4-amino-N-(4-(trifluoromethyl)benzyl)benzenesulfonamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-amino-N-(4-(trifluoromethyl)benzyl)benzenesulfonamide
• 英文别名: N-[4-(Trifluoromethyl)benzyl]-4-aminobenzenesulfonamide；4-amino-N-[[4-(trifluoromethyl)phenyl]methyl]benzenesulfonamide
• 化学式: C₁₄H₁₃F₃N₂O₂S
• 分子量: 330.331
• InChiKey: FZVQIHWCUNHVHX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  80.6
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-amino-N-(4-(trifluoromethyl)benzyl)benzenesulfonamide 、 5-氨基-2-甲基苯酚 在 盐酸 、 亚硝酸异戊酯 、 potassium carbonate 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 0.25h， 生成 (E)-4-((2-amino-4-hydroxy-5-methylphenyl)diazenyl)-N-(4-(trifluoromethyl)benzyl)benzenesulfonamide
  参考文献：
  名称：

  Structure-Guided Design of Potent Diazobenzene Inhibitors for the BET Bromodomains

  摘要：

  BRD4, characterized by two acetyl-lysine binding bromodomains and an extra-terminal (ET) domain, is a key chromatin organizer that directs gene activation in chromatin through transcription factor recruitment, enhancer assembly, and pause release of the RNA polymerase II complex for transcription elongation. BRD4 has been recently validated as a new epigenetic drug target for cancer and inflammation. Our current knowledge of the functional differences of the two bromodomains of BRD4, however, is limited and is hindered by the lack of selective inhibitors. Here, we report our structure-guided development of diazobenzene-based small-molecule inhibitors for the BRD4 bromodomains that have over 90% sequence identity at the acetyl-lysine binding site. Our lead compound, MS436, through a set of water-mediated interactions, exhibits low nanomolar affinity (estimated Ki of 30-50 nM), with preference for the first bromodomain over the second. We demonstrated that MS436 effectively inhibits BRD4 activity in NF-κB-directed production of nitric oxide and proinflammatory cytokine interleukin-6 in murine macrophages. MS436 represents a new class of bromodomain inhibitors and will facilitate further investigation of the biological functions of the two bromodomains of BRD4 in gene expression.

  DOI：

  10.1021/jm401334s
• 作为产物：
  描述：

  4-(三氟甲基)苄胺 在 盐酸 、 三乙胺 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 4.0h， 生成 4-amino-N-(4-(trifluoromethyl)benzyl)benzenesulfonamide
  参考文献：
  名称：

  发现次磺酰胺作为IDO1抑制剂在体内具有强大的抗肿瘤作用。

  摘要：

  吲哚胺2,3-二加氧酶1（IDO1）是色氨酸代谢的犬尿氨酸途径中的关键限速酶，在肿瘤免疫逃逸中起重要作用。本文中，合成了多种仲磺酰胺，并在基于HeLa细胞的IDO1 /犬尿氨酸测定中进行了评估，从而鉴定了新的IDO1抑制剂。其中，化合物5d，5l和8g显示出最强的抑制作用，并且与命中的化合物BS-1相比具有显着改善的活性。体外结果表明，这些化合物可恢复T细胞增殖并抑制幼稚CD4 + T细胞分化为高度免疫抑制的FoxP3 +调节性T（Treg）细胞，而不会影响HeLa细胞的活力和IDO1蛋白的表达。重要的，药效学分析表明，化合物5d在携带免疫功能小鼠的CT26和B16F1肿瘤中均具有有效的抗肿瘤作用，而在免疫缺陷小鼠中则没有。从功能上讲，后续实验表明化合物5d可有效抑制肿瘤细胞增殖，诱导细胞凋亡，上调IFN-γ和颗粒酶B的表达并抑制FoxP3 + Treg细胞分化，从而激活免疫系统。因此，化

  DOI：

  10.1080/14756366.2020.1765165

文献信息

• Cyclometalated palladium pre-catalyst for N-alkylation of amines using alcohols and regioselective alkylation of sulfanilamide using aryl alcohols
  作者：Ramesh Mamidala、Vanga Mukundam、Kunchala Dhanunjayarao、Krishnan Venkatasubbaiah

  DOI：10.1016/j.tet.2017.03.001

  日期：2017.4

  Simple pyrazole based palladacycle-phosphine with a high turnover has been developed and applied for the N-alkylation of amines and sulfanilamide using alcohols as substrates by hydrogen borrowing strategy. N-alkylation of primary and secondary amines resulted in high isolated yields at 100–130 °C, under solvent free conditions. More challenging secondary aliphatic as well as aromatic alcohols were

  已经开发出具有高周转率的简单的吡唑基四氢环磷酰胺，并将其用于通过醇借用策略以醇为底物的胺和磺胺的N-烷基化。在无溶剂条件下，伯胺和仲胺的N-烷基化可在100-130°C的条件下实现高分离产率。在相似的反应条件下，更具挑战性的仲脂族和芳族醇也成功地用作烷基化剂。使用苯甲醇对苯胺进行N-苄基化反应的周转数达到43000。值得注意的是，使用醇作为烷基化剂，已经实现了2-氨基苯并噻唑和4-氨基苯磺酰胺的区域选择性N-烷基化为相应的2-N-（烷基氨基）唑和4-氨基-（N-烷基）苯磺酰胺的区域选择性。 -膦系统。
• Chemical Compounds
  申请人：Packham Keith Graham

  公开号：US20080090788A1

  公开（公告）日：2008-04-17

  Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as a Nuclear Factor-kB (NF-kB) inhibitor wherein: A has the following structure; Z is —COOH, —P(O)(OH) 2 or —SO 2 OH; each R 1 is the same or different and is halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, thio, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro, cyano or —CO 2 R′, wherein R′ represents hydrogen or C 1-6 alkyl; n is 0, 1, 2 or 3; R 2 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; Y is a linking group; and X is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, -M-aryl, -M-heteroaryl, -M-carbocyclyl or -M-heterocyclyl, wherein M is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, -Q-Het-Q′- or -Q-Het- wherein Q and Q′ are the same or different and are C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene and Het is selected from —NR′—, —O—, —S—, —SO 2 —, —SO—, —C(O)—O—, —OC(O), —CO—, —C(O)—NR′— or —NR′—C(O)— wherein R′ is as defined above, provided that: when n is 0, Z is —COOH, R 2 is hydrogen and Y is —N═N—, X is other than 2-pyridyl.

  使用式(I)化合物或其药学上可接受的盐制备药物，用作核因子-kB（NF-kB）抑制剂，其中： A具有以下结构； Z为—COOH，—P（O）（OH）2或—SO2OH； 每个R1相同或不同，为卤素，羟基，C1-6烷基，C2-6烯基，C2-6炔基，C1-6烷氧基，C1-6烷基硫基，硫代基，氨基，单（C1-6烷基）氨基，二（C1-6烷基）氨基，硝基，氰基或—CO2R′，其中R′代表氢或C1-6烷基； n为0、1、2或3； R2为氢，C1-6烷基，C2-6烯基或C2-6炔基； Y为连接基； X为C1-6烷基，C2-6烯基，C2-6炔基，芳基，杂环芳基，碳环基，杂环基，—M-芳基，—M-杂环芳基，—M-碳环基或—M-杂环基，其中M为C1-6烷基，C2-6烯基，C2-6炔基，—Q-Het-Q′-或-Q-Het-，其中Q和Q′相同或不同，为C1-6烷基，C2-6烯基或C2-6炔基，Het选自—NR′—，—O—，—S—，—SO2—，—SO—，—C（O）—O—，—OC（O），—CO—，—C（O）—NR′—或—NR′—C（O）—，其中R′如上定义，但当n为0时，Z为—COOH，R2为氢，Y为—N═N—，X不为2-吡啶基。
• Effective Recognition of Different Types of Amino Groups: From Aminobenzenesulfonamides to Amino-(<i>N</i>-alkyl)benzenesulfonamides via Iridium-Catalyzed <i>N</i>-Alkylation with Alcohols
  作者：Lei Lu、Juan Ma、Panpan Qu、Feng Li

  DOI：10.1021/acs.orglett.5b00824

  日期：2015.5.15

  A simple, highly efficient, and general strategy for the direct synthesis of amino-(N-alkyl)benzenesulfonamides has been accomplished via direct N-alkylation of aminobenzenesulfonamides bearing both different types of amino groups with alcohols as alkylating agents. Notably, this research exhibited the potential for the recognition of different types of amino groups in the N-alkylation of complex molecules with alcohols, facilitating the progress of the transition-metal-catalyzed "hydrogen autotransfer (or hydrogen-borrowing) process.
• 10.1021/acs.joc.4c00166
  作者：Shen, Lu、Wu, Xingliang、Shi, Lili、Xu, Xiangchao、Zhang, Jin、Li, Feng

  DOI：10.1021/acs.joc.4c00166

  日期：——
• Structure-Guided Design of Potent Diazobenzene Inhibitors for the BET Bromodomains
  作者：Guangtao Zhang、Alexander N. Plotnikov、Elena Rusinova、Tong Shen、Keita Morohashi、Jennifer Joshua、Lei Zeng、Shiraz Mujtaba、Michael Ohlmeyer、Ming-Ming Zhou

  DOI：10.1021/jm401334s

  日期：2013.11.27

  BRD4, characterized by two acetyl-lysine binding bromodomains and an extra-terminal (ET) domain, is a key chromatin organizer that directs gene activation in chromatin through transcription factor recruitment, enhancer assembly, and pause release of the RNA polymerase II complex for transcription elongation. BRD4 has been recently validated as a new epigenetic drug target for cancer and inflammation. Our current knowledge of the functional differences of the two bromodomains of BRD4, however, is limited and is hindered by the lack of selective inhibitors. Here, we report our structure-guided development of diazobenzene-based small-molecule inhibitors for the BRD4 bromodomains that have over 90% sequence identity at the acetyl-lysine binding site. Our lead compound, MS436, through a set of water-mediated interactions, exhibits low nanomolar affinity (estimated Ki of 30-50 nM), with preference for the first bromodomain over the second. We demonstrated that MS436 effectively inhibits BRD4 activity in NF-κB-directed production of nitric oxide and proinflammatory cytokine interleukin-6 in murine macrophages. MS436 represents a new class of bromodomain inhibitors and will facilitate further investigation of the biological functions of the two bromodomains of BRD4 in gene expression.