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1.
Front Pharmacol ; 11: 599857, 2020.
Article in English | MEDLINE | ID: mdl-33324226

ABSTRACT

As an invasive nuclear medical imaging technology, positron emission tomography (PET) possess the possibility to imaging the distribution as well as the density of selective receptors via specific PET tracers. Inspired by PET, the development of radio-chemistry has greatly promoted the progress of innovative imaging PET tracers for adenosine receptors, in particular adenosine A2A receptors (A2ARs). PET imaging of A2A receptors play import roles in the research of adenosine related disorders. Several radio-tracers for A2A receptors imaging have been evaluated in human studies. This paper reviews the recent research progress of PET tracers for A2A receptors imaging, and their applications in the diagnosis and treatment of related disease, such as cardiovascular diseases, autoimmune diseases, neurodegenerative and psychiatric disease. The future development of A2A PET tracers were also discussed.

2.
Bioorg Med Chem Lett ; 27(14): 3201-3204, 2017 07 15.
Article in English | MEDLINE | ID: mdl-28539219

ABSTRACT

Herein we report the discovery of a series of new small molecule inhibitors of histone lysine demethylase 4D (KDM4D). Molecular docking was first performed to screen for new KDM4D inhibitors from various chemical databases. Two hit compounds were retrieved. Further structural optimization and structure-activity relationship (SAR) analysis were carried out to the more selective one, compound 2, which led to the discovery of several new KDM4D inhibitors. Among them, compound 10r is the most potent one with an IC50 value of 0.41±0.03µM against KDM4D. Overall, compound 10r could be taken as a good lead compound for further studies.


Subject(s)
Jumonji Domain-Containing Histone Demethylases/antagonists & inhibitors , Nitriles/chemistry , Pyrazoles/chemistry , Pyrimidines/chemistry , Binding Sites , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Jumonji Domain-Containing Histone Demethylases/metabolism , Molecular Docking Simulation , Nitriles/chemical synthesis , Nitriles/metabolism , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Protein Structure, Tertiary , Structure-Activity Relationship
3.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 47(1): 19-22, 38, 2016 Jan.
Article in Chinese | MEDLINE | ID: mdl-27062775

ABSTRACT

OBJECTIVE: To synthesize and study the specific binding affinity of tumor-penetrating peptide YCCS to non-small cell lung carcinoma (NSCLC) cells in vitro. METHODS: YCCS peptide was designed by fusing the neuropilin-1 (NRP-1) binding sequence and NSCLC binding peptide CS. YCCS peptide was synthesized and fluorescent labeled with N-terminal FITC. NRP-1 positive human NSCLC cell A549, NRP-1 positive human breast cancer cell MDA-MB-231, normal human bronchial epithelium HBE135-E6E7 and human liver cell HL-7702 were incubated respectively, then we observed the specific binding affinity of tumor-penetrating peptide YCCS to NSCLC cells. RESULTS: After treated with 5 µmol/L peptide, significant fluorescent signals of FITC-YCCS peptide were demonstrated only in NSCLC A549 cells but marginal captured signal in MDA-MB-231, normal human HBE135-E6E7 or HL-7702 cells, which revealed specific NSCLC cells binding affinity. In 20 µmol/L treated group, non-specific binding were found in MDA-MB-231 and HL-7702 cells. CONCLUSION: The results of this novel designed YCCS peptide indicated a promising strategy for improving tumor penetrating with delivery capability of drugs to NSCLC A549 cells when treated with 5 µmol/L peptide.


Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Cell-Penetrating Peptides/metabolism , Neuropilin-1/chemistry , Binding Sites , Cell Line, Tumor , Drug Carriers/metabolism , Humans
4.
Chem Biol Drug Des ; 87(4): 569-74, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26577270

ABSTRACT

Receptor interacting protein 1 (RIP1) kinase plays an important role in necroptosis, and inhibitors of the RIP1 kinase are thought to have a potential therapeutic value in the treatment of diseases related to necrosis. Herein, we report the structural optimization of a RIP1 kinase inhibitor, 1-(2,4-dichlorobenzyl)-3-nitro-1H-pyrazole (1a). A number of 1-benzyl-1H-pyrazole derivatives were synthesized and structure-activity relationship (SAR) analysis led to the discovery of a potent compound, 4b, which showed a Kd value of 0.078 µm against the RIP1 kinase and an EC50 value of 0.160 µm in a cell necroptosis inhibitory assay. Compound 4b also displayed considerable ability to protect the pancreas in an l-arginine-induced pancreatitis mouse model.


Subject(s)
Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Animals , Drug Design , HT29 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Protein Kinase Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 25(22): 5449-53, 2015 Nov 15.
Article in English | MEDLINE | ID: mdl-26428871

ABSTRACT

Despite a potential application of PRMT1 inhibitors in cancer treatment, very few of PRMT1 inhibitors have been reported. To obtain novel potent PRMT1 inhibitors, structure optimizations towards a hit compound, 4-((6-chloro-5-nitropyrimidin-4-yl)amino)benzimidamide, were carried out. A series of 4-((5-nitropyrimidin-4-yl)amino)benzimidamide derivatives were synthesized. Structure-activity relationship analysis led to the discovery of a number of PRMT1 inhibitors. The most potent compound corresponds to compound 6d, which showed an IC50 value of 2.0 µM against PRMT1. This compound also displayed a considerable anti-proliferative activity against three tumor cell lines, DLD-1, T24 and SH-SY-5Y, with IC50 values of 4.4 µM, 13.1 µM and 11.4 µM, respectively.


Subject(s)
Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Drug Discovery , Models, Biological , Protein-Arginine N-Methyltransferases/antagonists & inhibitors , Amides/chemistry , Amides/pharmacology , Animals , Binding Sites , Blotting, Western , Cell Line, Tumor , Cell Proliferation/drug effects , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Molecular Structure , Nitro Compounds/chemistry , Nitro Compounds/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship
6.
J Med Chem ; 58(9): 3957-74, 2015 May 14.
Article in English | MEDLINE | ID: mdl-25835317

ABSTRACT

A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were designed and synthesized. Structure-activity relationship (SAR) analysis of these compounds led to the discovery of compound 1j, which showed the highest inhibitory potency against the Src kinase and the most potent antiviability activity against the typical TNBC cell line MDA-MB-231 among all the synthesized compounds. Further kinase inhibition assays showed that compound 1j was a multikinase inhibitor and potently inhibited Src (IC50 = 0.0009 µM) and MAPK signaling protein kinases B-RAF and C-RAF. In an MDA-MB-231 xenograft mouse model, a once-daily dose of compound 1j at 30 mg/kg for 18 days completely suppressed the tumor growth with a tumor inhibition rate larger than 100% without obvious toxicity. It also displayed good pharmacokinetic properties in a preliminary pharmacokinetic assay. Western blot and immunohistochemical assays revealed that compound 1j significantly inhibited Src and MAPK signaling and markedly induced apoptosis in tumor tissues.


Subject(s)
Acetylene/analogs & derivatives , Acetylene/chemistry , Antineoplastic Agents/chemistry , Benzamides/chemistry , Pyrazoles/chemistry , Pyrimidines/chemistry , Triple Negative Breast Neoplasms/drug therapy , src-Family Kinases/antagonists & inhibitors , Acetylene/pharmacokinetics , Acetylene/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Benzamides/pharmacokinetics , Benzamides/pharmacology , Cell Cycle/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Drug Design , Drug Screening Assays, Antitumor , Heterografts , Humans , Male , Mice, SCID , Neoplasm Transplantation , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Triple Negative Breast Neoplasms/pathology , src-Family Kinases/chemistry
7.
J Psychiatr Res ; 45(11): 1518-24, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21820672

ABSTRACT

Free and Easy Wanderer Plus (FEWP) is a polyherbal preparation which therapeutic benefits have been extensively evaluated in patients with various depressive disorders. The purpose of this meta-analysis was to assess the overall effectiveness and safety of FEWP. Following systematic review, a total of 14 high-quality randomized controlled trials (RCTs) were identified and included in the meta-analysis. Statistically greater treatment effects were found in FEWP monotherapy compared to placebo and in FEWP combined with conventional anti-depressants (CADs) compared to CADs alone. Patients taking FEWP alone and combined with CADs experienced fewer adverse events of dizziness, headache, dry mouth, nausea, and constipation compared to CADs alone. These data suggest that FEWP may be an effective herbal agent in treating depressive symptoms. The addition of FEWP also enhances antidepressant effects of CADs. FEWP may have a higher safety profile compared to CADs.


Subject(s)
Antidepressive Agents/administration & dosage , Antidepressive Agents/adverse effects , Depressive Disorder/drug therapy , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/adverse effects , Constipation/chemically induced , Dizziness/chemically induced , Drug Therapy, Combination/adverse effects , Headache/chemically induced , Humans , Nausea/chemically induced , Randomized Controlled Trials as Topic , Treatment Outcome , Xerostomia/chemically induced
8.
Acta Crystallogr Sect E Struct Rep Online ; 65(Pt 8): o1837, 2009 Jul 11.
Article in English | MEDLINE | ID: mdl-21583538

ABSTRACT

The mol-ecule of the title compound, C(9)H(6)Cl(2)N(2)O, displays an E conformation about the C=N double bond. The N-cyano-imidate fragment is substanti-ally planar [maximum deviation 0.010 (4) Å] and perpendicular to the benzene ring [dihedral angle = 88.50 (14)°]. In the crystal packing, inter-molecular Cl⋯Cl inter-actions [3.490 (2) Å] are observed.

9.
J Biol Chem ; 282(5): 3391-402, 2007 Feb 02.
Article in English | MEDLINE | ID: mdl-17135237

ABSTRACT

Cysteine dioxygenase is a non-heme mononuclear iron metalloenzyme that catalyzes the oxidation of cysteine to cysteine sulfinic acid with addition of molecular dioxygen. This irreversible oxidative catabolism of cysteine initiates several important metabolic pathways related to diverse sulfurate compounds. Cysteine dioxygenase is therefore very important for maintaining the proper hepatic concentration of intracellular free cysteine. Mechanisms for mouse and rat cysteine dioxygenases have recently been reported based on their crystal structures in the absence of substrates, although there is still a lack of direct evidence. Here we report the first crystal structure of human cysteine dioxygenase in complex with its substrate L-cysteine to 2.7A, together with enzymatic activity and metal content assays of several single point mutants. Our results provide an insight into a new mechanism of cysteine thiol dioxygenation catalyzed by cysteine dioxygenase, which is tightly associated with a thioether-bonded tyrosine-cysteine cofactor involving Tyr-157 and Cys-93. This cross-linked protein-derived cofactor plays several key roles different from those in galactose oxidase. This report provides a new potential target for therapy of diseases related to human cysteine dioxygenase, including neurodegenerative and autoimmune diseases.


Subject(s)
Coenzymes/metabolism , Cysteine Dioxygenase/chemistry , Cysteine Dioxygenase/metabolism , Cysteine , Tyrosine , Amino Acid Sequence , Animals , Cloning, Molecular , Coenzymes/chemistry , Consensus Sequence , Conserved Sequence , Crystallography, X-Ray , Cysteine Dioxygenase/genetics , Cysteine Dioxygenase/isolation & purification , Humans , Kinetics , Mass Spectrometry , Molecular Sequence Data , Mutagenesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , Recombinant Proteins/metabolism , Sequence Alignment , Sequence Homology
10.
Article in English | MEDLINE | ID: mdl-16511085

ABSTRACT

Enolase-phosphatase E1 (MASA) is a bifunctional enzyme in the ubiquitous methionine-salvage pathway and catalyzes the continuous reaction of 2,3-diketo-5-methylthio-1-phosphopentane to yield the acireductone metabolite. Recombinant human E1 enzyme has been crystallized using the hanging-drop vapour-diffusion method and diffraction-quality crystals were grown at 291 K using PEG 4000 as precipitant. Diffraction data were collected to 1.7 A resolution from SeMet-derivative crystals at 100 K using synchrotron radiation. The crystals belong to space group P2(1)2(1)2(1), with unit-cell parameters a = 54.02, b = 57.55, c = 87.32 A. The structure was subsequently solved by the multi-wavelength anomalous diffraction (MAD) phasing method.


Subject(s)
Multienzyme Complexes/chemistry , Multienzyme Complexes/isolation & purification , Crystallization , Crystallography, X-Ray , Escherichia coli/genetics , Escherichia coli/metabolism , Humans , Multienzyme Complexes/genetics , Multienzyme Complexes/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Structure-Activity Relationship
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