemorrhages.

A polypeptide derived from pilose antler ameliorates CUMS-induced depression-like behavior by SENP2-PLCß4 signaling axis.

Neurogenesis is known to be closely associated with depression. We aimed to investigate whether a polypeptide monomer derived from pilose antler (polypeptide sequence LSALEGVFYP, PAP) exerts an antidepressant effect by influencing neurogenesis, and to elucidate the mechanism of its antidepressant action. Behavioral tests were performed to observe the antidepressant effect of PAP. Neurogenesis in the dentate gyrus (DG) region of hippocampus was observed by immunofluorescence. The expression of key proteins of Sentrin/SUMO-specific proteases 2 (SENP2)- Phosphoinositide-specific phospholipase C beta 4 (PLCß4) pathway was accessed by co-immunoprecipitation (Co-IP), and the calcium homeostasis associated proteins were observed via Western blot (WB). Subsequently, temozolomide (TMZ) pharmacologically blocked neurogenesis to verify the antidepressant effect of PAP on neurogenesis. The mechanism of PAP antidepressant effect was verified by constructing a sh-SENP2 virus vector to silence SENP2 protein. Finally, corticosterone (CORT)-induced PC12 cell model was used to verify whether PAP was involved in the process of deconjugated PLCß4 SUMOylated. The results showed that PAP improved depression-like behavior and neurogenesis induced by chronic unpredictable mild stimulation (CUMS). In addition, PAP acted on SENP2-PLCß4 pathway to deconjugate the SUMOylation of PLCß4 and affect calcium homeostasis. Pharmacological blockade of neurogenesis by TMZ treatment impaired the antidepressant efficacy of PAP. Knockout of SENP2 in the CUMS model attenuated the antidepressant response of PAP, and the impaired neurogenesis was not ameliorated by PAP treatment. In summary, PAP acted on the SENP2-PLCß4 signaling pathway to inhibit the SUMOylation of PLCß4 and maintain calcium homeostasis, thereby protecting neurogenesis and playing an antidepressant role.

Seven new 3,4-dihydro-furanocoumarin derivatives from Angelica dahurica.

Objective: To study the chemical constituents of the roots of Angelica dahurica, a well-known Chinese herbal medicine named Baizhi in Chinese. Methods: Compounds were separated by various chromatographies, and the structures of new compounds were elucidated based on the analysis of their spectroscopic and spectrometric data (1D, 2D NMR, HRESI MS, IR, and UV). The absolute configurations of new compounds were determined by the calculated electronic circular dichroism and chemical derivatization. The inhibitory activities of all isolates against nitric oxide (NO) production were evaluated using lipopolysaccharide-activated RAW 264.7 macrophage cells. Results: Seven new 3,4-dihydro-furanocoumarin derivatives (1a/1b, 2a/2b, 3a/3b, 4) together with a known furanocoumarin (5) were isolated from the roots of A. dahurica. The new compounds included three pairs of enantiomers, (4S, 2''R)-angelicadin A (1a)/(4R, 2''S)-angelicadin A (1b), (4S, 2''S)-angelicadin A (2a)/(4R, 2''R)-angelicadin A (2b), and (4S, 2''S)-secoangelicadin A (3a)/(4R, 2''R)-secoangelicadin A (3b), together with (4R, 2''R)-secoangelicadin A methyl ester (4). The known xanthotoxol (5) inhibited the NO production with the half-maximal inhibitory concentration (IC50) value of (32.8 ± 0.8) µmol/L, but all the new compounds showed no inhibitory activities at the concentration of 100 µmol/L. Conclusion: This is the first report of the discovery of 3,4-dihydro-furanocoumarins from A. dahurica. The results are not only meaningful for the understanding of the chemical constituents of A. dahurica, but also enrich the reservoir of natural products.

[Potentiating effect and mechanism of extract of Jingfang Granules on activation of macrophages].

This study aimed to explore the potentiating effect and mechanism of the extract of Jingfang Granules(JFG) on the activation of macrophages. The RAW264.7 cells were treated with JFG extract and then stimulated by multiple agents. Subsequently, mRNA was extracted, and reverse transcription-polymerase chain reaction(RT-PCR) was used to measure the mRNA transcription of multiple cytokines in RAW264.7 cells. The levels of cytokines in the cell supernatant were detected by enzyme-linked immunosorbent assay(ELISA). In addition, the intracellular proteins were extracted and the activation of signaling pathways was determined by Western blot. The results showed that JFG extract alone could not promote or slightly promote the mRNA transcription of TNF-α, IL-6, IL-1ß, MIP-1α, MCP-1, CCL5, IP-10, and IFN-ß, and significantly enhance the mRNA transcription of these cytokines in RAW264.7 cells induced by R848 and CpG in a dose-dependent manner. Furthermore, JFG extract also potentiated the secretion of TNF-α, IL-6, MCP-1, and IFN-ß by RAW264.7 cells stimulated with R848 and CpG. As revealed by mechanism analysis, JFG extract enhanced the phosphorylation of p38, ERK1/2, IRF3, STAT1, and STAT3 in RAW264.7 cells induced by CpG. The findings of this study indicate that JFG extract can selectively potentiate the activation of macrophages induced by R848 and CpG, which may be attributed to the promotion of the activation of MAPKs, IRF3, and STAT1/3 signaling pathways.

Modulating the Performance of the SAW Strain Sensor Based on Dual-Port Resonator Using FEM Simulation.

Surface acoustic wave (SAW) strain sensors fabricated on piezoelectric substrates have attracted considerable attention due to their attractive features such as passive wireless sensing ability, simple signal processing, high sensitivity, compact size and robustness. To meet the needs of various functioning situations, it is desirable to identify the factors that affect the performance of the SAW devices. In this work, we perform a simulation study on Rayleigh surface acoustic wave (RSAW) based on a stacked Al/LiNbO3 system. A SAW strain sensor with a dual-port resonator was modeled using multiphysics finite element model (FEM) method. While FEM has been widely used for numerical calculations of SAW devices, most of the simulation works mainly focus on SAW modes, SAW propagation characteristics and electromechanical coupling coefficients. Herein, we propose a systematic scheme via analyzing the structural parameters of SAW resonators. Evolution of RSAW eigenfrequency, insertion loss (IL), quality factor (Q) and strain transfer rate with different structural parameters are elaborated by FEM simulations. Compared with the reported experimental results, the relative errors of RSAW eigenfrequency and IL are about 3% and 16.3%, respectively, and the absolute errors are 5.8 MHz and 1.63 dB (the corresponding Vout/Vin is only 6.6%). After structural optimization, the obtained resonator Q increases by 15%, IL decreases by 34.6% and the strain transfer rate increases by 2.4%. This work provides a systematic and reliable solution for the structural optimization of dual-port SAW resonators.

Zuojinwan ameliorates CUMS-induced depressive-like behavior through inducing ubiquitination of MyD88 via SPOP/MyD88/NF-κB pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zuojinwan (ZJW) is a traditional Chinese medicine compound, which is often used clinically to treat gastritis and has anti-inflammatory activity. It was found that ZJW is involved in suppressing the expression of inflammatory factors, and neuroinflammation is thought to be associated with the development of depression. AIM OF THE STUDY: In this study, we investigated whether ZJW could exert antidepressant effects by regulating MyD88 ubiquitination in depressed mice and attempted to elucidate the possible mechanisms. MATERIALS AND METHODS: Six active compounds of Zuojinwan (ZJW) were identified by HPLC. Then, the effects of ZJW on depression-like behavior in mice were investigated by constructing a chronic unpredictable mild stimulation (CUMS) mouse model. Meanwhile, the effect of ZJW on hippocampal neurons was investigated by Nissl staining. In addition, western blotting, PCR, ELISA, co-immunoprecipitation and immunostaining were used to explore whether ZJW could inhibit neuroinflammation through SPOP/MyD88/NF-κB pathway and thus produce antidepressant effects. Finally, we constructed the AAV-Sh-SPOP virus vector to silence SPOP and verify the mechanism of ZJW's antidepressant action. RESULTS: ZJW could dramatically ameliorate the depressive behavior induced by CUMS stimulation and alleviate hippocampal neuronal damage. CUMS stimulation resulted in decreased SPOP expression, impaired MyD88 ubiquitination, and activation of downstream NF-κB signaling, which could be reversed by ZJW. In addition, ZJW could significantly ameliorate the abnormal activation of microglia, and the excessive levels of pro-inflammatory factors were inhibited. By blocking the expression of SPOP, we found that ZJW exerted anti-inflammatory and antidepressant effects mainly by promoting the ubiquitination of MyD88 and inhibiting the activation of downstream inflammatory signals. CONCLUSION: In conclusion, ZJW possesses alleviating effects on depression induced by CUMS stimulation. ZJW can inhibit neuroinflammation and improve neuroinflammation-induced depression-like behaviors through SPOP/MyD88/NF-κB pathway.

Signal Suppression in LC-ESI-MS/MS from Concomitant Medications and Its Impact on Quantitative Studies: An Example Using Metformin and Glyburide.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been widely used in the quantitative analysis of drugs. The ubiquitous concomitant drug scenario in the clinic has spawned a large number of co-analyses based on this technique. However, signal suppression caused by concomitant drugs during electrospray ionization may affect the quantification accuracy of analytes, which has not received enough attention. In this study, metformin (MET) and glyburide (GLY) were co-eluted by the conventional optimization of chromatographic conditions to illustrate the effect of signal suppression caused by the combined drugs on the quantitative analysis. The response of MET was not affected by GLY over the investigated concentration range. However, the GLY signal could be suppressed by about 30% in the presence of MET, affecting its pharmacokinetic analysis in simulated samples. As an attempt to solve the suppression of GLY by co-eluting MET, dilution can alleviate the suppression. However, this method still has limitations due to the sacrifice of sensitivity. The stable isotope-labeled internal standard could play a role in correction and improve the quantitative accuracy of GLY, which was further confirmed in the pharmacokinetic study of simulated samples. This study provided an example model to illustrate the possible effect of clinical drug combination on LC-MS/MS drug quantitative analysis and investigated the effective methods to solve this problem.

Synthesis of benzo[b][1,5]diazocin-6(5H)-one derivatives via the Cu-catalysed oxidative cyclization of 2-aryl-1H-indoles with 1,1-enediamines.

A novel protocol for the synthesis of highly functionalized benzo[b][1,5]diazocin-6(5H)-one derivatives (BDCOs, 4 and 5) from 2-aryl-1H-indoles and 1,1-enediamines was developed via a complex cascade of reactions including regioselective free radical oxidation, the 1,2-addition of imine, imine-enamine tautomerization, intramolecular cyclization, and ring expansion. The cascade reaction was enabled by refluxing a mixture of two substrates in the presence of di-tert-butyl peroxide (DTBP) as an oxidant and anhydrous CuI as a catalyst in toluene under argon protection. Consequently, a series of BDCOs (4 and 5) were synthesized with high regioselectivity in good yield. This protocol can be used for the synthesis of functionalized BDCOs via a one-pot oxidative annulation reaction rather than a multi-step reaction, which is suitable for both combinatorial and parallel syntheses of BDCOs.

Potency of olorofim (F901318) compared to contemporary antifungal agents against clinical Aspergillus fumigatus isolates, and review of azole resistance phenotype and genotype epidemiology in China.

Triazole resistance in A. fumigatus is an increasing worldwide problem that causes major challenges in the management of aspergillosis. New antifungal drugs are needed with novel targets, that are effective in triazole-resistant infection. In this study, we retrospectively evaluated potency of the novel drug olorofim compared to contemporary antifungal agents against 111 clinical A. fumigatus isolates collected from Huashan Hospital, Shanghai, China, using EUCAST methodology, and reviewed the literature on triazole resistant A. fumigatus published between 1966 and 2020 in China. Olorofim was active in vitro against all tested A. fumigatus isolates with MIC90 of 0.031mg/L (range 0.008-0.062 mg/L). For 4 triazole-resistant A. fumigatus (TRAF) isolates, the olorofim MIC ranged between 0.016-0.062mg/L. The reported rates of TRAF in China is 2.5% - 5.56% for clinical isolates, and 0-1.4% for environmental isolates.TR34/L98H/S297T/F495I is the predominant resistance mechanism, followed by TR34/L98H. Non TR-mediated TRAF isolates, mostly harboring a cyp51A single point mutation, showed greater genetic diversity than TR-mediated resistant isolates. Resistance due toTR34/L98H and TR34/L98H/S297T/F495I mutations among TRAF isolates might have evolved from separate local isolates in China. Continuous isolation of TRAF in China underscores the need for systematic resistance surveillance as well as the need for novel drug targets such as olorofim.

Anti-inflammatory flavonoid derivatives from the heartwood of Dalbergia odorifera T. Chen.

Two pairs of flavonoid enantiomers (1a/1b and 2a/2b) together with three known analogues (3-5) were isolated from the heartwood of Dalbergia odorifera T. Chen. Their structures were elucidated by extensive spectroscopic analysis (1 D and 2 D NMR, UV, IR, and HRMS) and experimental and calculated ECD data. Compound 2 features an unusual 2-methyl-3(2H)-furanone moiety forming the C-ring of flavonoid, and its putative biosynthetic pathway is also proposed. Compounds 3‒5 exhibited significant inhibition of nitric oxide production in lipopolysaccharide-stimulated RAW264.7 cells with IC50 values of 14.7 ± 0.3 µM, 40.2 ± 1.1 µM, and 3.2 ± 0.1 µM, respectively.

Simultaneous absolute protein quantification of seven cytochrome P450 isoforms in rat liver microsomes by LC-MS/MS-based isotope internal standard method.

The cytochrome P450 (CYP) enzymes play a pivotal role in drug metabolism. LC-MS/MS-based targeting technology has been applied to the analysis of CYP enzymes, promoting drug development and drug-drug interaction studies. Rat is one of the most commonly used models for drug metabolism assessment, but LC-MS/MS assay quantifying the abundance of CYP enzymes in rats is rarely reported. Herein, an accurate and stable LC-MS/MS based method was developed and validated for the simultaneous quantification of seven major rat CYP isoforms (CYP1A2, 2B1, 2C6, 2C11, 2D1, 2E1, and 3A1) in liver microsomes. The careful optimization of trypsin digestion and chromatography combined with isotope-labeled peptide as internal standard improved the efficiency and accuracy of the analysis. Highly specific surrogate peptides were obtained by a procedure including trypsin digestion for six hours and separated on a Hypersil Gold C18 column (100 × 2.1 mm, 3 µm) using gradient elution for 15 min with a mobile phase of water containing 0.1% formic acid and acetonitrile. In the method validation, linearity, matrix effect, recovery, stability, accuracy, and precision all meet the requirements. Subsequently, this method was applied to detect seven enzymes in rat liver microsomes from four different sources, and the correlation between the abundance and activity of CYP enzymes was further analyzed. The high-throughput detection method provided in this study will provide support for pertinent pharmaceutical research based on rat models.

Cu-Catalyzed decarboxylative annulation of N-substituted glycines with 3-formylchromones: synthesis of functionalized chromeno[2,3-b]pyrrol-4(1H)-ones.

A novel protocol was developed for preparing functionalized chromeno[2,3-b]pyrrol-4(1H)-ones 3 (CMPOs) from 3-formylchromones with N-substituted glycine derivatives. The method entailed decarboxylative annulation of the acyl group of 3-formylchromones by simply heating a mixture of substrates 1-2 and toluene oxidized by 2-di-tert-butyl peroxide (DTBP) and catalyzed by CuBr. As a result, a series of CMPOs 3 were produced via a cascade reaction. This protocol can be used to synthesize functionalized CMPOs via combinatorial and parallel syntheses in a one-pot reaction rather than a tedious multi-step reaction.

Equilibration for Electrospray Ionization Mass Spectrometry in Quantitative Analysis.

Electrospray ionization mass spectrometry (ESI-MS) is widely used in drug development, therapeutic drug monitoring, and other fields. However, unstable mass spectral signals, especially during the initial stages of instrument operation, plague analysts. Generally, in quantitative experiments, the stability of response can be achieved by running the analytical system for some time. However, the equilibration time required for the responses of different compounds to stabilize has been elusive. To investigate the response stability of the ESI-MS system, 72 compounds with different physicochemical properties were employed on three systems, and flow injection analysis was performed in positive ion mode. With the use of 5.00% (response stable factor, RSF) as the stability limit, about 80% of the compounds were stable within 60 min. Under a 2.00% criterion, the stabilization time was significantly longer. The stabilization time varies with different instruments and physicochemical properties of the compounds. When positive ion detection is performed in an acidic mobile phase, the octanol-water partition coefficient (Log P), molecular weight, and molar volume can all affect the time required to stabilize the response. In general, it is necessary to balance the ESI-MS system for an appropriate time before sample detection, especially for the analysis of compounds with strong hydrophilicity, small molecular weight, or small molar volume under the conditions above.

An Environmentally Benign Multicomponent Cascade Reaction of 3-Formylchromones, 2-Naphthols, and Heterocyclic Ketal Aminals: Site-Selective Synthesis of Functionalized Morphan Derivatives.

A novel protocol has been developed for the preparation of highly functionalized 2-azabicyclo[3.3.1]nonane (morphan) derivatives by the interesting three-component cascade reaction of 3-formylchromones, 2-naphthol, and heterocyclic ketal aminals (HKAs) in the ionic liquid [BMIM]PF6 promoted by the organic base Et3N. A complex cascade reaction is required, which includes a 1,2-addition, two Michael reactions, two tautomerizations, and an N-alkylation accompanied by a ring-opening reaction and involving the cleavage of one C-O bond and the formation of four bonds (one C-N bond, one C-O bond, and two C-C bonds). As a result, functionalized morphans (5 and 6) bearing naphthalene-structured skeletons were prepared by simple heating of a mixture of 3-formylchromones, 2-naphthols, and HKAs in the environmentally friendly ionic liquid [BMIM]PF6. This protocol can be used in the synthesis of various morphans and is suitable for combinatorial and parallel syntheses of natural-like morphan derivatives. This approach has several advantages such as the use of an environmentally friendly solvent, simple and practical operation (multicomponent one-pot reaction), and satisfactory yields (65-88%).