Transition-metal nanoparticles (NPs) catalysts supported on solid material represent one of the most important subjects in organic synthesis due to their reliable carbon–carbon or carbon–heteroatom bond-forming cross-coupling reactions. Therefore methodologically and conceptually novel immobilization methods for nonprecious transition-metal NPs are currently required for the development of organic, inorganic, green, materials, and medicinal chemistry. We discovered a self-assembled Au-supported Pd NPs catalyst (SAPd(0)) and applied it as a catalyst to Suzuki–Miyaura coupling, Buchwald–Hartwig reaction, Carbon(sp² and sp³)–Hydrogen bond functionalization, double carbonylation, removal of the allyl protecting groups of allyl esters, and redox switching. SAPd(0) comprises approximately 10 layers of self-assembled Pd(0) NPs, whose size is less than 5 nm on the surface of a sulfur-modified Au. The Pd NPs are wrapped in a sulfated p-xylene polymer matrix. We thought that the self-assembled Au-supported Pd NPs could be made by in situ metal NP and nanospace simultaneous organization (PSSO). This methodology involves 4 kinds of simultaneous procedures: i) reduction of a higher valence metal salt, ii) growth of metal NPs with appropriate size, iii) growth of a matrix with appropriate pores, and iv) wrapping of the metal NPs by matrix nanopores. This methodology is different from previously reported metal NPs-immobilizing methods, which use solid supports with preformed pores or coordination sites. We also applied the in situ PSSO method to prepare various immobilized transition-metal NPs, including base metals. For example, the in situ PSSO method can be applicable to easily prepare Ni, Ru, and Fe NPs with good recyclability and low metal leaching for use in organic synthesis.

A series of chemiluminescent compounds containing a hydrazide group as a nucleophilic functional group has been synthesized. The syntheses were started from chemiluminescent luminol and isoluminol. The linker moiety was easily introduced onto non-nucleophilic exocyclic amino groups of luminol and isoluminol by gentle heating with cyclic acid anhydrides such as glutaric anhydride. The resulting carboxy group was converted to hydrazide by a simple condensation reaction using carbodiimide. Although majority of the synthesized compounds did not emit strong light, a sufficient chemiluminescence intensity was obtained from luminol-amido-C2-hydrazide (L2H) comprising of luminol scaffold with a dimethylene linker. The ability of L2H to form a covalent bond with a macromolecule was further investigated by incubation with oxidized horseradish peroxidase. The analysis on matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) MS revealed that the coupling efficiency of L2H was similar to that of commercially available labelling reagent having a hydrazide group. These results suggested that L2H, the luminol hydrazide containing a dimethylene linker, could be useful for the labelling of macromolecules in the sensitive bioassay such as chemiluminescence immunoassay.

Nocardia is a potent bacterial producer of bioactive compounds. From a culture of Nocardia beijingensis NBRC 16342, we isolated four aromatic compounds, named beijinchromes A–D (1–4). We purified them by silica gel chromatography and reverse phase HPLC, and identified their structures by NMR and high resolution (HR)-MS analyses. 1, 2, and 4 are novel 1,2,3,8-tetrasubstituted naphthalenes, and 3 is a novel 3,8-disubstituted ortho-naphthoquinone. 1 and 2 exert antioxidant activities, and 3 exhibits antibiotic activity. Remarkably, the putative biosynthetic gene clusters for 1–4 are widely distributed in 37 Nocardia species, implying their potential to produce this family of compounds and important biological functions of beijinchromes.

Herbal formulae have a long history in clinical medicine in Asia. While the complexity of the formulae leads to the complex compound-target interactions and the resultant multi-target therapeutic effects, it is difficult to elucidate the molecular/therapeutic mechanism of action for the many formulae. For example, the Hua-Yu-Qiang-Shen-Tong-Bi-Fang (TBF), an herbal formula of Chinese medicine, has been used for treating rheumatoid arthritis. However, the target information of a great number of compounds from the TBF formula is missing. In this study, we predicted the targets of the compounds from the TBF formula via network analysis and in silico computing. Initially, the information of the phytochemicals contained in the plants of the herbal formula was collected, and subsequently computed to their corresponding fingerprints for the sake of structural similarity calculation. Then a compound structural similarity network infused with available target information was constructed. Five local similarity indices were used and compared for their performance on predicting the potential new targets of the compounds. Finally, the Preferential Attachment Index was selected for it having an area under curve (AUC) of 0.886, which outperforms the other four algorithms in predicting the compound-target interactions. This method could provide a promising direction for identifying the compound-target interactions of herbal formulae in silico.

Teriflunomide (TEF, A771726) is the active metabolite of leflunomide (LEF), a disease-modifying anti-rheumatic drug. The main purpose of this study was to develop and evaluate water-in-oil (W/O) microemulsion formulation of TEF. The W/O microemulsion was optimized formula is the physical and chemical stability of lecithin, ethanol, isopropyl myristate (IPM) and water (20.65/20.78/41.52/17.05 w/w) by using the pseudo-ternary phase diagram and the average droplet size is about 40 nm. The permeability of TEF microemulsion is about 6 times higher than control group in vitro penetration test. The results of anti-inflammatory effect showed that compared with the control group, the external TEF microemulsion group could significantly inhibit swelling of paw in rats, and no significant difference compared with oral LEF group. The results of hepatotoxicity test show that there were normal content of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and no obvious inflammatory infiltration of TEF microemulsion group compared with LEF group. The plasma concentration curve showed that compared with LEF group, the peak concentration of TEF microemulsion group was decreased, the half-life (t_1/2) was prolonged, and the relative bioavailability of TEF microemulsion was 75.35%. These results suggest that TEF W/O microemulsion can be used as a promising preparation to play an anti-inflammatory role while significantly reducing hepatotoxicity.

This paper presents a new probe for fluorescence detection of the acetylcholinesterase (AChE) activity based on molecularly imprinted polymer (MIP) coated carbon dots (C-dots) composite. The C-dots were hydrothermally synthesized with grafted silica surface and sealed with molecularly imprinted polymers in silica pores (MIP@C-dots) in situ. Removed the original template molecules, the MIP@C-dots composite exhibits quite high selectivity for acetylthiocholine (ACh). With AChE, its substrate ACh will be hydrolyzed into thiocholine and the fluorescence signals exhibit a dramatic decrease at 465 nm, Under optimal conditions, the fluorescent probe shows sensitive responses to AChE in the range of 0.01–0.6 mU/mL. The detection limits of AChE are as low as 3 µU/mL. These experiments results validate the novel fluorescent probe based on MIP@C-dots composite, paving a new way to evaluation of AChE activity and Screening inhibitors.

Granules prepared by a continuous twin screw granulator (TSG) were analyzed by X-ray micro-computed tomography (X-ray μCT) and the relationships between porosity of granules and granule properties were investigated. A model formulation containing ibuprofen, lactose monohydrate, microcrystalline cellulose, and hydroxypropyl cellulose was used. The porosity of granules was measured by X-ray μCT and mercury porosimetry. The data sets obtained by both methods showed linear correlation despite different values, which were attributed to the resolution of X-ray μCT and a low-signal-to-noise ratio of the original cross-sectional images. The porosity of granules measured by X-ray μCT decreased from 11–14 to 6–7% as liquid-to-solid ratio (L/S) increased, while the standard deviation (S.D.) of the porosity of individual granules decreased from 4–5 to 2%. L/S affected the porosity of granules. By contrast, the effect of screw speed was not significant. Pressure transmission, G, which indicates the liquid dispersion in wet kneaded masses, increased as the porosity of granules and the S.D. decreased. The cross-sectional images showed that granules were densified as L/S increased. Based on these results, the effect of L/S on the porosity of granules can be explained by liquid dispersion and densification of the wet granules. The porosity of granules measured by X-ray μCT showed good linear correlation with friability and drug dissolution rate (R² = 0.9107 and 0.8834, respectively). This study revealed that the drug dissolution rate was regulated by a disintegration step in which the porosity of granules plays an important role.

Helicobacter pylori (H. pylori) infection is common and can result in gastric and duodenal ulcers, and in some cases, gastric lymphoma and cancer. Omeprazole (OMP)—in combination with clarithromycin (CLR), amoxicillin (AMX), tinidazole (TND), or metronidazole (MET)—is used in double or triple combination therapy for eradication of H. pylori. However, the roles of the drugs other than OMP are not clearly understood. Therefore, in the present study, we aimed to investigate any effects of these drugs on OMP metabolism by wild-type CYP2C19 using spectroscopy and enzyme kinetics. The dissociation constants (K_d) for CYP2C19 with OMP, CLR, AMX, TND, and MET were 8.6, 126, 156, 174, and 249 µM, respectively. The intrinsic clearance of OMP was determined to be 355 mL/min/µmol of CYP2C19. Metabolism of OMP was significantly inhibited by 69, 66, 28, and 40% in the presence of CLR, TND, AMX, and MET, respectively. Moreover, the combination of CLR and TND resulted in 76% inhibition of OMP metabolism, while the combination of AMX and MET resulted in 48% inhibition of OMP metabolism. Both combinations of drugs not only have antibacterial effects, but also enhance the effect of OMP by inhibiting its metabolism by CYP2C19. These results indicate that drug–drug interactions of co-administered drugs can cause complex effects, providing a basis for OMP dose adjustment when used in combination therapy for H. pylori eradication.

In this present study a new co-crystals of zoledronic acid with DL-tartaric acid and nicotinamide has been developed with improved solubility. Zoledronic acid is a class III drug with poor oral bioavailability due to its poor permeability and low aqueous solubility; hence an attempt has been made to improve its solubility by co-crystallization technology. Pharmaceutical cocrystals are multi-component crystals with a stoichiometric ratio of active pharmaceutical ingredients (APIs) and cocrystal coformers (CCFs) that are assembled by noncovalent interactions such as hydrogen bonds, π–π packing, and Vander Waals forces. In this study the coformers selected were DL-tartaric acid and nicotinamide based on ease of hydrogen bond formation. The co-crystal of zoledronic acid with DL-tartaric acid were prepared in three ratios (1 : 1, 1 : 2 and 2 : 1) by slow solvent evaporation method and with nicotinamide in 1 : 1 ratio by dry grinding method. The formation of co-crystal was confirmed by powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC) and Fourier transform (FT)IR. The dynamic solubility of co-crystals with DL-tartaric acid in the ratios 1 : 1, 1 : 2 and 2 : 1 increased by fold as compared to pure drug.

We synthesized and evaluated novel 5-[2-(thiophen-2-yl)propan-2-yl]-4H-1,2,4-triazole derivatives as 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors. Optimization of the thiophene ring and the substituents on the 1,2,4-triazole ring produced 3,4-dicyclopropyl-5-{2-[3-fluoro-5-(trifluoromethyl)thiophen-2-yl]propan-2-yl}-4H-1,2,4-triazole monohydrochloride (9a), which showed potent and selective inhibitory activity against human 11β-HSD1. Compound 9a was also metabolically stable against human and mouse liver microsomes. Oral administration of 9a to diabetic ob/ob mice lowered corticosterone levels in adipose tissue, and thereby reduced plasma glucose and insulin levels in a dose-dependent manner.

Panacis Japonici Rhizoma (PJR) contains various kinds of saponins, which possesses extensive pharmacological activities, but studies of comprehensive analysis of its saponins were limited. Thus, ultra-fast liquid chromatography coupled with triple quadrupole-time of flight tandem mass spectrometry (UFLC-Triple TOF-MS/MS) and ultra-fast liquid chromatography coupled with triple quadrupole-linear ion trap tandem mass spectrometry (UFLC-QTRAP-MS/MS) methods were established for the qualitative and quantitative analysis of the saponins in PJR, separately. Fifty three saponins in PJR were identified by UFLC-Triple TOF-MS/MS method, 23 saponins of which were unequivocally identified by reference substances. In addition, fragmentation pathways of different types of saponins were preliminarily deduced by fragmentation behavior of 53 saponins. Furthermore, the simultaneous determination of the contents of 13 saponins in PJR samples harvested at different times were analyzed by UFLC-QTRAP-MS/MS method. Furthermore, the quality of the samples was evaluated by grey relational analysis. This study might be beneficial to the quality assessment and control of PJR. Meanwhile, it might provide the basic information for confirming its optimal harvested period.

Regenerative therapy with keratinocyte growth factor (KGF) is a novel therapeutic approach for treatment of chronic wounds. However, KGF cannot be used directly to the wound site due to its physicochemical instability. In previous study, sacran, a natural megamolecular polysaccharide, showed potential properties as a biomaterial for hydrogel film in wound healing. In this study, we fabricated sacran hydrogel film containing KGF (Sac/KGF-HF) and evaluated the effects of Sac/KGF-HF on fibroblasts migration and re-epithelialization process. We successfully prepared a homogenous and -amorphous Sac/KGF-HF by a casting method. In addition, Sac/KGF-HF had a high swelling ratio and flexibility. Sac/KGF-HF promoted a migration process of NIH3T3 cells and improved wound healing ability in mice with a percentage of wound closure reaching 90.4% at 9 d. Interestingly, the addition of KGF in Sac-HF considerably increased the number of epithelial cells compared to control, which is important in the re-epithelialization process. It could be concluded that KGF in Sac-HF has the potential for promoting Sac-HF abilities in wound healing process.

A highly rapid and sensitive ultra-performance liquid chromatography-tandem triple quadrupole mass spectrometry (UHPLC-TSQ-MS/MS) method was developed for the simultaneous determination of 7 constituents from Zaoren Anshen prescription (ZAP) and 4 endogenic components in rat plasma. The proteins in the plasma samples were removed using acetonitrile. The separation of the 11 components was performed on an Alltima C18 column (150 × 4.6 mm, 5 µm) with acetonitrile and 0.01% formic acid water as the mobile phase. Quantification of the 11 components was performed by multiple reaction monitoring (MRM), and the electrospray ion source polarity was switched between positive and negative modes. The method exhibited good linearity for the 11 components (R² > 0.9942). The lower quantitative limit for the 11 components was in the range from 0.90–9.95 ng/mL. The precision was evaluated by intraday and interday assays, with all relative standard deviation (RSD)% values within 14.92%. The relative error of the accuracy ranged from −9.90 to 14.93%. The recovery ranged from 73.94 to 101.06%, and the matrix effects of the 7 components ranged from 80.06 to 105.70%. The developed method was successfully applied for correlation analysis for the simultaneous quantification of the 7 constituents from ZAP and 4 endogenic components in rat plasma after ZAP treatment.

Lung cancer is one of the most common malignant cancers in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a second- or third-line therapy for mutated non-small cell lung cancer (NSCLC). It usually becomes drug resistance after a period of treatment. Triptolide (TPL) is an epoxy diterpenoid lactone compound extracted from Tripterygium wilfordii HOOK. F. and many studies demonstrated that TPL has a synergistic effect when combined with chemotherapy drugs. In this research, we plan to evaluate the combined effect of TPL and EGFR-TKIs (Gefitinib, Erlotinib, and Icotinib) and investigate the possible mechanisms. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was conducted to detect the cell viabilities, combined effect was evaluated by Combination Index. Molecular docking study was used to predict the binding ability of TPL. The expression of proteins was detected by Western blot. MTT results showed TPL had synergistic effect with three EGFR-TKIs at different concentrations on H1975 cells but not on H1299 cells. Molecular docking study demonstrated that TPL with T790M/L858R EGFR can form a more stable compound than that with wild type EGFR. Western blot results showed TPL inhibited the EGFR/Akt pathway and increased the expression of Bax and the ratio of Bax and Bcl-2 in H1975 cells. In conclusion, TPL had synergistic effect with three EGFR-TKIs on H1975 cells but not on H1299 cells, which may be due to the binding ability of TPL and different-type EGFR. The synergistic effect of TPL on H1975 cells may be partly related to the inhibition of the EGFR/Akt pathway.

A gold-catalyzed introduction of various terminal alkynes to acetals was investigated. Extensive optimization of the reaction conditions revealed that thermally stable cationic gold catalysts bearing bulky ligands such as 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene 3-1H-benzo[d][1,2,3]triazolyl gold trifluoromethanesulfonate (IPrAu(BTZ-H)OTf) were particularly suitable for the reaction. Additionally, significant solvent effects were observed. Ether solvents such as tetrahydrofuran (THF), cyclo pentyl methyl ether (CPME), and 1,4-dioxane were effective for the reaction. Studies on the scope of substrates and alkynes indicated that various alkynes and acetals were feasible to provide a wide range of propargylic ethers.

The 4-vinylpyrimidin-2-one nucleoside (T-vinyl) forms a cross-link with the RNA containing uracil at the complementary site at a high reaction rate. To obtain the stable T-vinyl derivative so that its reactivity is protected until it access to the target site, several derivatives were investigated, and the 2-thiopyridinyl- and 2-thiopyrimidinyl T-vinyl derivatives were determined to be good candidates. The 2-thiopyrimidinyl T-vinyl derivative was found to more efficiently cross-link with mRNA albeit having a better stability than the 2-thiopyridinyl T-vinyl derivative. The investigation using the luciferase (Luc) mRNA, the synthetic mRNA and non-cellular translation system revealed that the translation is terminated at the end of the cross-linked duplex between the mRNA and the oligoribonucleotide (ORN). Thus, the 2-thiopyrimidinyl T-vinyl derivative has successfully demonstrated both a good stability and high efficiency for the cross-linking reaction, and expanded its applicability in biological applications.

We developed a simple and sensitive HPLC method for the determination of selenocyanate (SeCN⁻). The König reaction, which is generally used for the determination of cyanide and thiocyanate, was applied for the post-column detection, and using barbituric acid as a fluorogenic reagent made it possible to detect SeCN⁻ with high sensitivity. The limits of detection (LOD) and quantification (LOQ) were 73.5 fmol and 245.1 fmol, respectively. Subsequently, the amounts of SeCN⁻ in human blood and in cultured cell samples were analyzed, and no SeCN⁻ was detected in human whole blood. Interestingly, we have found that some of the spiked SeCN⁻ decomposed to cyanide in human whole blood. Ascorbic acid suppressed the decomposition of SeCN⁻ to cyanide by reducing the ferric ion, which is typically involved in SeCN⁻ decomposition. Then, SeCN⁻ was detected in cultured HEK293 cells exposed to selenite. The established HPLC method with fluorescence detection of SeCN⁻ is useful for investigating small amounts of SeCN⁻ in biological samples.

New sugar hydrazones incorporating furan and/or 1,3,4-thiadiazole ring systems were synthesized by reaction of the corresponding hydrazide with different aldose sugars. Heterocyclization of the formed hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the heterocyclization process. The anticancer activity of the synthesized compounds was studied against human liver carcinoma cell (HepG-2) and at human normal retina pigmented epithelium cells (RPE-1). High activities were revealed by compounds 3, 12 and 14 with IC₅₀ values near to that of the reference drug doxorubicin.