Structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of inhibitors of RET and its drug resistance mutants.

The RET tyrosine kinase is an important therapeutic target for medullary thyroid cancer (MTC), and drug resistance mutations of RET, particularly V804M and V804L, are a main challenge for the current targeted therapy of MTC based on RET inhibitors. In this investigation, we report the structural optimization and structure-activity relationship studies of N-phenyl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine derivatives as a new class of RET inhibitors. Among all the obtained kinase inhibitors, 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-yl)amino)phenyl)urea (17d) is a multi-kinase inhibitor and potently inhibits RET and its drug resistance mutants.

Docetaxel load biodegradable porous microspheres for the treatment of colorectal peritoneal carcinomatosis.

Micro- and nanoparticle formulations are widely used to improve the bioavailability of low solubility drugs. In this study, biodegradable poly(L-lactide acid)-Pluronic L121-poly(L-lactide acid) (PLLA-L121-PLLA) was developed. And then a controlled drug delivery system (CDDS), docetaxel (DOC) loaded PLLA-L121-PLLA porous microsphere (DOC MS) was prepared for colorectal peritoneal carcinomatosis (CRPC) therapy.

Syntheses and cell-based phenotypic screen of novel 7-amino pyrido[2,3-d]pyrimidine-6-carbonitrile derivatives as potential antiproliferative agents.

A series of N-3-substituted 7-aminopyrido[2,3-d]pyrimidin-6-carbonitrile derivatives was readily synthesized and their anti-proliferative activities on five types of tumor cells were evaluated through a cell-based phenotypic screening approach. Compound 3k was found to be potent on human colon cancer SW620 cells with an IC(50) value of 12.5 mM.

Synthesis and biological evaluation of 2-(3-fluoro-4-nitro phenoxy)-n-phenylacetamide derivatives as novel potential affordable antitubercular agents.

A novel series of 2-(3-fluoro-4-nitrophenoxy)-N-phenylacetamide compounds were designed, synthesized and in vitro assessed for their antitubercular activities by a microdilution method. All the novel derivatives exerted potent or moderate active against M. tuberculosis H₃₇Rv, with MIC values ranging from 4 to 64 μg/mL.

4-(5-Oxo-5H-1,2,4-dithia-zol-3-yl)phenyl 4-methyl-benzene-sulfonate.

In the mol-ecular structure of the title compound, C(15)H(11)NO(4)S(3), the 1,2,4-dithia-zolone and central benzene rings are approximately coplanar, making a dihedral angle of 3.08 (7)°. The central benzene ring and the 4-methyl-benzene ring subtend a dihedral angle of 57.

(Z)2-(5-(4-methoxybenzylidene)-2, 4-dioxothiazolidin-3-yl) acetic acid protects rats from CCl(4) -induced liver injury.

Background And Aim: (Z)2-(5-(4-methoxybenzylidene)-2, 4-dioxothiazolidin-3-yl) acetic acid (MDA) is an aldose reductase (AR) inhibitor. Recent studies suggest that AR contributes to the pathogenesis of inflammation by affecting the nuclear factor κB (NF-κB)-dependent expression of cytokines and chemokines and therefore could be a novel therapeutic target for inflammatory pathology. The current study evaluated the in vivo role of MDA in protecting the liver against injury and fibrogenesis caused by CCl(4) in rats, and the underlying mechanisms.

3-Fluoro-4-nitro-phenyl 4-methyl-benzene-sulfonate.

In the title compound, C(13)H(10)FNO(5)S, the dihedral angle between the benzene rings is 47.63 (14)°. In the crystal, π-π stacking occurs between nearly parallel benzene rings of adjacent mol-ecules, the centroid-centroid distance being 3.

2,2-Dimethyl-5-{[(4-nitro-phen-yl)amino]-methyl-idene}-1,3-dioxane-4,6-dione.

In the title compound, C(13)H(12)N(2)O(6), the dihedral angle between the benzene ring and the amino-methyl-ene unit is 5.42 (16)°, while the angle between the amino-methyl-ene unit and the dioxane ring is 3.06 (43)°.

5-[(2-Chloro-4-nitro-anilino)methyl-idene]-2,2-dimethyl-1,3-dioxane-4,6-dione.

In the title compound, C(13)H(11)ClN(2)O(6), the dihedral angles between the benzene ring and the amino-methyl-ene unit and between the amino-methyl-ene group and the dioxane ring are 8.19 (14) and 1.39 (17)°, respectively.

Development of PLGA nanoparticles simultaneously loaded with vincristine and verapamil for treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the malignant tumors with poor chemo-sensitivity to vincristine sulfate (VCR) due to multi-drug resistance (MDR). Combinations of encapsulated VCR and verapamil hydrochloride (VRP, a chemo-sensitizer) might be a potential strategy to improve HCC therapeutic efficacy of VCR. PLGA nanoparticles (PLGANPs) simultaneously loaded with VCR and VRP (CVn) were prepared.

A phosphoinositide 3-kinase-gamma inhibitor, AS605240 prevents bleomycin-induced pulmonary fibrosis in rats.

Phosphoinositide 3-kinase-gamma (PI3Kgamma) has been identified to play the critical roles in inflammatory cells activation and recruitment in multiply inflammatory diseases and it promised to be a prospective target for relevant inflammatory diseases therapy. AS605240, a selective PI3Kgamma inhibitor, has been proved effective on several inflammatory diseases. In this study, we investigated the protective effect of AS605240 on bleomycin-induced pulmonary fibrosis in rats.

4-[4-(Piperidin-1-yl)piperidin-1-yl]benzonitrile.

In the title compound, C(17)H(23)N(3), both piperidine rings adopt chair conformations. In the crystal packing, intermolecular C-H⋯N hydrogen bonds and C-H⋯π interactions are present.

[SKLB-102 inhibits acute hepatitis induced by concanavalin A in mice].

Objective: To test the effect of 5-(4-methoxybenzylidene)-2-thioxo-dihydropyrimidine-4, 6 (1H, 5H)-dione (SKLB-102) on acute hepatic inflammatory induced by concanavalin A (ConA) in mice.

Methods: The inhibitive effect of SKLB-102 on RAW264.7 cell migration induced by recombinant rat monocyte chemotactic protein-1 (MCP-1) was tested.

Phosphoinositide 3-kinase gamma inhibitor ameliorates concanavalin A-induced hepatic injury in mice.

A pivotal role of phosphoinositide 3-kinase-gamma (PI3Kgamma) in inflammatory cell activation and recruitment makes it an attractive target for immunomodulatory therapy. In present study we investigated the therapeutic efficiency of AS605240, a selective PI3Kgamma inhibitor, on hepatitis and liver fibrosis in murine models induced by concanavalin A (ConA). Orally administration of AS605240 significantly improved survival, decreased the serum levels of alanine aminotransaminase (ALT), prevented inflammatory infiltration to liver in ConA-induced hepatitis.

5-(4-Chloro-anilinomethyl-ene)-2,2-dimethyl-1,3-dioxane-4,6-dione.

The title compound, C(13)H(12)ClNO(4), is approximately planar, with a dihedral angle of 8.23 (4)° between the mean plane of the amino-methyl-ene unit and the planar part of the dioxane ring. The dioxane ring has a half-boat conformation, in which the C atom between the dioxane O atoms is -0.