Regulation of PGC-1α of the Mitochondrial Energy Metabolism Pathway in the Gills of Indian Medaka (Oryzias dancena) under Hypothermal Stress.

Ectothermic fish exposure to hypothermal stress requires adjusting their metabolic molecular machinery, which was investigated using Indian medaka (Oryzias dancena; 10 weeks old, 2.5 ± 0.5 cm) cultured in fresh water (FW) and seawater (SW; 35‱) at room temperature (28 ± 1 °C). The fish were fed twice a day, once in the morning and once in the evening, and the photoperiod was 12 h:12 h light: dark. In this study, we applied two hypothermal treatments to reveal the mechanisms of energy metabolism via pgc-1α regulation in the gills of Indian medaka; cold-stress (18 °C) and cold-tolerance (extreme cold; 15 °C). The branchial ATP content was significantly higher in the cold-stress group, but not in the cold-tolerance group. In FW- and SW-acclimated medaka, the expression of genes related to mitochondrial energy metabolism, including pgc-1α, prc, Nrf2, tfam, and nd5, was analyzed to illustrate differential responses of mitochondrial energy metabolism to cold-stress and cold-tolerance environments. When exposed to cold-stress, the relative mRNA expression of pgc-1α, prc, and Nrf2 increased from 2 h, whereas that of tfam and nd5 increased significantly from 168 h. When exposed to a cold-tolerant environment, prc was significantly upregulated at 2 h post-cooling in the FW and SW groups, and pgc-1α was significantly upregulated at 2 and 12 h post-cooling in the FW group, while tfam and nd5 were downregulated in both FW and SW fish. Hierarchical clustering revealed gene interactions in the cold-stress group, which promoted diverse mitochondrial energy adaptations, causing an increase in ATP production. However, the cold-tolerant group demonstrated limitations in enhancing ATP levels through mitochondrial regulation via the PGC-1α energy metabolism pathway. These findings suggest that ectothermic fish may develop varying degrees of thermal tolerance over time in response to climate change. This study provides insights into the complex ways in which fish adjust their metabolism when exposed to cold stress, contributing to our knowledge of how they adapt.

Discovery of new DHA ethanolamine derivatives as potential anti-inflammatory agents targeting Nur77.

Docosahexaenoic acid (DHA) has a strong anti-inflammatory effect and is reported to bind to the ligand-binding domain (LBD) of the anti-inflammatory modulator Nur77. Recently, we have found that DHA ethanolamine (DHA-EA) exerts anti-inflammatory activity as a Nur77 modulator. Herein, using a fragment splicing-based drug design strategy, nineteen new DHA-EA derivatives were synthesized starting from DHA algae oil and then evaluated for their anti-inflammatory activity. The cell-based cytotoxicity assays showed that compounds J2, J9, and J18 had no noticeable effect on the cell morphology and viability of RAW 264.7, LO2, and MCR-5 cells. Meanwhile, J9 was identified as the most potent anti-inflammatory molecule in LPS-stimulated RAW 264.7 cells. Also, the molecular docking study and SPR assay demonstrated that J9 exhibited in vitro Nur77-binding affinity (KD = 8.58 × 10-6 M). Moreover, the mechanism studies revealed that the anti-inflammatory activity of J9 was associated with its inhibition of NF-κB activation in a Nur77-dependent manner. Notably, J9 could attenuate LPS-induced inflammation in the mouse acute lung injury (ALI) model. Overall, the DHA-EA derivative J9 targeting Nur77 is a potential candidate for developing anti-inflammatory and ALI-treating agents.

Development of a Pure Certified Reference Material of D-Mannitol.

A new certified reference material (CRM) of D-mannitol (GBW(E) 100681) has been developed in this study. We describe the preparation, structure determination, characterization, homogeneity study, stability study, as well as uncertainty estimation. The main component was 99.91% ± 0.01%. The moisture content of the candidate CRM was 0.036% ± 0.002%, as measured by Karl Fischer titration. The nonvolatile and volatile impurities in the candidate CRM were all much less than 0.01%, which was determined by the ICP-MS and headspace GC-FID methods, respectively. The purity of the D-mannitol CRM was 99.9% ± 1.1% (k = 2), as measured by the two independent approaches involving the mass balance method (MB) and quantitative nuclear magnetic resonance technique (qNMR). The D-mannitol CRM was stable during the monitoring period for each temperature. It is stable for up to 48 months at room temperature and 28 days at 50 °C. The uncertainty was evaluated by combining the contributions from characterization, homogeneity, and stability. The developed D-mannitol CRM would effectively support method validation and proficiency testing, as well as effectively guarantee the accuracy, reliability, and comparability of results.

Umami taste evaluation based on a novel mouse taste receptor cell-based biosensor.

Umami, a taste sensation known for its savory and delicious properties, has garnered considerable attention from both consumers and the food industry. However, current understanding and evaluation of umami characteristics remain limited, presenting a long-standing issue. To address this challenge, we have developed a self-assembled biosensor based on matured taste receptor cells (TRCs), obtained through isolation and culture of taste stem cells. TRCs, as the recognition element, were mounted onto the surface of a glassy carbon electrode (GCE) treated with gold nanoparticles (AuNPs) and poly-L-lysine (PLL). Key parameters including the cell incubation time and concentration were optimized to ensure the optimal performance of the TRCs-based biosensor. AuNPs were deposited onto the GCE surface via 90 s electrochemical reduction. TRCs concentration of 106 cells/mL and incubation time of 12 h were chosen by electrochemical characterization. Using this novel, rapid, and sensitive TRCs-based biosensor, we successfully detected L-monosodium glutamate (MSG) and other umami substances, demonstrating a good linear relationship within the range of 10-9 - 10-5 M between response signals and concentration of MSG stimuli. Our results provide insights into taste signal transduction mechanisms and suggest the potential for biomimetic sensors in intelligent perception applications.

Effects of fatty acid-ethanol amine (FA-EA) derivatives on lipid accumulation and inflammation.

This study aimed to investigate the effect of fatty acid-ethanol amine (FA-EA) derivatives (L1-L10) on the mitigation of intracellular lipid accumulation and downregulation of pro-inflammatory cytokines in vitro. First, the series of FA-EA derivatives were synthesized and characterized. Then, their cytotoxic, intracellular lipid accumulation and inhibition of pro-inflammatory cytokines were evaluated. The oil red O staining experiment showed that the tested compounds L4, L6, L8, L9, and L10 could reduce intracellular lipid accumulation induced by palmitic acid (PA). Moreover, ω-3/ω-6 PUFA-EA derivatives showed inhibitory effect on the production of pro-inflammatory cytokines in lipopolysaccharide (LPS) -stimulated RAW 264.7 cells. ω-3/ω-6 PUFA-EA derivatives at a concentrations of 10 µM could significantly decrease mRNA levels of IL-6, IL-1ß, and TNF-α, inhibit NO production, and alleviate the protein expression of IL-1ß in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. These data suggest that ω-3 PUFA-EA derivatives can be beneficial for further pharmaceutical development to treat chronic low-grade inflammation diseases such as obesity.

Comparison of UV and UV-LED activated sodium percarbonate for the degradation of O-desmethylvenlafaxine.

As an active metabolite of venlafaxine and emerging antidepressant, O-desmethylvenlafaxine (ODVEN) was widely detected in different water bodies, which caused potential harm to human health and environmental safety. In this study, the comparative work on the ODVEN degradation by UV (254 nm) and UV-LED (275 nm) activated sodium percarbonate (SPC) systems was systematically performed. The higher removal rate of ODVEN can be achieved under UV-LED direct photolysis (14.99%) than UV direct photolysis (4.57%) due to the higher values of photolysis coefficient at the wavelength 275 nm. Significant synergistic effects were observed in the UV/SPC (80.38%) and UV-LED/SPC (53.57%) systems and the former exhibited better performance for the elimination of ODVEN. The degradation of ODVEN all followed the pseudo-first-order kinetics well in these processes, and the pseudo-first-order rate constant (kobs) increased with increasing SPC concentration. Radicals quenching experiments demonstrated that both ·OH and CO3·- were involved in the degradation of ODVEN and the second-order rate constant of ODVEN with CO3·- (1.58 × 108 (mol/L)-1 sec-1) was reported for the first time based on competitive kinetic method. The introduction of HA, Cl-, NO3- and HCO3- inhibited the ODVEN degradation to varying degrees in the both processes. According to quantum chemical calculation, radical addition at the ortho-position of the phenolic hydroxyl group was confirmed to be the main reaction pathways for the oxidation of ODVEN by ·OH. In addition, the oxidation of ODVEN may involve the demethylation, H-abstraction, OH-addition and C-N bond cleavage. Eventually, the UV-LED/SPC process was considered to be more cost-effective compared to the UV/SPC process, although the UV/SPC process possessed a higher removal rate of ODVEN.

Efficient Preparation of High-Purity Fucoxanthinol by SpyTag-Tailored Active Cholesterol Esterase Aggregates.

A novel approach to producing high-purity fucoxanthinol (FXOH) was exploited as a sustainable method to maximize fucoxanthin (FX) utilization. Through fusing the genes of cholesterol esterase and SpyTag and then expressing them in Escherichia coli, the fusion chimera was self-assembled into insoluble active aggregates by SpyTag, which could be regarded as carrier-free immobilization. The immobilization yield of the active cholesterol esterase aggregates could reach 60%. They have expressed good activity retention at 92.48% and 60.13% after 3 and 12 cycles, respectively, which is an exciting finding. The conversion ratio of FX to FXOH is 95.02%, which is remarkably higher than those realized via the conventional chemical reduction method (55.86%) and the enzymatic hydrolysis method by free cholesterol esterases (84.51%). The purity of FXOH obtained by this method is as high as 98%, which is much higher than those obtained by other methods. Thus, a promising method for simultaneously purifying and immobilizing active cholesterol esterase aggregates is demonstrated in this study by SpyTag tailoring. In addition, this study provides an eco-friendly method for producing high-purity FXOH from FX in a highly efficient manner.

Development of certified reference materials for four polyunsaturated fatty acid esters.

Certified reference materials (CRMs) with high accuracy and traceability are essential tools for the validation of analytical methods and calibration of equipment. In this study, purity CRMs for four polyunsaturated fatty acids (PUFAs) esters, namely, cis-(4,7,10,13,16,19)- Docosahexaenoic acid methyl ester (DHA-ME), cis-4,7,10,13,16,19- Docosahexaenoic acid ethyl ester (DHA-EE), cis-(5,8,11,14,17)- Eicosapentaenoic acid methyl ester (EPA-ME) and cis-(5,8,11,14,17)- Eicosapentaenoic acid ethyl ester (EPA-EE), were first developed according to the ISO Guide. The CRMs' purity values were assigned based on the average of quantitative nuclear magnetic resonance and mass balance approaches. The certified value with expanded uncertainties (k = 2, 95% confidence interval) were determined to be (98.8 ± 0.4) %, (99.0 ± 0.3) %, (98.9 ± 0.4) % and (98.9 ± 0.4) % for DHA-ME, DHA-EE, EPA-ME and EPA-EE, respectively. The four PUFAs esters were homogeneous and stable for 12 months at -4 °C and 7 days at 50 °C.

Fucoxanthin Loaded in Palm Stearin- and Cholesterol-Based Solid Lipid Nanoparticle-Microcapsules, with Improved Stability and Bioavailability In Vivo.

Fucoxanthin (FX) is a marine carotenoid that has proven to be a promising marine drug due to the multiple bioactivities it possesses. However, the instability and poor bioavailability of FX greatly limit its application in pharmaceuticals or functional foods. In this study, the creative construction of a solid lipid nanoparticle-microcapsule delivery system using mixed lipids of palm stearin and cholesterol wrapped with gelatin/Arabic gum to load lipophilic FX was fabricated, aiming to improve the stability and bioavailability of FX. The results showed that the encapsulated efficiency (EE) and drug loading capacity (LC) of optimized FX microcapsules (FX-MCs) obtained were as high as 96.24 ± 4.60% and 0.85 ± 0.04%, respectively, after single-factor experiments. The average particle size was 1154 ± 54 nm with negative Zeta potential (-20.71 ± 0.93 mV) as depicted with size-zeta potential spectrometer. The differential scanning calorimeter (DSC) and thermogravimetric analyzer (TG) results indicated that FX-MC has a higher Tg and slower weight loss than FX monomers (FX crystal) and blank MCs. Besides, The Fourier transform infrared spectrometer (FTIR) confirmed the good double encapsulation of FX into the solid lipid and composite coacervate. Moreover, the encapsulated FX showed higher storage stability, sustained release (55.02 ± 2.80% release in 8 h), and significantly improved bioavailability (712.33%) when compared to free FX. The research results can provide a principle theoretical basis for the development and application of FX in pharmaceuticals or functional foods.

Synthesis and discovery of ω-3 polyunsaturated fatty acid- alkanolamine (PUFA-AA) derivatives as anti-inflammatory agents targeting Nur77.

In this work, three series of ω-3 polyunsaturated fatty acid-alkanolamine derivatives (PUFA-AAs) were synthesized, characterized and their anti-inflammatory activity in vivo was evaluated. Compounds 4a, 4f, and 4k exhibited marked anti-inflammatory activity in LPS-stimulated RAW 264.7 cells. The most promising compound 4k dose-dependently suppressed the cytokines with IC50 values in the low micromolar range. Further, 4k exhibited potential in vitro Nur77-binding affinity (Kd = 6.99 × 10-6 M) which is consistent with the result of docking studies. Next, the anti-inflammatory mechanism of 4k was found to be through NF-κB signal pathway in a Nur77-dependent manner. Moreover, we also observed 4k significantly inhibited LPS-induced expression of cytokines (IL-6, TNF-α, and IL-1ß) through suppressing NF-κB activation and attenuated LPS-induced inflammation in mouse acute lung injury (ALI) model. In conclusion, the study strongly suggests that the PUFA-AA derivatives can be particularly as new Nur77 mediators for further treatment in inflammatory diseases.

Development and validation of a specific and sensitive liquid chromatography tandem mass spectrometry method for determination of tetrodotoxin in human urine and its pharmacokinetic study.

Tetrodotoxin (TTX) exhibits the therapeutic potential in blocking pain and in low doses can safely relieve severe pain. The urinary excretion profiles of TTX in humans have not been reported due to the extremely low lethal dose. In this study, a rapid and specific method based on protein precipitation coupled to liquid chromatography tandem mass spectrometry was developed to determine the level of TTX in human urine samples. 11-Deoxytetrodotoxin was used as an internal standard (IS). Multiple reaction monitoring mode was used for quantification using target fragment ions m/z 320.0 → 162.1 for TTX and m/z 304.0 → 176.0 for 11-deoxyTTX. The separation of analytes was achieved on a hydrophilic interaction liquid chromatography column (250 × 4.6 mm, 5.0 µm). The mobile phase consisted of 5 mM ammonium formate in water (pH = 4.50) and 5 mM ammonium formate in acetonitrile (pH = 4.50). The flow rate was set at 0.80 mL/min in a gradient condition. Calibration plots were linear throughout the range 0.986-98.6 ng/mL of TTX in human urine. The intra-assay accuracies and precisions were within the acceptable range. The method was successfully applied to a urinary excretion study after intravenous administration of TTX to healthy volunteers. The developed method will be helpful for future pharmacological studies of TTX.

Anti-Inflammatory Effects of Fucoxanthinol in LPS-Induced RAW264.7 Cells through the NAAA-PEA Pathway.

Palmitoylethanolamide (PEA) is an endogenous lipid mediator with powerful anti-inflammatory and analgesic functions. PEA can be hydrolyzed by a lysosomal enzyme N-acylethanolamine acid amidase (NAAA), which is highly expressed in macrophages and other immune cells. The pharmacological inhibition of NAAA activity is a potential therapeutic strategy for inflammation-related diseases. Fucoxanthinol (FXOH) is a marine carotenoid from brown seaweeds with various beneficial effects. However, the anti-inflammatory effects and mechanism of action of FXOH in lipopolysaccharide (LPS)-stimulated macrophages remain unclear. This study aimed to explore the role of FXOH in the NAAA-PEA pathway and the anti-inflammatory effects based on this mechanism. In vitro results showed that FXOH can directly bind to the active site of NAAA protein and specifically inhibit the activity of NAAA enzyme. In an LPS-induced inflammatory model in macrophages, FXOH pretreatment significantly reversed the LPS-induced downregulation of PEA levels. FXOH also substantially attenuated the mRNA expression of inflammatory factors, including inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and markedly reduced the production of TNF-α, IL-6, IL-1ß, and nitric oxide (NO). Moreover, the inhibitory effect of FXOH on NO induction was significantly abolished by the peroxisome proliferator-activated receptor α (PPAR-α) inhibitor GW6471. All these findings demonstrated that FXOH can prevent LPS-induced inflammation in macrophages, and its mechanisms may be associated with the regulation of the NAAA-PEA-PPAR-α pathway.

Comparison of acetaminophen degradation in UV-LED-based advance oxidation processes: Reaction kinetics, radicals contribution, degradation pathways and acute toxicity assessment.

Ultraviolet light emitting diode (UV-LED)-based advanced oxidation processes (AOPs) including UV-LED/chloramine (UV-LED/NH2Cl), UV-LED/hydrogen peroxide (UV-LED/H2O2) and UV-LED/persulfate (UV-LED/PS), were adopted for acetaminophen (AAP) removal. Results showed that AAP could be effectively degraded by the hybrid processes compared to solely using with UV irradiation and oxidants. The AAP degradation in the three UV-LED-based AOPs were in the order of UV-LED/PS > UV-LED/H2O2 > UV-LED/NH2Cl and followed a pseudo-first-order kinetics. The degradation rate constant (kobs) increased with increasing oxidant dosage, whereas overdosing lowered the AAP degradation. The second-order rate constants of HO, SO4-, and Cl with AAP were calculated as 5.15 × 109, 7.66 × 109 and 1.08 × 1010 M-1 s-1, respectively. Under neutral conditions, the contributions of UV-LED, HO, and Cl to AAP degradation were 4.21%, 60.15% and 35.64% in the UV-LED/NH2Cl system, whereas the respective contributions of UV-LED, HO and SO4- to AAP degradation were 2.09%, 22.84% and 75.07% in UV-LED/PS system, respectively. Meanwhile, the corresponding contributions of the involved reactive species were found to be pH-dependence. The natural organic materials (NOM) inhibited the AAP degradation, and the presence of Cl-, HCO3-, and NO3- had different effects on AAP degradation in the three hybrid processes. The AAP degradation was significantly inhibited in the three UV-LED-based AOPs in real water. In addition, the intermediate products were also identified, and possible degradation pathways were proposed in the three UV-LED-based AOPs. The acute toxicity bioassay using bacterium Vibrio fischeri suggested that the UV-LED/PS process was more effective than the UV-LED/H2O2 and UV-LED/NH2Cl processes in reducing the acute toxicity of the reacted AAP solution. Among the three UV-LED-based AOPs, the UV-LED/PS was found to be the most efficient process for AAP degradation.

Analgesia Effect of Enteric Sustained-Release Tetrodotoxin Pellets in the Rat.

Tetrodotoxin (TTX) was identified as a latent neurotoxin that has a significant analgesia effect. It was rapidly absorbed and excreted in rat after intramuscular (i.m.) injection. To maintain the effect, frequent injections were required. The enteric sustained-release TTX pellets with sucrose pellets as a drug carrier was prepared by fluidized bed spray irrigation, coated in sequence with Eudragit NE30D as a sustained-release layer, hydroxypropyl methylcellulose (HPMC) as a barrier layer and Eudragit L30D-55 as an enteric coating. TTX in the pellets could be sustained released for 12 h in dissolution test. In vivo, TTX pellets reached Cmax at 5 h, and t1/2 was 14.52 ± 2.37 h after intragastrically (i.g.) administration in rat. In acetic acid induced writhing test in rat, the pellets at the dosages of 20, 40, 60 and 80 µg·kg-1 produced analgesic effect at about 1.5 h to 9 h and the strongest effect was at about 3 h to 6 h. Simultaneously, the LD50 of the enteric sustained-release TTX pellets was 840.13 µg·kg-1, and the ED50 was about 30 µg·kg-1. Thus, the therapeutic index was about 25. The enteric sustained-release TTX pellets with absolute analgesia effect and greatly enhanced safety was prepared.

Determination of fucoxanthinol in rat plasma by liquid chromatography-tandem mass spectrometry.

Previous studies have indicated that dietary fucoxanthin is mainly converted into fucoxanthinol (the deacetylated form) in mammals, but the pharmacokinetics of fucoxanthinol remains unknown. In this study, after intravenous (i.v.) and intragastric gavage (i.g.) administration of fucoxanthinol to rats at 0.8 and 20 mg/kg respectively, one-step protein precipitation with methanol was employed to prepared plasma samples, and an accurate and precise liquid chromatography-tandem mass spectroscopy (LC-MS/MS) method was developed to determine fucoxanthinol. Plasma samples were resolved by LC-MS/MS on a reverse-phase SB-C18 column equilibrated and eluted with acetonitrile (A, 0.1% formic acid) and water (B, 0.1% formic acid) (A:B = 92:8, v/v) at a flow rate of 0.5 mL/min and the injection volume was 5 µL. Analytes were monitored by Selected-reaction monitoring in positive electrospray ionization mode. The calibration curves for fucoxanthinol were linear over the range 1.17-300 ng/mL. The inter-day and intra-day accuracy and precision were within 1.55%-7.90%. The method was applied successfully in a pharmacokinetic study of fucoxanthinol and the resulting bioavailability was calculated.

Determination of trehalose by ion chromatography and its application to a pharmacokinetic study in rats after intramuscular injection.

An ion chromatography method was established for detecting trehalose in rat plasma. The samples were analyzed using a CPMA1 column (250 × 4.0 mm, Thermo) with 120 mm NaOH as eluent at a flow rate of 0.7 mL/min. The standard curve was y = 1.4316x - 0.0654 (R = 0.9992), and the linear range was 0.2-10 mg/L. The relative standard deviations of within-run and between-run precisions at low, medium and high concentrations were within 0.96-8.33%, and the accuracy was within 80.09-114.99%. The method was verified by rigorous methods, and applied to a pharmacokinetic study in rats after intramuscular injection (20 mg/kg, n = 6). The pharmacokinetic parameters, specifically AUC0-t , AUC0-∞ , t1/2 , CL and Vd , were 15.542 ± 3.122 mg h/L, 15.599 ± 3.141 mg h/L, 0.73 ± 0.347 h, 1.331 ± 0.293 L/h kg and 1.403 ± 0.735 L/kg, respectively. The developed ion chromatography method met the requirements of biological sample measurement, and will be helpful for future pharmacological studies of trehalose.

Degradation of triclosan by chlorine dioxide: Reaction mechanism,2,4-dichlorophenol accumulation and toxicity evaluation.

The mechanism and toxicity of TCS degradation by ClO2 was investigated. Intermediate products during the oxidation process were identified by GC/MS and LC/MS. A microtox bioassay and a SOS/umu assay were employed to evaluate the acute toxicity and genotoxicity of the resulting solutions during the chlorination process. The results showed that the reaction between TCS and ClO2 was of second-order overall. The pseudo first-order rate constants (kobs) exhibited significant dependence on solution pH and chlorine dioxide concentration, with the apparent second-order rate constant, kapp, being 7.07 × 104 M-1s-1 in the pH range of 6.80-7.02. TCS decomposition was accompanied by the accumulation of 2,4-dichlorophenol (2,4-DCP), and the maximum molar yield ratios of 2,4-DCP/TCS were in the range of 31.71%-35.43%. The major intermediates identified were 2,7/2,8-dichlorodibenzop-dioxin (2,7/2.8-Cl2DD), 2,4-DCP, 2,4,6-trichlorophenol (2,4,6-TCP), tetraclosan and pentaclosan. The proposed mechanism for TCS oxidation involved the cleavage of the ether link in TCS, chlorination of the phenolic ring and ring closure of a single TCS molecule. The transformation and degradation of TCS led to reduction of the acute toxicity and genotoxicity. However, irregular fluctuations in the toxicity changes indicated that the oxidation of TCS was not a simultaneous detoxification process.

Copper-Catalyzed Direct Coupling of Unprotected Propargylic Alcohols with P(O)H Compounds: Access to Allenylphosphoryl Compounds under Ligand- and Base-Free Conditions.

The first facile and efficient copper-catalyzed direct C-P cross-coupling of unprotected propargylic alcohols with P(O)H compounds has been developed, providing a general, one-step approach to construct valuable allenylphosphoryl frameworks with operational simplicity and high step- and atom-economy under ligand-, base-, and additive-free conditions.

Silver-Catalyzed, Aldehyde-Induced α-C-H Functionalization of Tetrahydroisoquinolines with Concurrent C-P Bond Formation/N-Alkylation.

The first facile and efficient silver-catalyzed, aldehyde-induced three-component reaction of N-unprotected tetrahydroisoquinolines, aldehydes, and dialkyl phosphonates has been developed, providing a general one-step approach to structurally diverse C1-phosphonylated THIQs accompanied by concurrent C-P bond formation/N-alkylation with remarkable functional group tolerance and excellent regioselectivity for endo products.