1-(4-(methylsulfonyl)phenyl)-5-(p-tolyl)-1H-pyrazole-3-carboxylic acid | 960214-98-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-(4-(methylsulfonyl)phenyl)-5-(p-tolyl)-1H-pyrazole-3-carboxylic acid
• 英文别名: 1-(4-sulfamoylphenyl)-5-(p-tolyl)-1H-pyrazole-3-carboxylic acid；5-(4-Methylphenyl)-1-(4-methylsulfonylphenyl)pyrazole-3-carboxylic acid
• CAS: 960214-98-6
• 化学式: C₁₈H₁₆N₂O₄S
• 分子量: 356.402
• InChiKey: YXWUNVKPNNVSOO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  97.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(4-(methylsulfonyl)phenyl)-5-(p-tolyl)-1H-pyrazole-3-carboxylic acid 在 三异丙基硅烷醇 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 氯仿 为溶剂， 反应 1.5h， 生成 N-(7-(hydroxyamino)-7-oxoheptyl)-1-(4-(methylsulfonyl)phenyl)-5-(p-tolyl)-1H-pyrazole-3-carboxamide
  参考文献：
  名称：

  Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase

  摘要：

  We herein disclose a series of compounds with potent inhibitory activities towards histone deacetylases (HDAC) and cyclooxygenases (COX). These compounds potently inhibited the growth of cancer cell lines consistent with their anti-COX and anti-HDAC activities. While compound 2b showed comparable level of COX-2 selectivity as celecoxib, compound lib outperformed indomethacin in terms of selectivity towards COX-2 relative to COX-1. An important observation with our lead compounds (2b, 8, 11b, and 17b) is their enhanced cytotoxicity towards androgen dependent prostate cancer cell line (LNCaP) relative to androgen independent prostate cancer cell line (DU-145). Interestingly, compounds 2b and 17b arrested the cell cycle progression of LNCaP in the S-phase, while compound 8 showed a G0/G1 arrest, similar to SAHA. Relative to SAHA, these compounds displayed tumor-selective cytotoxicity as they have low anti-proliferative activity towards healthy cells (VERO); an attribute that makes them attractive candidates for drug development. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2016.12.032
• 作为产物：
  描述：

  ethyl 1-(4-(methylsulfonyl)phenyl)-5-(p-tolyl)-1H-pyrazole-3-carboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 以100%的产率得到1-(4-(methylsulfonyl)phenyl)-5-(p-tolyl)-1H-pyrazole-3-carboxylic acid
  参考文献：
  名称：

  Bifunctional conjugates with potent inhibitory activity towards cyclooxygenase and histone deacetylase

  摘要：

  We herein disclose a series of compounds with potent inhibitory activities towards histone deacetylases (HDAC) and cyclooxygenases (COX). These compounds potently inhibited the growth of cancer cell lines consistent with their anti-COX and anti-HDAC activities. While compound 2b showed comparable level of COX-2 selectivity as celecoxib, compound lib outperformed indomethacin in terms of selectivity towards COX-2 relative to COX-1. An important observation with our lead compounds (2b, 8, 11b, and 17b) is their enhanced cytotoxicity towards androgen dependent prostate cancer cell line (LNCaP) relative to androgen independent prostate cancer cell line (DU-145). Interestingly, compounds 2b and 17b arrested the cell cycle progression of LNCaP in the S-phase, while compound 8 showed a G0/G1 arrest, similar to SAHA. Relative to SAHA, these compounds displayed tumor-selective cytotoxicity as they have low anti-proliferative activity towards healthy cells (VERO); an attribute that makes them attractive candidates for drug development. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2016.12.032

文献信息

• Methods and compositions for diagnostic and therapeutic targeting of COX-2
  申请人：Marnett J. Lawrence

  公开号：US20070292352A1

  公开（公告）日：2007-12-20

  The presently disclosed subject matter provides compositions that selectively bind cyclooxygenase-2 and comprise a therapeutic and/or diagnostic moiety. Also provided are methods for using the disclosed compositions for diagnosing (i.e., by imaging) a target cell and/or treating a disorder associated with a cyclooxygenase-2 biological activity.

  目前公开的主题提供了选择性结合环氧合酶-2并包含治疗和/或诊断基团的组合物。还提供了使用公开的组合物进行诊断（即通过成像）目标细胞和/或治疗与环氧合酶-2生物活性相关的疾病的方法。
• METHODS AND COMPOSITIONS FOR DIAGNOSTIC AND THERAPEUTIC TARGETING OF COX-2
  申请人：Marnett Lawrence J.

  公开号：US20130052138A1

  公开（公告）日：2013-02-28

  The presently disclosed subject matter provides compositions that selectively bind cyclooxygenase-2 and comprise a therapeutic and/or diagnostic moiety. Also provided are methods for using the disclosed compositions for diagnosing (i.e., by imaging) a target cell and/or treating a disorder associated with a cyclooxygenase-2 biological activity.

  目前披露的主题提供了选择性结合环氧合酶-2并包含治疗和/或诊断部分的组合物。还提供了使用所披露的组合物进行诊断（即通过成像）靶细胞和/或治疗与环氧合酶-2生物活性相关的疾病的方法。
• Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors
  作者：Luisa M. Bachmann、Maria Hanl、Felix Feller、Laura Sinatra、Andrea Schöler、Jens Pietzsch、Markus Laube、Finn K. Hansen

  DOI：10.3390/molecules28031061

  日期：——

  Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological in vitro assays demonstrated that several

  多靶点药物 (MTD) 是联合疗法的新兴替代品。由于已知组蛋白去乙酰化酶 (HDAC) 和环氧合酶 2 (COX-2) 在多种癌症类型中过表达，我们在此报告了双重 HDAC-COX 抑制剂库的设计、合成和生物学评估。所设计的化合物是通过使用预加载固相树脂的高效平行合成方法合成的。生物体外测定表明，几种合成化合物对 HDAC 和 COX 亚型具有显着的抑制活性。通过全细胞 HDAC 抑制测定和免疫印迹实验证实了所选化合物的膜通透性和细胞 HDAC 活性抑制作用。最有前途的双重抑制剂，C3 和 C4，在低微摩尔浓度范围内引起抗增殖作用，并导致凋亡细胞显着增加。与之前的报道相反，双重 HDAC-COX 抑制剂或与伏立诺他和塞来昔布的联合治疗同时抑制 HDAC 和 COX 活性不会导致累加或协同抗癌活性。
• Diazen-1-ium-1,2-diolated nitric oxide donor ester prodrugs of 1-(4-methanesulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids: Synthesis, nitric oxide release studies and anti-inflammatory activities
  作者：Khaled R.A. Abdellatif、Morshed Alam Chowdhury、Ying Dong、Edward E. Knaus

  DOI：10.1016/j.bmc.2008.05.028

  日期：2008.7.1

  A new group of hybrid nitric oxide-releasing anti-inflammatory drugs (NONO-coxibs) wherein an O(2)-acetoxymethyl-1-(N-ethyl-N-methylamino)diazen-1-ium-1,2-diolate (11a-c) NO-donor moiety is attached directly to the carboxylic acid group of 1-(4-methanesulfonylphenyl)-5-aryl-1H-pyrazol-3-carboxylic acids were synthesized. The diazen-1-ium-1,2-diolate compounds 11a-c all released a low amount of NO upon incubation with phosphate buffer (PBS) at pH 7.4 (7.7-9.3% range). In comparison, the percentage of NO released was significantly higher (67.5-73.6% of the theoretical maximal release of two molecules of NO/molecule of the parent hybrid ester prodrug) when the diazen-1-ium-1,2-diolate ester prodrugs were incubated in the presence of rat serum. These incubation studies suggest that both NO and the anti-inflammatory 1-(4-methanesulfonylphenyl)-5-(4-H, 4-F or 4-Me-phenyl)-1H-pyrazol-3- carboxylic acid (9a-c) would be released from the parent NONO-coxib upon in vivo cleavage by non-specific serum esterases. The 1-(4-methanesulfonylphenyl)-5-(4-H, 4-F or 4-Me-phenyl)-1H-pyrazol-3- carboxylic acids (9a-c) exhibited AI activities (ID(50) = 85.2-104.4 mg/kg po range) between that exhibited by the reference drugs aspirin (ID(50) = 128.7 mg/kg po) and celecoxib (ID(50) = 10.8 mg/kg po). Hybrid ester anti-inflammatory/NO-donor prodrugs (NONO-coxibs) offers a potential drug design concept targeted toward the development of anti-inflammatory drugs that are devoid of adverse ulcerogenic and/or cardiovascular effects. (c) 2008 Elsevier Ltd. All rights reserved.
• US7736624B2
  申请人：——

  公开号：US7736624B2

  公开（公告）日：2010-06-15