Effect of pyridone agent on blood-retinal barrier in diabetic mice

AIM： To evaluate the therapeutic effect of fluorofenidone on disrupted blood-retinal barrier in the diabetic mice and uncover its underlying mechanism. METHODS： db/db mice were randomly chosen for treatment with daily doses of fluorofenidone or placebo at 5-week-old, treatment continued until mice reach 24-week- old. Then, expression of transcriptiona factor insulin gene enhancer binding protein-1 （Islet-I） and vascular endothelial growth factor （VEGF） in murine retinas were evaluated. Retinal vascular permeability was assessed by examining the level of albumin in db/db murine retinas. Furthermore, the retinal vessel tight junction was estimated by checking the level of occludin in the murine retinal tissues. RESULTS： After occurrence of diabetic retinopthy in db/ db mice, expressions of transcritpional factor Islet-1 was found to be upregulated in db/db murine retinas compared with non-diabetic controls. Similar to expression pattern of Islet-l, VEGF were also demonstrated to be increased in retinas of db/db mice, which was accompanied by increased retinal vascular leakage and decreased tight junction protein level. Systemetic administration of fluorofenidone repaired broken retinal vascular tight junction by restoring occludin expression in db/db retinal tissue. Consequently, retinal vascular premeability were indicated to be reduced by examining the transudative albumin level in diabetic retinal tissues. Both Islet-1 and VEGF expression were inhibited in the retinas of db/db mice after treatment with fluorofenidone. CONCLUSION： Fluorofenidone significantly protectes retinal tight junction and reduces retinal vascular leakage. The phenomenon can be partially attributed to reducing overexpression of Islet-1 and VEGF in diabetic retinal tissues.

Effects of Two Anti-TNF-α Compounds: Etanercept and 5-Ethyl-1-Phenyl-2-(1H)-Pyridone on Secreted and Cell-Associated TNF-α <i>In Vitro</i>

Tumor necrosis factor-alpha (TNF-α) is a potent inflammatory cytokine and its exaggerated production has been implicated in acute, chronic and autoimmune inflammatory diseases. Proteinaceous and non-proteinaceous anti-TNF-α agents have been developed to reduce its circulating levels either by neutralizing, binding or inhibiting the de novo synthesis with the aim of achieving desirable therapeutic effects. In the present study, we compared the effects of a protein-based anti-TNF-α drug, etanercept, and a non-protein-based anti-TNF-α small molecule, 5-ethyl-1-phenyl-2-(1H) pyridone (5-EPP), on the LPS-stimulated secretion of TNF-α in the medium and TNF-α associated with the THP-1 cells in vitro. Both drugs had marked concentration-dependent inhibitory effects on the LPS-stimulated secretion of TNF-α. However, their effects on the LPS-stimulated cell-associated TNF-α were diametrically opposed to each other. For instance, etanercept further increased the level by up to 12-fold, whereas 5-EPP inhibited the level in a dose dependent manner. In addition, 5-EPP caused a significant reduction in the elevated level of cell associated TNF-α caused by LPS + etanercept. The differences in the levels of cell-associated TNF-α as reported in the present study may partly explain the adverse effects of some protein-based anti-TNF-α drugs including etanercept as opposed to a non-protein-based anti-TNF-α drug such as pirfenidone, a structural analogue of 5-EPP, for treatment of some TNF-α mediated diseases. It was concluded from the findings of this study that drugs which elevate the levels of cell associated-TNF-α will potentially have more adverse events even after reducing the secreted levels of TNF-α than the drugs which reduce both the secreted and cell-associated TNF-α levels.

Synthesis of Some Azo Disperse Dyes from 1-Substituted 2-Hydroxy-6-pyridone Derivatives and Their Colour Assessment on Polyester Fabric

The synthesis of a series of 3-(p-substituted phenylazo)-6-pyridone dyes which is suitable for the dyeing of polyester fabrics, is described. Visible absorption spectra of the dyes were examined in various solvents and the compounds in solution exhibited hydrazone-common anion equilibrium. The electronic absorption spectra cover a λmax range of 404 - 464 nm in DMF at uniformly high absorption intensity between 5.33 × 104 - 8.55 × 104 lmol–1cm–1 and gave bright intense hues of yellow to orange on polyester fabrics. The colour parameters of the dyed fabrics were measured and the dyes have excellent exhaustion between 72% - 79% for polyester fabrics, more intense and of very good fastness properties on polyester fabrics. The remarkable degree of levelness and brightness after washing is indicative of good penetration and excellent affinity of these dyes for the polyester fabric.

New phenylpyridone derivatives from the Penicillium sumatrense GZWMJZ-313,a fungal endophyte of Garcinia multiflora

Citridones E-G (1-3), three new phenylpyridone derivatives together with two known curvularins (4 and 5) were isolated from the solid culture of the endophytic fungus Penicillium sumatrense GZWMJZ-313 in Garcinia multiflora. The structures of new compounds were determined in the light of spectroscopic data,X-ray and ECD calculation. Compounds 1 and 3 are racemates, while compound 2 is optically pure.Compounds 1 and 4 showed antibacterial and antifungal activities against Staphylococcus aureus,Pseudomonas aeruginosa, Clostridium perfringens, Escherichia coli and Candida albicans with MIC values ranging from 8 μg/mL to 64 μg/mL.

A Singlet Oxygen Reservoir Based on Poly-Pyridone and Porphyrin Nanoscale Metal-Organic Framework for Cancer Therapy

Here,a methacrylate-modified pyridone derivative(mPYR)was loaded into a porphyrin nanoscale metal-organic framework(porphyrin-nMOF).Then,the loaded mPYR was further polymerized to obtain poly-pyridone(poly-mPYR)to form poly-mPYR loaded porphyrin-nMOF,which is designated as PLP and used as a reservoir of singlet oxygen(^(1)O_(2)).It was found that PLP could quickly capture^(1)O_(2)in vitro and slowly release^(1)O_(2)in vivo to induce cancer cell death.The release of^(1)O_(2)was light and oxygen independent,and the entire process did not cause intracellular oxygen consumption.PLP also displayed good therapeutic effect in the treatment of both solid tumor and lung metastasis cancer.This strategy of oxygenand light-independent^(1)O_(2)treatment presents great potential for treating refractory cancer.Also,the form of^(1)O_(2)capturing polymer-loaded nMOF expands the biomedical applications of MOFs and polymers,which can be used as a platform for biomedical applications.

Base-Promoted Synthesis of 3-Alkenyl-2-pyridones from N-Propargyl-β-enaminones and Aryl Aldehydes

Main observation and conclusion In this article,we report a base-promoted sequential cyclization/aldol-type condensation/isomerization cascade reaction of N-propargyl-β-enaminones with aryl aldehydes.The key step in this protocol is the generation of 1,4-oxazepine anions from N-propargyl-β-enaminones under basic conditions,which are captured by aryl aldehydes.The method allows the formation of one pyridone core and one C—C double bond in“one pot”,and the preparation of a variety of densely decorated pyridone derivatives in moderate to good yields with broad functional group tolerance.

Green Synthesis of Novel 5-Arylazo-2-[(2S, 3S, 4R, 5R)-3, 4, 5-Trihydroxy-6-(Hydroxymethyl) Tetrahydro-2H-Pyran-2-Yloxy]-4, 6-Dimethyl 3-Nicotinonitrile

Introduction: Pyridone derivatives played important roles in the last decade to approach many and different functionalities, especially as antitumor, antibacterial, anti-fungal, and many of pharmacological activities. Methodology: Novel compounds of 5-Arylazo-2-[(substituted)-3, 4, 5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yloxy]-4, 6-dimethylnicotinonitrile, (3a-e), generally called (fluroarylazopyridine glucosides) were synthesised via green protocol, microwave. Results: The compounds were investigated by (IR, 1HNMR, 13CNMR and mass spectrometry). Where some of pharmacological activities like antibacterial and antifungal studies had been investigated and characterized. It was found that 3a-d had characterized by high activities as antibacterial and antifungal. Where microwave synthetic methods were more efficient, gave higher products quantity, and more saving for time requirement and for using of much more solvents.

Synthesis,spectroscopic properties and applications of novel N-heterocycle-containing benzotriazoles as UV absorbers

Two novel N-heterocycle-containing benzotriazole compounds, 5-（5-chloro-2-benzotriazolyl）-6-hydroxy-l,4-dimethyl-3-car- bonitrile-2-pyddone （2） and 4-（5-chloro-2-benzotdazolyl）-5-methyl-2-phenyl-3-pyrazolone （4）, were synthesized from reactant 4- chloro-2-nitroaniline via diazotization, azo coupling, reductive cyclization and acidification. Their structures were confirmed by Fr-IR, 1H NMR, mass spectroscopy and elemental analysis. Their spectral properties were investigated and compared with that of a common commercial benzotriazole UV absorber Tinuvin 326. It is found that the novel N-heterocycle-containing benzotriazole compounds exhibit sharp single peak in the range of 280-400 nm and have much higher molar extinction coefficients than that of Tinuvin 326. Their anti-UV protection properties on polyester fabric were also evaluated and compound 4 was much superior to compound 2 due to its higher exhaustion.

Synthesis and insecticidal bioactivities of 2,3-dihydroimidazo[1,2-a] pyridin-5(1H)-one derivatives

A novel synthesis of 2,3-dihydroimidazo[1,2-a]pyridin-5 (1H)-one 4 and its derivatives were described.Preliminary bioassays showed that some of the target compounds exhibited excellent insecticidal activities against brown planthopper (Nilaparvata lugens), cowpea aphids (Aphis craccivora) (4,5 a, 5 c, 5 g,5 h, 5 j, 5 r, 6 b, 6 e) and carmine spider mite (Tetranychus cinnabarinus (5 f, 5 s, 6 a) at 500 mg/L. Among them,compound 4 was still active against brown planthopper and cowpea aphids at 4 mg/L. The insecticidal activities were influenced by the types and position of the substituents, which provided guidance for the structure modifications.

Structure-based design of novel heterocyclesubstituted ATDP analogs as non-nucleoside reverse transcriptase inhibitors with improved selectivity and solubility

Following on our recently developed biphenyl-ATDP non-nucleoside reverse transcriptase inhibitor ZLM-66(SI=2019.80,S=1.9μg/mL),a series of novel heterocycle-substituted ATDP derivatives with significantly improved selectivity and solubility were identified by replacement of the biphenyl moiety of ZLM-66 with heterocyclic group with lower lipophilicity.Evidently,the representative analog 7w in this series exhibited dramatically enhanced selectivity and solubility(SI=12,497.73,S=4472μg/mL)in comparison with ZLM-66(SI=2019.80,S=1.9μg/mL).This new NNRTI conferred low nanomolar inhibition of wild-type HIV-1 strain and tested mutant strains(K103N,L1001,Y181C,E138K,and K103N+Y181C).The analog also demonstrated favorable safety and pharmacokinetic profiles,as evidenced by its insensitivity to CYP and hERG,lack of mortality and pathological damage,and good oral bioavailability in rats(F=27.1%).Further development of 7w for HIV therapy will be facilitated by this valuable information.

PhlCl_(2)/NH_(4)SCN-Mediated Oxidative Regioselective Thiocyanation of Pyridin-2(1H)-ones

The reaction of pyridin-2(1H)·ones with PhlCl_(2) and NH_(4)SCN enables an efficient regioselective thiocyanation,leading to the synthesis of the biologically interesting C5 thiocyanated 2-pyridones in good to high yields.The mechanistic pathway of this metal-free approach is postulated to involve the formation of the reactive thiocyanogen chloride from the reaction of PhlCl_(2) and NH4SCN followed with the regioselective electrophilic thiocyanation of the pyridin-2(1H)-one ring.