1,1-bis(4-hydroxyphenyl)-2-phenylpent-1-ene

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: 1,1-bis(4-hydroxyphenyl)-2-phenylpent-1-ene
• 英文别名: 4-[1-(4-Hydroxyphenyl)-2-phenylpent-1-enyl]phenol
• 化学式: C₂₃H₂₂O₂
• 分子量: 330.426
• InChiKey: UTLLHWVRVATSPI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  40.5
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1,1-bis(4-hydroxyphenyl)-2-phenylpent-1-ene 在 吡啶 、 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.5h， 生成 (E)-4-{1-[4-(2-dimethylaminoethoxy)phenyl]-2-phenylpent-1-enyl}phenyl acetate
  参考文献：
  名称：

  雌激素相关受体ERRγ和ERRβ的新型反向激动剂的鉴定

  摘要：

  雌激素相关受体（ERRs，α，β和γ）是与雌激素受体（ERα和ERβ）序列最密切相关的孤儿核受体。近年来，由于ERRs作为代谢障碍病因中涉及的新的治疗靶标的潜在作用，已经引起了人们的极大关注。尽管迄今为止尚未发现任何ERR同工型的内源性配体，但已证明了使用合成小分子调节其活性的潜力。在本研究中，使用三芳基乙烯的区域和立体特异性直接取代合成了一系列新型的ERRγ和ERRβ反向激动剂。评估了这些化合物调节ERRs活性的能力。合理的定向替代方法和广泛的SAR研究导致了化合物的发现4a（DY40）是迄今为止描述的最有效的ERRγ反向激动剂，具有混合的ERRγ/ERRβ功能活性，可 在基于细胞的报告基因测定中有效抑制ERRγ的转录功能，IC 50 = 0.01μM，并有效拮抗ERRγ大约是其类似物Z-4-OHT（Z -4-hydroxytamoxifen）的60倍。此外，化合物3h（DY181）被鉴

  DOI：

  10.1016/j.bmc.2017.01.019
• 作为产物：
  描述：

  4-甲氧基-2-苯基苯乙酮 在 potassium tert-butylate 、 三溴化硼 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 为溶剂， 反应 72.0h， 生成 1,1-bis(4-hydroxyphenyl)-2-phenylpent-1-ene
  参考文献：
  名称：

  Investigations on Estrogen Receptor Binding. The Estrogenic, Antiestrogenic, and Cytotoxic Properties of C2-Alkyl-Substituted 1,1-Bis(4-hydroxyphenyl)-2-phenylethenes

  摘要：

  C2-Alkyl-substituted 1,1-bis(4-hydroxyphenyl)-2-phenylethenes were synthesized and assayed for estrogen receptor binding in a competition experiment with radiolabeled estradiol ([H-3]-E-2) using calf uterine cytosol. The relative binding affinity decreased with the length of the side chain R = H (3a: 35.2%) > Me (3b: 32.1%) > Et (3c: 6.20%); CH2CF3 (3d: 5.95%) > n-Pr (3e: 2.09%) > Bu (3f: 0.62%). Agonistic and antagonistic effects were evaluated in the luciferase assay with MCF-7-2a cells stably transfected with the plasmid ERE(wtc)luc. All compounds showed high antiestrogenic activity without significant agonistic potency. The comparison of the IC50 values for the inhibition of E2 (1 nM) documented the dependence of the antagonistic effects on the kind of the side chain: 3a (IC50 = 150 nM), 3b (IC50 = 30 nM), and 3f (IC50 = 500 nM) were weak antagonists, while 3c (IC50 = 15 nM), 3d (IC50 = 9 nM), and 3e (IC50 = 50 nM) were full antiestrogens and antagonized the effect of E2 completely. The most active compound 3d possessed the same antagonistic potency as 4-hydroxytamoxifen (40HT: IC50 = 7 nM) without bearing a basic side chain. 3d as well as all other 1,1-bis(4-hydroxyphenyl)-2-phenylalkenes were not able to influence the proliferation of hormone dependent MCF-7 cells despite the antagonistic mode of action. In this assay tamoxifen (TAM) and 40HT reduced the cell growth concentration dependent up to T/C-corr = 15% and 25%, respectively.

  DOI：

  10.1021/jm0209230

文献信息

• Design and Synthesis of Norendoxifen Analogues with Dual Aromatase Inhibitory and Estrogen Receptor Modulatory Activities
  作者：Wei Lv、Jinzhong Liu、Todd C. Skaar、David A. Flockhart、Mark Cushman

  DOI：10.1021/jm501218e

  日期：2015.3.26

  Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for treatment of breast cancer. Our previous efforts led to the discovery of norendoxifen as the first compound with dual aromatase inhibitory and estrogen receptor binding activities. To optimize its efficacy and aromatase selectivity versus other cytochrome P450 enzyme, a series of structurally related norendoxifen analogues were designed and synthesized. The most potent compound, 4'-hydroxynorendoxifen (10), displayed elevated inhibitory potency against aromatase and enhanced affinity for estrogen receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 eniymes was also superior to norendoxifen. 4'-Hydroxynorendoxifen is therefore an interesting lead for further development to obtain new anticancer agents of potential value for the treatment of breast cancer.
• A novel tamoxifen derivative, ridaifen-F, is a nonpeptidic small-molecule proteasome inhibitor
  作者：Makoto Hasegawa、Yukari Yasuda、Makoto Tanaka、Kenya Nakata、Eri Umeda、Yanwen Wang、Chihiro Watanabe、Shoko Uetake、Tatsuki Kunoh、Masafumi Shionyu、Ryuzo Sasaki、Isamu Shiina、Tamio Mizukami

  DOI：10.1016/j.ejmech.2013.11.009

  日期：2014.1

  In a survey of nonpeptide noncovalent inhibitors of the human 20S proteasome, we found that a novel tamoxifen derivative, RID-F (compound 6), inhibits all three protease activities of the proteasome at submicromolar levels. Structure activity relationship studies revealed that a RID-F analog (RID-F-S*4, compound 25) is the smallest derivative compound capable of inhibiting proteasome activity, with a potency similar to that of RID-F. Kinetic analyses of the inhibition mode and competition experiments involving biotin-belactosin A (a proteasome inhibitor) binding indicated that the RID-F derivatives interact with the protease subunits in a different manner. Culturing of human cells with these compounds resulted in accumulation of ubiquitinated proteins and induction of apoptosis. Thus, the RID-F derivatives may be useful lead chemicals for the generation of a new class of proteasome inhibitors. (C) 2013 Elsevier Masson SAS. All rights reserved.
• BORON-BASED 4-HYDROXYTAMOXIFEN AND ENDOXIFEN PRODRUGS AS TREATMENT FOR BREAST CANCER
  申请人：Xavier University

  公开号：EP2822955B1

  公开（公告）日：2017-07-26
• Identification of novel inverse agonists of estrogen-related receptors ERRγ and ERRβ
  作者：Donna D. Yu、Janice M. Huss、Hongzhi Li、Barry M. Forman

  DOI：10.1016/j.bmc.2017.01.019

  日期：2017.3

  α, β, and γ) are orphan nuclear receptors most closely related in sequence to estrogen receptors (ERα and ERβ). Much attention has been paid recently to the functions of ERRs for their potential roles as new therapeutic targets implicated in the etiology of metabolic disorders. While no endogenous ligand has been identified for any of the ERR isoforms to date, the potential for using synthetic small

  雌激素相关受体（ERRs，α，β和γ）是与雌激素受体（ERα和ERβ）序列最密切相关的孤儿核受体。近年来，由于ERRs作为代谢障碍病因中涉及的新的治疗靶标的潜在作用，已经引起了人们的极大关注。尽管迄今为止尚未发现任何ERR同工型的内源性配体，但已证明了使用合成小分子调节其活性的潜力。在本研究中，使用三芳基乙烯的区域和立体特异性直接取代合成了一系列新型的ERRγ和ERRβ反向激动剂。评估了这些化合物调节ERRs活性的能力。合理的定向替代方法和广泛的SAR研究导致了化合物的发现4a（DY40）是迄今为止描述的最有效的ERRγ反向激动剂，具有混合的ERRγ/ERRβ功能活性，可 在基于细胞的报告基因测定中有效抑制ERRγ的转录功能，IC 50 = 0.01μM，并有效拮抗ERRγ大约是其类似物Z-4-OHT（Z -4-hydroxytamoxifen）的60倍。此外，化合物3h（DY181）被鉴
• Investigations on Estrogen Receptor Binding. The Estrogenic, Antiestrogenic, and Cytotoxic Properties of C2-Alkyl-Substituted 1,1-Bis(4-hydroxyphenyl)-2-phenylethenes
  作者：Veronika Lubczyk、Helmut Bachmann、Ronald Gust

  DOI：10.1021/jm0209230

  日期：2002.11.1

  C2-Alkyl-substituted 1,1-bis(4-hydroxyphenyl)-2-phenylethenes were synthesized and assayed for estrogen receptor binding in a competition experiment with radiolabeled estradiol ([H-3]-E-2) using calf uterine cytosol. The relative binding affinity decreased with the length of the side chain R = H (3a: 35.2%) > Me (3b: 32.1%) > Et (3c: 6.20%); CH2CF3 (3d: 5.95%) > n-Pr (3e: 2.09%) > Bu (3f: 0.62%). Agonistic and antagonistic effects were evaluated in the luciferase assay with MCF-7-2a cells stably transfected with the plasmid ERE(wtc)luc. All compounds showed high antiestrogenic activity without significant agonistic potency. The comparison of the IC50 values for the inhibition of E2 (1 nM) documented the dependence of the antagonistic effects on the kind of the side chain: 3a (IC50 = 150 nM), 3b (IC50 = 30 nM), and 3f (IC50 = 500 nM) were weak antagonists, while 3c (IC50 = 15 nM), 3d (IC50 = 9 nM), and 3e (IC50 = 50 nM) were full antiestrogens and antagonized the effect of E2 completely. The most active compound 3d possessed the same antagonistic potency as 4-hydroxytamoxifen (40HT: IC50 = 7 nM) without bearing a basic side chain. 3d as well as all other 1,1-bis(4-hydroxyphenyl)-2-phenylalkenes were not able to influence the proliferation of hormone dependent MCF-7 cells despite the antagonistic mode of action. In this assay tamoxifen (TAM) and 40HT reduced the cell growth concentration dependent up to T/C-corr = 15% and 25%, respectively.