Formate and CO2 Enable Reductive Carboxylation of Imines: Synthesis of Unnatural α-Amino Acids.

Herein, a photocatalytic umpolung strategy for reductive carboxylation of imines for the synthesis of α-amino acids was disclosed. Carbon dioxide radical anion (CO2•-) generated from formate is the key single electron reductant in the reactions. An unprecedentedly broad substrate scope of imines with excellent reaction yields was obtained with carbon dioxide (CO2) and formate salt as carbon sources.

An oral 2-hydroxypropyl-ß-cyclodextrin-loaded spirooxindole-pyrrolizidine derivative restores p53 activity via targeting MDM2 and JNK1/2 in hepatocellular carcinoma.

Validation of a small molecular compound targeting the oncogenic pathways is the primary approach for the development of the anti-cancer drugs. In the present study, we employed the computational mimic drug targets prediction software to foresee the molecular targets of a series of spirooxindole-pyrrolizidine derivatives, which were synthesized by our laboratory viatargeted combinational chemistry. We found that CPHSP, a novel spirooxindole-pyrrolizidine derivative, can target the MDM2/p53 signaling that is essential for the tumorigenesis of hepatocellular carcinoma (HCC). To validate its anti-tumoral function, we firstly established the soluble receipt of CPHSP through 2-hydroxypropyl-ß-cyclodextrin (HBC) loading and showed that oral administration of HBC-loaded CPHSP significantly inhibited the tumor growth and prolonged the survival time of tumor-bearing mice in the subcutaneously human hepatoma cells-xenografted nude mouse model of HCC. Immunohistochemistry staining showed that HBC-loaded CPHSP treatment suppressed the proliferation and induced apoptosis of tumor cells in this model. Our mechanistic studies showed that CPHSP treatment inhibited MDM2 protein expression and up-regulated p53 activity and activated MKK4/MKK7/JNK1/2/C-Jun signaling pathway, which resulted in cell cycle arrest and apoptosis of HepG2 cells in vitro. Moreover, we showed that JNK1/2 activation could also up-regulate p53 expression in CPHSP-treated HepG2 cells. Finally, we documented the antitumor activities of oral administration of the HBC-loaded CPHSP in the ML-1 bearing orthotopic mouse model. In summary, this study suggests that oral administration of HBC-loaded CPHSP is a safe and effective treatment for HCC, of which the clinical potency for patients with HCC warrants further studies.

Oral administration of indole substituted dipyrido[2,3-d]pyrimidine derivative exhibits anti-tumor activity via inhibiting AKT and ERK1/2 on hepatocellular carcinoma.

Development of an effective and safe anti-cancer drug is an urgent request for hepatocellular carcinoma (HCC). In this study, we synthesized a series of novel indole substituted dihydropyrido[2,3-d]pyrimidines through the multicomponent reactions to connect pyrido[2,3-d]pyrimidine and indole moities via an one-pot three-component reaction of 3-cyanoacetyl indoles 1, various aromatic aldehyde 2, and 2,6-diaminopyrimidin-4(3H)-one 3. Subsequently, we screened their cytotoxicity via CCK-8 assay in HepG2 cells, a human hepatoma cell line and chose compound 4p that showed the lowest dosage of IC50 to study the antitumor activities to HCC. Interestingly, 4p significantly induced the cell cycle arrest and apoptosis of HepG2 via targeting AKT and ERK1/2 signaling pathways in vitro. To improve the solubility of compound 4p, we hosted this compound into the substituted glucopyranose ring of (2-Hydroxypropyl)-ß-cyclodextrin (HBC), a cosolvent approved by FDA with the help of ultrasonication and heating. Finally, we showed that oral administration of HBC-hosted 4p effectively inhibited tumor growth and prolonged the survival time of tumor-bearing mice in subcutaneously xenografted model. These results suggest that multicomponent reactions connecting pyrido[2,3-d]pyrimidine and indole moities is a productive and economical method for the synthesis of anticancer compound, and oral administration of HBC-hosted 4p is an effective and safe agents for treatment of HCC, whose clinical application potency warrant further studies.

A Simple and Efficient Synthesis of Highly Substituted Indeno[1,2-b]pyrrole and Acenaphtho[1,2-b]pyrrole Derivatives by Tandem Three-Component Reactions.

A green, convenient and tandem procedure for the efficient synthesis of highly substituted indeno[1,2-b]pyrrole and acenaphtho[1,2-b]pyrrole derivatives by domino three-component reaction of tryptamine/benzylamine, 1,3-dicarbonyl compounds and ninhydrin/ acenaphthenequinone is described. The significant features of this procedure were characterized by mild reaction conditions, high yields, operational simplicity and it being environmentally benign.

Highly enantioselective asymmetric transfer hydrogenation (ATH) of α-phthalimide ketones.

A mild catalyst system for the synthesis of chiral amino alcohols via asymmetric transfer hydrogenation (ATH) of α-phthalimide ketones has been developed by using a chiral Ru-TsDPEN complex as the catalyst in DMF/MeOH at 40 °C. The reaction exhibits high reaction activity and excellent enantioselectivity where up to 96% yield and 99% ee of the product were obtained.

Regulatory T cell activity is partly inhibited in a mouse model of chronic Pseudomonas aeruginosa lung infection.

OBJECTIVES: We aimed to investigate the activity of regulatory T (Treg) cells in chronic Pseudomonas aeruginosa (PA) lung infection and its influence on effector T-cell responses. MATERIALS AND METHODS: C57BL/6 mice were randomly inoculated with PA-laden agarose beads (1 × 10(5) CFU/50 µL) or planktonic PA (1 × 10(5) CFU/50 µL), and euthanized at the time points of 4 hour, day 1, 3, 5, and 7. Bacterial load, bronchoalveolar lavage (BAL) fluid cell counts, and lung tissue histology were assessed. BAL fluid concentrations of TGF-ß1, IFN-γ, IL-1ß, IL-4, IL-6, IL-10, and IL-17A were measured. Messenger RNA (mRNA) levels of TGF-ß1, IL-10 and CD4(+) T-cell subtype-specific transcription factors were determined. The expression of CD4(+)CD25(+)forkhead box P3 (FoxP3)(+) cells in lungs and spleens were analyzed. RESULTS: Mice inoculated with PA-laden agarose beads developed chronic PA lung infection during 7-day study period, while mice inoculated with planktonic PA cleared bacteria in 3 days. Compared with mice recovered from acute PA lung infection, those with chronic infection had significantly increased effector T-cell responses, accompanied by a more severe neutrophilic inflammation. Mice with chronic PA lung infection had significantly lower concentration of TGF-ß1 and higher concentrations of IFN-γ, IL-1ß, IL-6, and IL-17A in BAL fluid. Meanwhile, they had significantly lower mRNA levels of TGF-ß1, IL-10 and FoxP3 in lung tissues, and lower expression of CD4(+)CD25(+)FoxP3(+) cells in lungs and spleens. CONCLUSIONS: These findings indicate that Treg cell activity is partly inhibited in mice with chronic PA lung infection, which contributes to the enhanced effector T-cell responses in airways.

Bleomycin-induced pulmonary fibrosis is attenuated by an antibody against KL-6.

BACKGROUND: Elevated levels of KL-6 are reported in the serum and/or bronchoalveolar lavage fluid (BALF) of patients with interstitial lung disease (ILD) and are useful to estimate the severity and prognosis of the disease. However, whether the anti-KL-6 antibody could attenuate pulmonary fibrosis remains unclear. OBJECTIVES: This study aims to investigate the therapeutic effects and mechanisms of anti-KL-6 antibody on bleomycin-induced pulmonary fibrosis. METHODS: A mouse model of pulmonary fibrosis was established by intratracheal injection of bleomycin (5 mg/kg). Mouse received anti-KL-6 antibody (20 ug/day, once a day) from day 7 to 21 after bleomycin injection. The effects of anti-KL-6 antibody were evaluated by pathological examination, measuring hydroxyproline measurements in lung tissues, leukocyte counts in BALF and the expression of collagen type I and type III using qRT-PCR. The expression of profibrotic cytokine (transforming growth factor-ß1, TGF-ß1), antifibrotic cytokine (hepatocyte growth factor, HGF), and KL-6 in lung tissues were analyzed by ELISA. The apoptosis of epithelial cell was examined by TUNEL staining. RESULTS: Anti-KL-6 antibody significantly reduced the number of alveolar inflammatory leukocytes (total and differential counts) in BALF of mice with bleomycin-induced pulmonary fibrosis as well as the content of hydroxyproline in the lung tissues. Treatment with anti-KL-6 antibody downregulated the expression of collagen type I, TGF-ß1 and KL-6, upregulated the expression of HGF and inhibited the apoptosis of epithelial cells. CONCLUSIONS: These findings indicated the anti-KL-6 antibody may potentially be developed as a useful inhibitor of pulmonary fibrosis.

Low-dose clarithromycin therapy modulates CD4(+) T-cell responses in a mouse model of chronic Pseudomonas aeruginosa lung infection.

BACKGROUND AND OBJECTIVE: Low-dose clarithromycin (CAM) is widely used for the treatment of chronic respiratory infections. However, its anti-inflammatory mechanisms have not been fully explored. As CD4(+) T cells play an important role in the initiation of immune responses to infectious microorganisms, we aimed to investigate the effects of low-dose CAM on CD4(+) T-cell responses. METHODS: Fifty-four BALB/c mice were randomly divided into three groups: a control group (inoculated with sterile agarose beads and treated with saline from day 7), a saline group (inoculated with Pseudomonas aeruginosa-loaded beads and treated with saline from day 7) and a CAM group (identical to the saline group, except that saline was replaced by CAM solution). Bronchoalveolar lavage (BAL) fluid cell counts, bacterial load, lung tissue histology and pulmonary CD3(+) CD4(+) cell numbers were assessed. Levels of T helper (Th)1/Th2/Th17 cytokines and suppressor cytokines (interleukin (IL)-10 and transforming growth factor-ß1) were analysed. Messenger RNA (mRNA) levels for transcription factors for CD4(+) T-cell subsets were determined. RESULTS: The CAM group had lower BAL fluid cell counts, pathological scores and pulmonary CD3(+) CD4(+) cell numbers compared with the saline group, whereas the bacterial load was not significantly different. Levels of Th1/Th17 cytokines and expression of a transcription factor for naturally occurring regulatory T cells (Treg) were significantly decreased in the CAM group compared with the saline group, whereas there was no significant difference in GATA-3 mRNA expression. CONCLUSIONS: This study demonstrated a downregulation of Th1/Th17/naturally occurring Treg responses after treatment with low-dose CAM in mice with chronic P. aeruginosa lung infection.

An efficient one-pot synthesis of pyrano[3,2-c]quinolin-2,5-dione derivatives catalyzed by L-proline.

A series of 4-aryl-6-methyl-3,4-dihydro-2H-pyrano[3,2-c]quinolin-2,5(6H)-diones were synthesized via the three-component reactions of aromatic aldehydes, 4-hydroxy-1-methylquinolin-2(1H)-one, and Meldrum's acid catalyzed by L-proline. The structures of the products were identified by spectroscopic analysis. A mechanism for this three-component reaction catalyzed by L-proline was proposed.

4-(4-Chloro-phen-yl)-2,6-bis-(1H-indol-3-yl)-1,4-dihydro-pyridine-3,5-dicarbo-nitrile ethanol monosolvate.

In the title compound, C(29)H(18)ClN(5)·C(2)H(6)O, the dihydro-pyridine ring adopts a strongly flattened envelope conformation, with a maximum deviation of 0.139 (2) Šfrom its best plane for the Csp(3) atom. The dihedral angles between the dihydro-pyridine ring plane and the two indole rings in positions 2 and 6 are 34.28 (5) and 40.50 (6)°, respectively. In turn, the benzene ring and the dihydro-pyridine ring are oriented at a dihedral angle of 74.69 (6)°. An intra-molecular C-H⋯Cl hydrogen bond occurs. In the crystal, mol-ecules are linked by N-H⋯N, N-H⋯O and O-H⋯N hydrogen bonds into layers parallel to (001). There are short C-H⋯Cl contacts between mol-ecules in neighboring layers.

Defluorinative Alkylation of Trifluoromethylbenzimidazoles Enabled by Spin-Center Shift: A Synergistic Photocatalysis/Thiol Catalysis Process with CO2•.

We describe a catalytic strategy for direct single C(sp3)-F bond alkylation of trifluoromethylbenzimidazoles under a photoinduced thiol catalysis process. The CO2 radical anion (CO2•-) proved to be the most efficient single-electron reductant to realize such a transformation. The spin-center shift of the generated radical anion intermediate is the key step in realizing C-F bond activation under mild conditions with high efficiency.

4-Bromo-3-hy-droxy-3-(4-hy-droxy-2-oxo-2H-chromen-3-yl)indolin-2-one.

In the mol-ecule of the title compound, C(17)H(10)BrNO(5), the indoline system and the attached coumarin ring are each essentially planar with maximum deviations of 0.074 (2) and 0.062 (2) Å, respectively. The dihedral angle between them is 85.09 (3)°. In the crystal, all heteroatoms (except for the coumarin oxo O atoms) are involved in intra- and inter-molecular hydrogen bonds. An intra-molecular O-H⋯O hydrogen bond occurs. In the crystal, mol-ecules are linked through O-H⋯O, N-H⋯O and C-H⋯O contacts, forming a complex three-dimensional structure.

Ethyl 2-amino-7,7-dimethyl-2',5-dioxo-spiro-[5,6,7,8-tetra-hydro-4H-chromene-4,3'(2'H)-1H-indole]-3-carboxyl-ate.

In the mol-ecule of the title compound, C(21)H(22)N(2)O(5), the indole system and the spiro-pyran ring are almost planar [maximum deviations of 0.0447 (17) and 0.0781 (17) Å, respectively]; the dihedral angle between them is 84.6 (3)°. The remaining six-membered ring adopts a twisted conformation. Intra-molecular N-H⋯O hydrogen bonds occur. In the crystal structure, intera-molecular N-H⋯O and C-H⋯O hydrogen bonds link the mol-ecules.

Methyl 6'-amino-5'-cyano-2'-methyl-2-oxospiro-[indoline-3,4'-pyran]-3'-carboxyl-ate.

In the mol-ecule of the title compound, C(16)H(13)N(3)O(4), the atoms of the spiro pyran ring are nearly planar with a maximum deviation of 0.095 (2) Å. The indole and pyran rings are oriented at a dihedral angle of 87.3 (9)°. In the crystal, mol-ecules are linked by inter-molecular N-H⋯N and N-H⋯O hydrogen bonds.

Ethyl 6'-amino-5'-cyano-2'-methyl-2-oxospiro-[indoline-3,4'-pyran]-3'-carboxyl-ate.

In the title compound, C(17)H(15)N(3)O(4), the atoms of the spiro pyran ring are nearly planar with a maximum deviation of 0.0188 (14) Å. The benzene and pyrrole rings make a dihedral angle of 5.71 (6)°. The indole system and the pyran ring are oriented at a dihedral angle of 82.94 (3)°. The crystal structure is stabilized by inter-molecular classical and non-classical N-H⋯O, N-H⋯N and C-H⋯O hydrogen bonds.

2'-Amino-1'-(4-chloro-phen-yl)-1,7',7'-trimethyl-2,5'-dioxo-5',6',7',8'-tetra-hydrospiro-[indoline-3,4'(1'H)-quinoline]-3'-carbonitrile dimethyl-formamide solvate dihydrate.

In the mol-ecule of the title compound, C(26)H(23)ClN(4)O(2)·C(3)H(7)NO·2H(2)O, the indole and dihydro-pyridine rings are planar and make a dihedral angle of 89.86 (7)°. The dihydro-pyridine ring forms a dihedral angle of 79.95 (7)° with the attached benzene ring. In the crystal structure, inter-molecular N-H⋯O and O-H⋯O hydrogen bonds link the mol-ecules. Intermolecular C-H⋯N and C-H⋯Cl interactions are also present.

6-(1H-Indol-3-yl)-4-phenyl-2,2'-bi-pyridine-5-carbonitrile.

In the mol-ecule of the title compound, C(25)H(16)N(4), the pyridine rings are oriented at a dihedral angle of 0.92 (3)°, while the dihedral angle between the benzene ring and the adjacent pyridine ring is 56.51 (3)°. In the crystal structure, inter-molecular N-H⋯N hydrogen bonds link the mol-ecules into centrosymmetric dimers, forming R(2) (2)(16) ring motifs. π-π contacts between the pyridine ring and the indole ring system and between the pyridine rings [centroid-centroid distances = 3.923 (2) and 3.724 (2) Å] may further stabilize the structure. Two weak C-H⋯π inter-actions are also present.

2-Amino-4'-bromo-2',5-dioxo-4H,5H-pyrano[3,2-c]chromene-4-spiro-3'(2'H)-1'H-indole-3-carbonitrile N,N-dimethyl-formamide solvate.

In the mol-ecule of the title compound, C(20)H(10)BrN(3)O(4)·C(3)H(7)NO, the spiro pyran ring adopts a twist conformation. The indole and coumarin ring systems are each nearly planar, and are oriented at a dihedral angle of 79.29 (3)°. In the crystal structure, inter-molecular N-H⋯O, N-H⋯N, C-H⋯O and C-H⋯N hydrogen bonds link the mol-ecules.

Combinatorial synthesis of functionalized spirooxindole-pyrrolidine/pyrrolizidine/pyrrolothiazole derivatives via three-component 1,3-dipolar cycloaddition reactions.

A series of diverse polycyclic heterocycles containing spirooxindole, pyridine/thiophene, and pyrrolidine/pyrrolizidine/pyrrolothiazole rings have been synthesized through the 1,3-dipolar cycloaddition of azomethine ylides generated in situ by the condensation of dicarbonyl compounds (isatin or acenaphthenequinone) and secondary amino acids with dipolarophiles. The method is simple and provides diverse and biologically interesting products with excellent yields.

New potential calcium channel modulators: design and synthesis of compounds containing two pyridine, pyrimidine, pyridone, quinoline and acridine units under microwave irradiation.

The synthesis of bifunctional pyridine, pyrimidine, pyridone, quinoline and acridine derivatives was investigated using dialdehyde as a precursor. A rapid and efficient method was developed for the synthesis of a range of bifunctional monocyclic, bicyclic and tricyclic products related to 1,4-DHPs with the aim of finding new classes of biologically active compounds.