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Teng Ai, Rose Willett, Jessica Williams, Rui Ding, Daniel J Wilson, Jiashu Xie, Do-Hyung Kim, Rosa Puertollano, Liqiang Chen
Guided by antiproliferative activity in MIA PaCa-2 cells, we have performed preliminary structure-activity relationship studies on N-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)benzamides. Two selected compounds showed submicromolar antiproliferative activity and good metabolic stability. Both compounds reduced mTORC1 activity and increased autophagy at the basal level. In addition, they disrupted autophagic flux by interfering with mTORC1 reactivation and clearance of LC3-II under starvation/refeed conditions, as evidenced by accumulation of LC3-II and abnormal LC3 labeled punctae...
January 12, 2017: ACS Medicinal Chemistry Letters
Sarawoot Impeng, Siwarut Siwaipram, Sareeya Bureekaew, Michael Probst
We first investigate the feasibility of designing a Fe-oxo complex for the activation of alkane C-H bonds by (a) incorporating an Fe ion into a Zn-based cluster derived from a metal-organic framework (MOF) and (b) creating the Fe-oxo complex via decomposition of N2O over a Fe(2+)-substituted Zn-based cluster (Fe-Zn3O(pyrazole)6). From the energy profile, it turns out that both steps should be feasible and that the resulting Fe-oxo complex is stable. In the main step, we then investigate the reactivity of this Fe-oxo cluster for the C-H bond cleavage of ethane by calculating the reaction energy profile and analyzing the electronic structure along the relevant steps...
January 19, 2017: Physical Chemistry Chemical Physics: PCCP
Berelli Anupama, Airva Aruna, Vijjulatha Manga, Sreekanth Sivan, Madamsetty Vijay Sagar, Ravula Chandrashekar
Ternary Cu(II) complexes [Cu(II)(L)(bpy)Cl] 1, [Cu(II)(L)(Phen)Cl] 2 [L = 2,3-dimethyl-1-phenyl-4(2 hydroxy-5-methyl benzylideneamino)-pyrazol-5-one, bpy = 2,2(') bipyridine, phen =1,10 phenanthroline) were synthesized and characterized by elemental analyses, UV-Visible, FT-IR, ESR, Mass, thermogravimetric and SEM EDAX techniques. The complexes exhibit octahedral geometry. The interaction of the Cu(II) with cailf thymus DNA (CT-DNA) was explored by using absorption and fluorescence spectroscopic methods...
January 17, 2017: Journal of Fluorescence
Jeffrey M Witkin, Linda M Rorick-Kehn, Mark J Benvenga, Benjamin L Adams, Scott D Gleason, Karen M Knitowski, Xia Li, Steven Chaney, Julie F Falcone, Janice W Smith, Julie Foss, Kirsti Lloyd, John T Catlow, David L McKinzie, Kjell A Svensson, Vanessa N Barth, Miguel A Toledo, Nuria Diaz, Celia Lafuente, Alma Jiménez, Alfonso Benito, Conception Pedregal, Maria A Martínez-Grau, Anke Post, Michael A Ansonoff, John E Pintar, Michael A Statnick
Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide whose receptor is designated ORL1 or nociceptin receptor (NOP). We utilized a potent, selective, and orally bioavailable antagonist with documented engagement with NOP receptors in vivo to assess antidepressant- and anxiolytic-related pharmacological effects of NOP receptor blockade along with measures of cognitive and motor impingement. LY2940094 ([2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)methyl]-3-methyl-pyrazol-1-yl]-3-pyridyl]methanol) displayed antidepressant-like behavioral effects in the forced-swim test in mice, an effect absent in NOP (-/-) mice...
December 2016: Pharmacology Research & Perspectives
Anton Vladimirovich Lukashenko, Vitaly Aleksandrovich Osyanin, Dmitry Vladimirovich Osipov, Yuri N Klimochkin
A simple and efficient method for the synthesis of 4H-chromenes and 1H-benzo[f]chromenes containing trifluoroacetyl or aroyl group in pyran ring from o-quinone methide precursors and push-pull enaminoketones has been developed. The chromenes are presumably formed through an initial oxa-Diels-Alder reaction followed by an elimination of amine. Possibility of further transformations of given chromenes to o-hydroxybenzylated pyrazoles, isoxazoles and pyridines has been demonstrated.
January 16, 2017: Journal of Organic Chemistry
Quande Wang, Lisi He, Kin Keung Li, Gavin Chit Tsui
A copper-mediated synthesis of 4-(trifluoromethyl)pyrazoles is described. In one step from readily accessible α,β-alkynic tosylhydrazones, a remarkable domino sequence of cyclization, trifluoromethylation, and detosylation takes place to furnish the 4-CF3 N-H pyrazole cores with good functional group compatibility. The reaction conditions are mild and convenient, at room temperature in air, using the commercially available trifluoromethyltrimethylsilane (TMSCF3) as the CF3 source. The method can be applied to the synthesis of a 4-CF3 analogue of the anti-inflammatory drug celecoxib...
January 12, 2017: Organic Letters
Wenjun Zhang, Chunfang Yang, Chunshuai Huang, Liping Zhang, Haibo Zhang, Qingbo Zhang, Cheng-Shan Yuan, Yiguang Zhu, Changsheng Zhang
Pyrazolofluostatins A-C (1-3), three new benzo[a]fluorenes with an unprecedented carbon skeleton, were obtained from the South China Sea-derived Micromonospora rosaria SCSIO N160. Their structures were elucidated by extensive spectroscopic analyses. The structure of pyrazolofluostatin A (1) was confirmed by X-ray crystallographic analysis. Notably, 1-3 possessed a benzo[cd]indeno[2,1-f]indazol skeleton with a pyrazole-fused 6/5/6/6/5 pentacyclic ring system. Pyrazolofluostatin A (1) showed moderate antioxidation activity (EC50 48...
January 11, 2017: Organic Letters
Devin Allison, Evan Delancey, Hunter Ramey, Conrad Williams, Zakeyah Ali Alsharif, Hessa Al-Khattabi, Allyn Ontko, David Gilmore, Mohammad A Alam
Microbial resistance to antibiotics is a global concern. The World Health Organization (WHO) has identified antimicrobial resistance as one the three greatest threats for human beings in the 21st century. Without urgent and coordinated action, the world is moving toward a post-antibiotic era, in which normal infections or minor injuries may become fatal. In an effort to find new agents, we report the synthesis and antimicrobial activities of 40 novel 1,3-diphenyl pyrazole derivatives. These compounds have shown zones of growth inhibition up to 85mm against Acinetobacter baumannii...
December 29, 2016: Bioorganic & Medicinal Chemistry Letters
Wen Zhang, Chun Pong Tam, Jiawei Wang, Jack W Szostak
Many high-resolution crystal structures have contributed to our understanding of the reaction pathway for catalysis by DNA and RNA polymerases, but the structural basis of nonenzymatic template-directed RNA replication has not been studied in comparable detail. Here we present crystallographic studies of the binding of ribonucleotide monomers to RNA primer-template complexes, with the goal of improving our understanding of the mechanism of nonenzymatic RNA copying, and of catalysis by polymerases. To explore how activated ribonucleotides recognize and bind to RNA templates, we synthesized an unreactive phosphonate-linked pyrazole analogue of guanosine 5'-phosphoro-2-methylimidazolide (2-MeImpG), a highly activated nucleotide that has been used extensively to study nonenzymatic primer extension...
December 28, 2016: ACS Central Science
Mei-Quan Cai, Li Feng, Li-Qiu Zhang
Aminopyrine (AMP) has been frequently detected in the aquatic environment. In this study, the transformation mechanism of AMP by free available chlorine (FAC) oxidation was investigated. The results showed that FAC reacted with AMP rapidly, and a 74% elimination was achieved for 1.30 μM AMP after 2 min at 14.08 μM FAC dose. AMP chlorination was strongly pH-dependent, and its reaction included second- and third-order kinetic processes. Three active FAC species, including chlorine monoxide (Cl2O), molecular chlorine (Cl2), and hypochlorous acid (HOCl), were observed to contribute to AMP degradation...
December 26, 2016: Chemosphere
Veera Swamy Konkala, Pramod Kumar Dubey
An efficient and green synthesis of pyrazolyl-2,4-thiazolidinediones/pyrazolyl-2-iminothiazolidine-4-ones 7(a-j) has been developed using urea/thiourea as catalyst. Two methods (A and B) have been introduced for the synthesis of these compounds. Method A performed well for the condensation of pyrazole-4-carboxaldehydes 4(a-e) with 2-iminothiazolidin-4-one 5a and with 2,4-thiazolidinedione 5b at 110 [Formula: see text] for 16-20 min to furnish (Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)thiazolidine-2,4-diones 7(a-j) in excellent yields...
January 4, 2017: Molecular Diversity
Galal Elgemeie, Nahed Fathy, Wafaa Zaghary, Ayman Farag
A one-pot reaction of a sodium 2-cyanoethylene-1-thiolate salt with 2,3,4,6-tetra-O-acetyl-α-D-gluco- and galactopyranosyl bromides affords a new class of cyanoethylene thioglycosides. The conversion to the corresponding 5-aminopyrazoles confirms the E-configuration of these cyanoethylene thioglycosides.
January 3, 2017: Nucleosides, Nucleotides & Nucleic Acids
René Nowak, Eko Adi Prasetyanto, Luisa De Cola, Beate Bojer, Renée Siegel, Jürgen Senker, Ernst Rössler, Birgit Weber
Here we report the completely reversible spin state switch of the naturally diamagnetic tris(bipyridine)iron(ii) complex and the spin crossover complex bis(2,6-bis(1H-pyrazol-3-yl)pyridine)iron(ii) by the variation of the pH followed by (1)H-NMR, UV-Vis spectroscopy, and magnetic and relaxivity measurements in solution and as composite materials encapsulated in a zeolite matrix.
January 3, 2017: Chemical Communications: Chem Comm
Jean'ne Shreeve, Ping Yin, Lauren Mitchell, Damon Parrish
In the design of advanced energetic materials, high-dense explosophores play a pivotal role because of their remarkable enhancement of both density and molecular stability. However, given the requirement of high energetic performance, introduction of an excess of various functionalities often weakens the chemical bonds in molecules leading to an unexpected decrease in thermal and impact stabilities. Using diversified functionalization strategies, a comparative study involving various nitropyrazole anions shows that these are crucially important in determining performance and stability...
January 2, 2017: Chemistry, An Asian Journal
Heba A H Elshemy, Eman K A Abdelall, Amany A Azouz, Abeer Moawad, Waleed A M Ali, Nesreen M Safwat
Three novel triazines series were prepared. These series are pyrazolines (4a and 4b), pyrazoles (6a, 6b and 8a-d) and isoxazoles (7a and 7b). Such series were designed as COX-2 inhibitors. All compounds were characterized by using spectroscopic methods and elemental analysis. Regarding COX-2, compounds 5b, 4a and 3b were the most active with IC50 in the range of 0.55-0.87 μM. Most of synthesized compounds were relatively more potent to celecoxib (0.78 μM), diclofenac (2.94 μM) and indomethacin (7.24 μM)...
December 23, 2016: European Journal of Medicinal Chemistry
Hui Zhou, Zhao Wei, Jinlong Zhang, Huameng Yang, Chungu Xia, Gaoxi Jiang
A highly enantioselective regiodivergent addition of alkoxyallenes to pyrazolones was developed to afford multiply functionalized alkylated products bearing a quaternary carbon stereocenter in high yields with excellent stereoselectivities. One approach is enabled by palladium catalysis, thus leading to branched allylic pyrazol-5-ones under mild reaction conditions. The other is catalyzed by a chiral Brønsted acid to give linear products exclusively. Moreover, the usefulness of this new method was highlighted by converting the allylic products into other interesting multifunctionalized pyrazolone derivatives which would be of great potential for the exploitation of pharmaceutically important molecules...
December 30, 2016: Angewandte Chemie
Lingwei Wang, Jie Li, Jian Zhang, Qi He, Xuanwen Weng, Minjie Guan, Chen Qiu
Airway hyperresponsiveness (AHR), airway remodeling and inflammation are the fundamental pathological alterations that occur in asthma. Transient receptor potential canonical 3 (TRPC3) has been implicated in diverse functions of airway smooth muscle cells (ASMCs) in asthma. However, the underlying mechanisms remain incompletely understood. We investigated the mRNA and protein expression of TRPC3 in ASMCs from normal and OVA-sensitized mouse. And the effects of inhibition or knockdown of TRPC3 with Ethyl-1- (4- (2,3,3-trichloroacrylamide) phenyl) -5 - (trifluoromethyl) -1H -pyrazole -4-carboxylate (Pyr3) and lentiviral shRNA on OVA-sensitized mouse AHR, airway remodeling, circulating inflammatory cytokines, cell proliferation and migration...
December 26, 2016: Biochemical and Biophysical Research Communications
JinFeng Zhang, Le Su, Qing Ye, ShangLi Zhang, HsiangFu Kung, Fan Jiang, GuoSheng Jiang, JunYing Miao, BaoXiang Zhao
Nuclear factor-erythroid 2-related factor 2 (Nrf2) is persistently activated in many human tumors including acute myeloid leukemia (AML). Therefore, inhibition of Nrf2 activity may be a promising target in leukemia therapy. Here, we used an antioxidant response element-luciferase reporter system to identify a novel pyrazolyl hydroxamic acid derivative, 1-(4-(tert-Butyl)benzyl)-3-(4-chlorophenyl)-N-hydroxy-1H pyrazole-5-carboxamide (4f), that inhibited Nrf2 activity. 4f had a profound growth-inhibitory effect on three AML cell lines, THP-1, HL-60 and U937, and a similar anti-growth effect in a chick embryo model...
December 9, 2016: Oncotarget
Liming Hu, Tingting Cao, Yongjuan Lv, Yiming Ding, Leifu Yang, Qiang Zhang, Mingzhou Guo
A series of 4-((pyrazolo[1,5-a]pyrimidin-6-yl)-1H-pyrazol-1-yl)phenyl-3-benzamide derivatives and 4-((imidazo[1,2-b]pyridazin-3-yl)-1H-pyrazol-1-yl-)phenyl-3-benzamide derivatives were designed, synthesized as new BCR-ABL tyrosine kinase inhibitors by using combinational strategies of scaffold hopping and conformational constraint. These new compounds were screened for BCR-ABL1 kinase inhibitory activity, and most of them appeared good inhibitory activity against BCR-ABL1 kinase. One of the most potent compounds 16a strongly suppressed BCR-ABL1 kinase with IC50 value of 8...
October 18, 2016: Bioorganic & Medicinal Chemistry Letters
Muhammad Arba, Sunandar Ihsan, La Ode Ahmad Nur Ramadhan, Daryono Hadi Tjahjono
Cyclin-Dependent Kinases (CDKs) are known to play crucial roles in controlling cell cycle progression of eukaryotic cell and inhibition of their activity has long been considered as potential strategy in anti-cancer drug research. In the present work, a series of porphyrin-anthraquinone hybrids bearing meso-substituents, i.e. either pyridine or pyrazole rings were designed and computationally evaluated for their Cyclin Dependent Kinase-2 (CDK2) inhibitory activity using molecular docking, molecular dynamics simulation, and binding free energy calculation...
December 19, 2016: Computational Biology and Chemistry
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