[2-(4-Ethenylphenyl)-6-hydroxy-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: [2-(4-Ethenylphenyl)-6-hydroxy-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone
• 化学式: C₃₀H₂₉NO₃S
• 分子量: 483.631
• InChiKey: QTRNBRCYOZEWCV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  35
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  78
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [2-(4-Ethenylphenyl)-6-hydroxy-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone 在 甲酸 、 palladium 10% on activated carbon 、 camphor-10-sulfonic acid 、 氢气 、 羟胺 、 potassium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 120.17h， 生成 N-hydroxy-5-(4-(6-hydroxy-3-(4-(2-(piperidin-1-yl)ethoxy)benzoyl)benzo[b]thiophen-2-yl)phenyl)pentanamide
  参考文献：
  名称：

  雷洛昔芬/组蛋白脱乙酰酶抑制剂杂合体的设计、合成及其在乳腺癌中的抗增殖活性

  摘要：

  抗雌激素/组蛋白脱乙酰酶抑制剂 (HDACi) 杂合体的设计是通过将雷洛昔芬与辛二酰苯胺异羟肟酸的结构合并，将 HDACi 单元纳入抗雌激素的酚环中。这些杂交体是用一系列 HDACi 链长度合成的，并评估了双功能性。四种杂交体（YW471）、（YW490）、（YW486）和（YW487）在 BRET 测定和荧光 HDACi 测定中都显示出良好的抗雌激素效力。杂合体的抗增殖活性在 ER+ MCF7 和 ER-MDA-MB-231 乳腺癌细胞系中得到证实。

  DOI：

  10.1016/j.ejmech.2024.116533
• 作为产物：
  描述：

  [4-[6-[Tert-butyl(dimethyl)silyl]oxy-3-[4-(2-piperidin-1-ylethoxy)benzoyl]-1-benzothiophen-2-yl]phenyl] trifluoromethanesulfonate 在 palladium diacetate 、 1,3-双(二苯基膦)丙烷 、 四丁基氟化铵 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.0h， 生成 [2-(4-Ethenylphenyl)-6-hydroxy-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone
  参考文献：
  名称：

  Structure−Activity Relationships of Selective Estrogen Receptor Modulators:  Modifications to the 2-Arylbenzothiophene Core of Raloxifene

  摘要：

  The 8-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. A series of raloxifene analogs which contain modifications to the 2-arylbenzothiophene core have been prepared and evaluated for the ability to bind to the estrogen receptor and inhibit MCF-7 breast cancer cell proliferation in vitro. Their ability to function as tissue-selective estrogen agonists in vivo has been assayed in a short-term, ovariectomized (OVX) rat model with end points of serum cholesterol lowering, uterine weight gain, and uterine eosinophil peroxidase activity. These studies have demonstrated that (1) the 6-hydroxy and, to a lesser extent, the 4'-hydroxy substituents of raloxifene are important for receptor binding and in vitro activity, (2) small, highly electronegative 4'-substituents such as hydroxy, fluoro, and chloro are preferred both in vitro and in vivo, (3) increased steric bulk at the 4'-position leads to increased uterine stimulation in, vivo, and (4) additional substitution of the 2-aryl moiety is tolerated while additional substitution at the 4-, 5-, or 7-position of the benzothiophene results in reduced biological activity. In addition, compounds in which the 2-aryl group is replaced by alkyl, cycloalkyl, and naphthyl substituents maintain a profile of in vitro and in vivo biological activity qualitatively similar to that of raloxifene. Several novel structural variants including 2-cyclohexyl, 2-naphthyl, and 6-carbomethoxy analogs also demonstrated efficacy in preventing bone loss in a chronic OVX rat model of postmenopausal osteopenia, at doses of 0.1-10 mg/kg.

  DOI：

  10.1021/jm9606352

文献信息

• Versatile raloxifene triflates
  作者：Michael J. Martin、Timothy A. Grese、Andrew L. Glasebrook、Ken Matsumoto、Lewis D. Pennington、D.Lynn Phillips、Lorri L. Short

  DOI：10.1016/s0960-894x(97)00130-3

  日期：1997.1

  Methodology has been employed that permits the differentiation of the phenols of raloxifene. Transition metal mediated transformations of raloxifene triflates have subsequently provided a number of analogs that were evaluated further in two in vitro models predictive of estrogen receptor mediated biological activity. (C) 1997 Elsevier Science Ltd.
• Structure−Activity Relationships of Selective Estrogen Receptor Modulators:  Modifications to the 2-Arylbenzothiophene Core of Raloxifene
  作者：Timothy A. Grese、Stephen Cho、Don R. Finley、Alexander G. Godfrey、Charles D. Jones、Charles W. Lugar、Michael J. Martin、Ken Matsumoto、Lewis D. Pennington、Mark A. Winter、M. Dee Adrian、Harlan W. Cole、David E. Magee、D. Lynn Phillips、Ellen R. Rowley、Lorri L. Short、Andrew L. Glasebrook、Henry U. Bryant

  DOI：10.1021/jm9606352

  日期：1997.1.1

  The 8-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. A series of raloxifene analogs which contain modifications to the 2-arylbenzothiophene core have been prepared and evaluated for the ability to bind to the estrogen receptor and inhibit MCF-7 breast cancer cell proliferation in vitro. Their ability to function as tissue-selective estrogen agonists in vivo has been assayed in a short-term, ovariectomized (OVX) rat model with end points of serum cholesterol lowering, uterine weight gain, and uterine eosinophil peroxidase activity. These studies have demonstrated that (1) the 6-hydroxy and, to a lesser extent, the 4'-hydroxy substituents of raloxifene are important for receptor binding and in vitro activity, (2) small, highly electronegative 4'-substituents such as hydroxy, fluoro, and chloro are preferred both in vitro and in vivo, (3) increased steric bulk at the 4'-position leads to increased uterine stimulation in, vivo, and (4) additional substitution of the 2-aryl moiety is tolerated while additional substitution at the 4-, 5-, or 7-position of the benzothiophene results in reduced biological activity. In addition, compounds in which the 2-aryl group is replaced by alkyl, cycloalkyl, and naphthyl substituents maintain a profile of in vitro and in vivo biological activity qualitatively similar to that of raloxifene. Several novel structural variants including 2-cyclohexyl, 2-naphthyl, and 6-carbomethoxy analogs also demonstrated efficacy in preventing bone loss in a chronic OVX rat model of postmenopausal osteopenia, at doses of 0.1-10 mg/kg.
• 10.1016/j.ejmech.2024.116533
  作者：Wang, Yufei、Sauvage, Madline、Diennet, Marine、Weber, Sandra、Mader, Sylvie、Gleason, James L.

  DOI：10.1016/j.ejmech.2024.116533

  日期：——

  Antiestrogen/histone deacetylase inhibitor (HDACi) hybrids were designed by merging structures of raloxifene with suberoylanilide hydroxamic acid, incorporating the HDACi unit into the phenolic ring of the antiestrogen. These hybrids were synthesized with a range of HDACi chain lengths and assessed for bifunctionality. Four hybrids, (YW471), (YW490), (YW486), and (YW487) showed good potency both as

  抗雌激素/组蛋白脱乙酰酶抑制剂 (HDACi) 杂合体的设计是通过将雷洛昔芬与辛二酰苯胺异羟肟酸的结构合并，将 HDACi 单元纳入抗雌激素的酚环中。这些杂交体是用一系列 HDACi 链长度合成的，并评估了双功能性。四种杂交体（YW471）、（YW490）、（YW486）和（YW487）在 BRET 测定和荧光 HDACi 测定中都显示出良好的抗雌激素效力。杂合体的抗增殖活性在 ER+ MCF7 和 ER-MDA-MB-231 乳腺癌细胞系中得到证实。