- Design, synthesis, and biological evaluation of novel thiazolyl substituted bis-pyrazole oxime derivatives with potent antitumor activities by selectively inducing apoptosis and ros in cancer cells
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Background: A large number of pyrazole derivatives have different biological activities such as anticancer, antimicrobial, anti-inflammatory, analgesic and antiepileptic activity. Among them, pyrazole oximes have attracted much attention due to their potential pharmacological activities, particularly anticancer activities. Objective: Our goal is to synthesize novel thiazolyl substituted bis-pyrazole oxime derivatives with potent antitumor activities by selectively inducing apoptosis and Reactive Oxygen Species (ROS) accumulation in cancer cells. Methods: Eighteen bis-pyrazole oximes were synthesized by conjugating thiazolyl substituted pyrazoles with pyrazoxime. The target compounds were characterized by1HNMR,13C NMR, and HRMS, and screened for their antiproliferative activity against four cancer cells in MTT assay. The most potent compound was examined for its inhibitory effect and ROS accumulation in both cancer cells HCT116 and normal intestinal epithelial cells CCD841. Finally, the most potent compound was further evaluated for its apoptotic induction by flow cytometry analysis and immunoblot analysis of apoptosis-related proteins and DNA damage proteins. Results: Most compounds displayed potent antiproliferative activity against four cancer cell lines in vitro, displaying potencies superior to 5-FU. In particular, the most potent compound 13l selectively inhibited proliferation of colorectal cancer HCT116 cells but not normal colon CCD841 cells. Furthermore, compound 13l also selectively promoted intracellular ROS accumulation in HCT116 which was involved in 13l inhibition of cancer cell proliferation and induction of cell apoptosis. Finally, compound 13l also dose-dependently induced cancer cell apoptosis by regulating apoptotic and DNA damage related proteins expressions. Conclusion: Our synthetic bis-pyrazole oxime derivatives possess potent antitumor activities by selectively inducing apoptosis and ROS accumulation in cancer cells, which may hold great promise as therapeutic agents for the treatment of human cancers.
- Xiong, Biao,Chen, Shi,Zhu, Peng,Huang, Meiling,Gao, Weijie,Zhu, Rui,Qian, Jianqiang,Peng, Yanfu,Zhang, Yanan,Dai, Hong,Ling, Yong
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p. 743 - 754
(2019/11/02)
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- Fragment-based lead generation of 5-phenyl-1H-pyrazole-3-carboxamide derivatives as leads for potent factor xia inhibitors
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FXIa is suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding. In this paper, we defined 5-phenyl-1H-pyrazole-3-carboxylic acid derivatives as privileged fragments for FXIa inhibitors' lead discovery. After repla
- Wei, Qunchao,Zheng, Zhichao,Zhang, Shijun,Zheng, Xuemin,Meng, Fancui,Yuan, Jing,Xu, Yongnan,Huang, Changjiang
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- 1. 3, 5 - tri-substituted pyrazole compound and its preparation method and application
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The invention discloses 1,3,5-trisubstituted pyrazole compounds, and a preparation method and application thereof. The structure of the compounds is shown as a general formula (I), and in the general formula (I), R1 is hydrogen, halogens, methyl or triflu
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Paragraph 0114; 0115; 0116; 0118
(2017/04/18)
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- Base mediated 1,3-dipolar cycloaddition of α-substituted vinyl phosphonates with diazo compounds for synthesis of 3-pyrazolylphosphonates and 5-pyrazolcarboxylates
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5-Aryl-substituted pyrazol-3-ylphosphonates have been conveniently synthesized by 1,3-dipolar cycloaddition of 1-formamidovinylphosphonates and aryldiazomethanes under K2CO3/MeOH conditions at room temperature. These pyrazoles are formed in one pot via spontaneous elimination of formamide. Basic conditions prevent competitive formation of cyclopropylphosphonates. 3-Aryl substituted pyrazol-5-carboxylates can be synthesized by the same methodology from 1-arylvinylphosphonates and ethyl diazoacetate, although a stronger base NaH is necessary to ensure the success of the aromatization stage with the elimination of the diethoxylphosphoryl moiety.
- Goulioukina, Nataliya S.,Makukhin, Nikolay N.,Shinkarev, Egor D.,Grishin, Yuri K.,Roznyatovsky, Vitaly A.,Beletskaya, Irina P.
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p. 10000 - 10010
(2016/11/06)
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- Cascade regioselective synthesis of pyrazoles from nitroallylic acetates and N-tosyl hydrazine
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A simple, practical, and regioselective synthetic protocol for the formation of pyrazoles was developed. Unlike all other previously reported reactions of nitroallylic acetates, this process was initiated by a S N2 reaction at the electrophilic γ site. A plausible mechanism for the cascade SN2-Michael synthesis is proposed.
- Shao, Nana,Chen, Tong,Zhang, Taotao,Zhu, Huajian,Zheng, Qunxiong,Zou, Hongbin
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p. 795 - 799
(2014/01/23)
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- Pyrazole-oxadiazole conjugates: Synthesis, antiproliferative activity and inhibition of tubulin polymerization
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A number of pyrazole-oxadiazole conjugates were synthesized and evaluated for their ability to function as antiproliferative agents on various human cancer cell lines. These conjugates are comprised of pyrazole and oxadiazole scaffolds closely attached to each other without any spacer as two structural classes. The Type I class has a trimethoxy substituent and the type II class has a 3,4-(methylenedioxy) substituent on their A rings. Among these conjugates, 11a, 11d and 11f manifest potent cytotoxicity with IC50values ranging from 1.5 μM to 11.2 μM and inhibit tubulin polymerization with IC50values of 1.3 μM, 3.9 μM and 2.4 μM respectively. The cell cycle assay showed that treatment with these conjugates results in accumulation of cells in the G2/M phase and disrupts the microtubule network. Elucidation of zebrafish embryos revealed that the conjugates cause developmental defects. Molecular docking simulations determined the binding modes of these potent conjugates at the colchicine site of tubulin.
- Kamal, Ahmed,Shaik, Anver Basha,Polepalli, Sowjanya,Santosh Reddy, Vangala,Bharath Kumar,Gupta, Soma,Rama Krishna,Nagabhushana, Ananthamurthy,Mishra, Rakesh K.,Jain, Nishant
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p. 7993 - 8007
(2015/02/18)
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- Synthesis, Structure-Activity Relationship, and Pharmacophore Modeling Studies of Pyrazole-3-Carbohydrazone Derivatives as Dipeptidyl Peptidase IV Inhibitors
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Type 2 diabetes mellitus (T2DM) is a metabolic disease and a major challenge to healthcare systems around the world. Dipeptidyl peptidase IV (DPP-4), a serine protease, has been rapidly emerging as an effective therapeutic target for the treatment for T2DM. In this study, a series of novel DPP-4 inhibitors, featuring the pyrazole-3-carbohydrazone scaffold, have been discovered using an integrated approach of structure-based virtual screening, chemical synthesis, and bioassay. Virtual screening of SPECS Database, followed by enzymatic activity assay, resulted in five micromolar or low-to-mid-micromolar inhibitory level compounds (1-5) with different scaffold. Compound 1 was selected for the further structure modifications in considering inhibitory activity, structural variability, and synthetic accessibility. Seventeen new compounds were synthesized and tested with biological assays. Nine compounds (6e, 6g, 6k-l, and 7a-e) were found to show inhibitory effects against DPP-4. Molecular docking models give rational explanation about structure-activity relationships. Based on eight DPP-4 inhibitors (1-5, 6e, 6k, and 7d), the best pharmacophore model hypo1 was obtained, consisting of one hydrogen bond donor (HBD), one hydrogen bond acceptor (HBA), and two hydrophobic (HY) features. Both docking models and pharmacophore mapping results are in agreement with pharmacological results. The present studies give some guiding information for further structural optimization and are helpful for future DPP-4 inhibitors design.
- Wu, Deyan,Jin, Fangfang,Lu, Weiqiang,Zhu, Jin,Li, Cui,Wang, Wei,Tang, Yun,Jiang, Hualiang,Huang, Jin,Liu, Guixia,Li, Jian
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experimental part
p. 897 - 906
(2012/07/27)
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- Design and synthesis of novel pyrazole-based Lp-PLA2 inhibitors
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A series of novel pyrazole-based lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitors have been designed and synthetized by a variety of acetophenones via a 10-step convergent approach. The synthetic approach is carefully opt
- Wang, Yi,Xu, Weiren,Shao, Hua,Xie, Yafei,Wang, Jianwu
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experimental part
p. 2039 - 2048
(2012/03/26)
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- Synthesis of pyrazole-3-carboxylates and pyrazole-1,5-dicarboxylates by one-pot cyclization of hydrazone dianions with diethyl oxalate
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The one-pot cyclization of hydrazone dianions with diethyl oxalate allows a convenient synthesis of pyrazole-3-carboxylates and pyrazole-1,5-dicarboxylates.
- Dang, Tung T.,Dang, Tuan T.,Fischer, Christine,G?rls, Helmar,Langer, Peter
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p. 2207 - 2215
(2008/09/18)
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- One-pot synthesis of pyrazole-5-carboxylates by cyclization of hydrazone 1,4-dianions with diethyl oxalate
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The cyclization of hydrazone dianions with diethyl oxalate afforded pyrazole-5-carboxylates.
- Dang, Tuan Thanh,Dang, Tung Thanh,Langer, Peter
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p. 3591 - 3593
(2008/02/02)
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- Design, synthesis, and preliminary biological evaluation of novel ethyl 1-(2′-hydroxy-3′-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxyla te
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We synthesized a series of novel small molecules, ethyl 1-(2′-hydroxy-3′-aroxypropyl)-3-aryl-1H-pyrazole-5-carboxyla te derivatives 3a-3o, by the reaction of ethyl 3-aryl-1H-pyrazole-5-carboxylate with 2-aryloxymethylepoxide in the presence of potassium c
- Wei, Fang,Zhao, Bao-Xiang,Huang, Bin,Zhang, Lu,Sun, Chun-Hui,Dong, Wen-Liang,Shin, Dong-Soo,Miao, Jun-Ying
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p. 6342 - 6347
(2007/10/03)
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- Pyrazole derivatives as partial agonists for the nicotinic acid receptor
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Nicotinic acid as a hypolipidemic agent appears unique due to its potential to increase HDL cholesterol levels to a greater extent than other drugs. However, it has some side effects, among which severe skin flushing is the most frequent and often limits patients' compliance. In a search for novel agonists for the recently identified and cloned G protein-coupled nicotinic acid receptor, we synthesized a series of substituted pyrazole-3-carboxylic acids that proved to have substantial affinity for this receptor. The affinities were measured by inhibition of [3H] nicotinic acid binding to rat spleen membranes. Potencies and intrinsic activities relative to nicotinic acid were determined by their effects on [35S]GTPγS binding to rat adipocyte and spleen membranes. Interestingly, most compounds were partial agonists. In particular, 2-diazabicyclo-[3,3,O 4,8]octa-3,8-diene-3-carboxylic acid (4c) and 5-propylpyrazole-3-carboxylic acid (4f) proved active with Ki values of approximately 0.15 μM and EC50 values of approximately 6 μM, while their intrinsic activity was only ~50% when compared to nicotinic acid. Even slightly more active was 5-butylpyrazole-3-carboxylic acid (4g) with a Ki value of 0.072 μM, an EC50 value of 4.12 μM, and a relative intrinsic activity of 75%. Of the aralkyl derivatives, 4q (5-(3-chlorobenzyl)pyrazole-3-carboxylic acid) was the most active with a relatively low intrinsic activity of 39%. Partial agonism of the pyrazole derivatives was confirmed by inhibition of G protein activation in response to nicotinic acid by these compounds. The pyrazoles both inhibited the maximum effect elicited by 100 μM nicotinic acid and concentration dependently shifted nicotinic acid concentration-response curves to the right, pointing to a competive mechanism of action.
- Van Herk,Brussee,Van den Nieuwendijk,Van der Klein,IJzerman,Stannek,Burmeister,Lorenzen
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p. 3945 - 3951
(2007/10/03)
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