methyl (E)-4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzoate | 1143460-71-2

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: methyl (E)-4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzoate
• 英文别名: methyl 4-[(E)-3-(oxan-2-yloxyamino)-3-oxoprop-1-enyl]benzoate
• CAS: 1143460-71-2
• 化学式: C₁₆H₁₉NO₅
• 分子量: 305.331
• InChiKey: TVWGCSIROWXUCC-JXMROGBWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  73.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl (E)-4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzoate 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 2.0h， 生成 (E)-4-(2-(4-(3-(hydroxyamino)-3-oxoprop-1-en-1-yl)-N-methylbenzamido)ethoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide
  参考文献：
  名称：

  Design, Synthesis and Biological Evaluation of Nitro Oxide Donating <i>N</i>-Hydroxycinnamamide Derivatives as Histone Deacetylase Inhibitors

  摘要：

  设计并合成了新颖的硝基氧（NO）供体N-羟基肉桂酰胺衍生物12a–j，通过各种二醇或烷醇胺将N-羟基肉桂酰胺的羧基与苯磺酰呋咱耦合，并评价了它们在体外的生物活性。研究发现，大多数目标化合物显示出良好的组蛋白去乙酰化酶（HDACs）抑制和抗肿瘤活性，特别是12j，其HDACs抑制活性（IC50s=0.15–0.26 µM）和抗增殖效应（IC50s=3.21–7.12 µM）与丁酸酰胺羟肟酸（SAHA）相当（HDACs的IC50s=0.16–1.41 µM，癌细胞抑制的IC50s=3.15–7.45 µM）。此外，具有强抗肿瘤活性的化合物12j在结肠癌细胞中产生高水平的NO（高达8.0 µM的亚硝酸盐/硝酸盐），其抗增殖活性几乎被血红蛋白（10 µM，一种NO清除剂）减半。这些结果表明，12j的强抗增殖活性可能归因于其在癌细胞中高水平NO产生和HDAC抑制的叠加效应。

  DOI：

  10.1248/cpb.c14-00449
• 作为产物：
  描述：

  对甲酰基苯甲酸甲酯 在 哌啶 、 N-甲基吗啉 、 吡啶 、 氯甲酸乙酯 作用下， 以 四氢呋喃 为溶剂， 反应 5.0h， 生成 methyl (E)-4-(3-oxo-3-(((tetrahydro-2H-pyran-2-yl)oxy)amino)prop-1-en-1-yl)benzoate
  参考文献：
  名称：

  Design, Synthesis and Biological Evaluation of Nitro Oxide Donating <i>N</i>-Hydroxycinnamamide Derivatives as Histone Deacetylase Inhibitors

  摘要：

  设计并合成了新颖的硝基氧（NO）供体N-羟基肉桂酰胺衍生物12a–j，通过各种二醇或烷醇胺将N-羟基肉桂酰胺的羧基与苯磺酰呋咱耦合，并评价了它们在体外的生物活性。研究发现，大多数目标化合物显示出良好的组蛋白去乙酰化酶（HDACs）抑制和抗肿瘤活性，特别是12j，其HDACs抑制活性（IC50s=0.15–0.26 µM）和抗增殖效应（IC50s=3.21–7.12 µM）与丁酸酰胺羟肟酸（SAHA）相当（HDACs的IC50s=0.16–1.41 µM，癌细胞抑制的IC50s=3.15–7.45 µM）。此外，具有强抗肿瘤活性的化合物12j在结肠癌细胞中产生高水平的NO（高达8.0 µM的亚硝酸盐/硝酸盐），其抗增殖活性几乎被血红蛋白（10 µM，一种NO清除剂）减半。这些结果表明，12j的强抗增殖活性可能归因于其在癌细胞中高水平NO产生和HDAC抑制的叠加效应。

  DOI：

  10.1248/cpb.c14-00449

文献信息

• NOVEL BIFUNCTIONAL COMPOUNDS WHICH INHIBIT PROTEIN KINASES AND HISTONE DEACETYLASES
  申请人：Bar Thomas

  公开号：US20110065734A1

  公开（公告）日：2011-03-17

  The present invention relates to a bifunctional compound of formula I or its pharmaceutically acceptable salts or solvates A-L-B (I) wherein A is a histone deacetylase (HDAC) inhibitory moiety, L is a single bond or a linker group and B is a protein kinase inhibitory moiety. The bifunctional compound according to formula (I) is useful for the treatment of malignant and non-malignant neoplasia and diseases related to abnormal cell growth.

  本发明涉及一种式I的双功能化合物或其药学上可接受的盐或溶剂A-L-B(I)，其中A是组蛋白去乙酰化酶（HDAC）抑制基团，L是单键或连接基团，B是蛋白激酶抑制基团。根据式（I）的双功能化合物对于治疗恶性和非恶性肿瘤以及与异常细胞生长相关的疾病非常有用。
• Novel bifunctional compounds which inhibit protein kinases and histone deacetylases
  申请人：4SC AG

  公开号：EP2060565A1

  公开（公告）日：2009-05-20

  The present invention relates to a bifunctional compound of formula I or its pharmaceutically acceptable salts or solvates         A-L-B     (I) wherein A is a histone deacetylase (HDAC) inhibitory moiety, L is a single bond or a linker group and B is a protein kinase inhibitory moiety. The bifunctional compound according to formula (I) is useful for the treatment of malignant and non-malignant neoplasia and diseases related to abnormal cell growth.

  本发明涉及式 I 的双官能团化合物或其药学上可接受的盐或溶解物 A-L-B (I) 其中 A 是组蛋白去乙酰化酶（HDAC）抑制分子，L 是单键或连接基团，B 是蛋白激酶抑制分子。根据式（I）的双功能化合物可用于治疗恶性和非恶性肿瘤以及与细胞异常生长有关的疾病。
• Histone deacetylase (HDAC) inhibitor specificity determinants are preserved in a class of dual HDAC/non-covalent proteasome inhibitors
  作者：Alexandria M. Chan、Ashley Mitchell、Lena Grogan、Paul Shapiro、Steven Fletcher

  DOI：10.1016/j.bmc.2024.117680

  日期：2024.4

  HDAC6 inhibitor ricolinostat and the proteasome inhibitor bortezomib, we herein describe a focused family of dual HDAC/non-covalent proteasome inhibitors, and explore the impact of linker and zinc-binding group identities on HDAC1/6 isozyme selectivity. In general, previously reported specificity determinants of monovalent HDAC1/6 inhibitors were preserved in our dual HDAC/proteasome inhibitors.

  许多疾病状态需要多种药物来抑制多个靶点以进行有效的治疗/管理，即药物鸡尾酒疗法或“多药治疗”。相比之下，多药理学是开发可以抑制多个靶点的单一药物。每个策略都与优点和缺点相关。受 HDAC6 抑制剂利可林司他和蛋白酶体抑制剂硼替佐米联合治疗多发性骨髓瘤的有希望的临床试验数据的启发，我们在此描述了双 HDAC/非共价蛋白酶体抑制剂的重点家族，并探讨了接头和锌的影响- HDAC1/6 同工酶选择性的结合基团身份。一般来说，先前报道的单价 HDAC1/6 抑制剂的特异性决定因素保留在我们的双 HDAC/蛋白酶体抑制剂中。
• Design of Chimeric Histone Deacetylase- and Tyrosine Kinase-Inhibitors: A Series of Imatinib Hybrides as Potent Inhibitors of Wild-Type and Mutant BCR-ABL, PDGF-Rβ, and Histone Deacetylases
  作者：Siavosh Mahboobi、Stefan Dove、Andreas Sellmer、Matthias Winkler、Emerich Eichhorn、Herwig Pongratz、Thomas Ciossek、Thomas Baer、Thomas Maier、Thomas Beckers

  DOI：10.1021/jm800988r

  日期：2009.4.23

  Inhibitors of histone deacetylases are a new class of cancer therapeutics with possibly broad applicability. Combinations of HDAC inhibitors with the kinase inhibitor 1 (Imatimb) in recent studies showed additive and synergistic effects. Here we present a new concept by combining inhibition of protein kinases and HDACs, two independent pharmacological activities, in one synthetic small molecule. In general, the HDAC inhibition profile, the potencies, and the probable binding modes to HDAC1 and HDAC6 were similar as for 6 (SAHA). Inhibition of AN kinase in biochemical assays was maintained for Most compounds, but in general the kinase selectivity profile differed from that of I with nearly equipotent inhibition of the wildtype and the Imatimb resistant Abl (TI)-I-315 mutant. A potent cellular inhibition of PDGFR and cytotoxicity toward EOL-1 cells, a model for idiopathic hypereosinophilic syndrome (HES), are restored or enhanced for selected analogues (12b, 14b, and 18b). Cytotoxicity was evaluated by using a broad panel Of tumor cell lines, with selected analogues displaying mean IC50 values between 3.6 and 7.1 mu M.
• Discovery of Peptide Boronate Derivatives as Histone Deacetylase and Proteasome Dual Inhibitors for Overcoming Bortezomib Resistance of Multiple Myeloma
  作者：Yi Zhou、Xiaoting Liu、Junxin Xue、Lulu Liu、Tao Liang、Wen Li、Xinying Yang、Xuben Hou、Hao Fang

  DOI：10.1021/acs.jmedchem.9b02161

  日期：2020.5.14

  While proteasome inhibitors such as bortezomib showed satisfactory clinical benefits in the initial treatment of multiple myeloma (MM), drug resistance and relapse are unavoidable. Recent studies suggested inhibition of histone deacetylases (HDACs) restored sensitivity of bortezomib-resistant MM. Hence, we designed dual inhibitors targeting both HDACs and proteasomes to address the resistance of bortezomib

  尽管蛋白酶体抑制剂（如硼替佐米）在多发性骨髓瘤（MM）的初始治疗中显示出令人满意的临床益处，但耐药性和复发是不可避免的。最近的研究表明，抑制组蛋白脱乙酰基酶（HDACs）可恢复耐硼替佐米的MM的敏感性。因此，我们设计了针对HDAC和蛋白酶体的双重抑制剂，以解决硼替佐米的耐药性。最有效的抑制剂ZY-2和ZY-13对蛋白酶体表现出优异的抑制作用，并对HDAC具有良好的选择性。特别是ZY-2不仅对MM细胞系RPMI-8226，U266和KM3表现出良好的抗增殖活性（IC50值为6.66、4.31和10.1 nM，