4,4'-((1r,3r,5r,7r)-adamantan-2-ylidenemethylene)diphenol | 23646-17-5

• 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: 4,4'-((1r,3r,5r,7r)-adamantan-2-ylidenemethylene)diphenol
• 英文别名: 4,4'-((adamantan-2-ylidene)methylene)diphenol；di-p.hydroxyphenyl adamantylidene methane；2-[Bis(4-hydroxyphenyl)methylene]adamantane；4-[2-adamantylidene-(4-hydroxyphenyl)methyl]phenol
• CAS: 23646-17-5
• 化学式: C₂₃H₂₄O₂
• 分子量: 332.442
• InChiKey: YJEWKPAUMRNEES-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.39
• 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：

  4,4'-((1r,3r,5r,7r)-adamantan-2-ylidenemethylene)diphenol 在 caesium carbonate 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 4-((adamantan-2-ylidene)(4-(2-aminoethoxy)phenyl)-methyl)phenol
  参考文献：
  名称：

  新型的选择性雌激素受体降解剂（SERD）：扩展PROTAC污垢的工具箱。

  摘要：

  乳腺癌的有效内分泌治疗是选择性和有效降解雌激素受体（ER）。迄今为止，基本上只有两种分子支架能够做到这一点。在这项研究中，我们已经开发出具有选择性雌激素受体降解剂（SERD）和ER拮抗特性的新型支架。这些新颖的SERD可以有效抑制MCF-7乳腺癌细胞的增殖和ER靶基因的表达，其功效与Fulvestrant相当。与Fulvestrant不同的是，这些新型SERD的模块化蛋白靶向嵌合体（PROTAC）型设计应易于分散到类似物库中，以进一步微调其药代动力学特性，包括口服有效性。

  DOI：

  10.1021/acsmedchemlett.8b00106
• 作为产物：
  描述：

  4,4'-二甲氧基二苯甲酮 在 二甲基硫 、 三氟化硼 、 四氯化钛 、 锌 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 1.5h， 生成 4,4'-((1r,3r,5r,7r)-adamantan-2-ylidenemethylene)diphenol
  参考文献：
  名称：

  Bridged Bicyclic Cores Containing a 1,1-Diarylethylene Motif Are High-Affinity Subtype-Selective Ligands for the Estrogen Receptor

  摘要：

  The actions of estrogens are mediated through the two estrogen receptors, ERalpha and ERbeta. Compounds that interact selectively with ERalpha or ERbeta are of interest because they could be used to explore the biological roles of these ER subtypes and they might be interesting estrogen pharmaceuticals. In a new approach to develop ER subtype-selective ligands, we have embellished the 1,1-diarylethylene motif, common to many nonsteroidal estrogens, with various bridged bicyclic or tricyclic cores, including ones based on bicyclo [3.3.1] nonane, bicyclo [2.2.1] heptane, and selected bi- and tricyclic terpenoids. This design leads to three-dimensional ER ligands of unusual structure that we have used to probe the size and shape of the ligand binding pocket of ERalpha and ERbeta. Many of these compounds have high binding affinities, with the best having a bicyclo[3.3.1]nonane core and binding 3-5 times better than estradiol to both ER subtypes. Some of the compounds show significant affinity selectivity in favor of ERbeta (4- to 5-fold), and in cell-based assays for transcriptional activity most are partial agonists on ERalpha and full antagonists on ERbeta.

  DOI：

  10.1021/jm0204800

文献信息

• Adamantyl Antiestrogens with Novel Side Chains Reveal a Spectrum of Activities in Suppressing Estrogen Receptor Mediated Activities in Breast Cancer Cells
  作者：Jian Min、Valeria Sanabria Guillen、Abhishek Sharma、Yuechao Zhao、Yvonne Ziegler、Ping Gong、Christopher G. Mayne、Sathish Srinivasan、Sung Hoon Kim、Kathryn E. Carlson、Kendall W. Nettles、Benita S. Katzenellenbogen、John A. Katzenellenbogen

  DOI：10.1021/acs.jmedchem.7b00585

  日期：2017.7.27

  To search for new antiestrogens more effective in treating breast cancers, we explored alternatives to the acrylic acid side chain used in many antiestrogens. To facilitate our search, we used a simple adamantyl ligand core that by avoiding stereochemical issues enabled rapid synthesis of acrylate ketone, ester, and amide analogs. All compounds were high affinity estrogen receptor α (ERα) ligands but

  为了寻找在乳腺癌中更有效的新型抗雌激素，我们探索了许多抗雌激素中丙烯酸侧链的替代物。为了方便我们的搜索，我们使用了一个简单的金刚烷基配体核心，该核心通过避免立体化学问题而实现了丙烯酸酯，酯和酰胺类似物的快速合成。所有化合物均为高亲和力雌激素受体α（ERα）配体，但作为抗增殖剂和ERα下调剂表现出一系列功效和功效。具有微小结构变化的化合物之间的活性差异很大，但抗增殖和ERα下调的功效通常相互平行。一些具有侧链极性基团的化合物具有特别高的亲和力。次生羧酰胺具有最佳的细胞活性，3-羟丙基酰胺在抑制细胞增殖和基因表达方面与氟维司群一样有效。这项研究基于简单的金刚烷基核心结构以及针对细胞拮抗剂活性进行了优化的丙烯酸酯侧链，生产出了结构新颖的抗雌激素药。
• [EN] ANTIESTROGEN COMPOUNDS<br/>[FR] COMPOSÉS ANTI-OESTROGÈNE
  申请人：SHARMA ABHISHEK

  公开号：WO2019241231A1

  公开（公告）日：2019-12-19

  A genus of proteolysis-targeting chimeras (PROTACs)-type compounds/antiestrogens has now been found that act as selective estrogen receptor degraders (SERDs) and estrogen receptor antagonists by degrading and antagonizing ERa in breast cancer cells. The compounds are of the following genus: The compounds described herein exhibit anti-proliferative effects, and are potentially useful, alone or in combination with other therapies, for the treatment of breast cancer. In general, these compounds combine a tight binding ERa targeting ligand tethered to a recognition motif or degron. Once bound, the degron recruits destructive cellular components and the targeted receptor (i.e., ERa) is degraded (i.e., destroyed) or antagonized.

  一种蛋白水解靶向嵌合物（PROTACs）类化合物/抗雌激素现已被发现，其作为选择性雌激素受体降解物（SERDs）和雌激素受体拮抗剂，通过在乳腺癌细胞中降解和拮抗ERa发挥作用。这些化合物属于以下类别：本文描述的化合物展示了抗增殖效果，并且可能单独或与其他疗法结合使用，用于乳腺癌的治疗。总的来说，这些化合物将紧密结合的ERa靶向配体与识别基序或降解标记相结合。一旦结合，降解标记将招募破坏性细胞组分，从而降解（即破坏）或拮抗目标受体（即ERa）。
• Antagonists for Constitutively Active Mutant Estrogen Receptors: Insights into the Roles of Antiestrogen-Core and Side-Chain
  作者：Abhishek Sharma、Weiyi Toy、Valeria Sanabria Guillen、Naina Sharma、Jian Min、Kathryn E. Carlson、Christopher G. Mayne、Shengjia Lin、Michael Sabio、Geoffrey Greene、Benita S. Katzenellenbogen、Sarat Chandarlapaty、John A. Katzenellenbogen

  DOI：10.1021/acschembio.8b00877

  日期：2018.12.21

  A major risk for patients having estrogen receptor alpha (ER alpha)-positive breast cancer is the recurrence of drug resistant metastases after initial successful treatment with endocrine therapies. Recent studies have implicated a number of activating mutations in the ligand-binding domain of ER alpha that stabilize the agonist conformation as a prominent mechanism for this acquired resistance. There are several critical gaps in our knowledge regarding the specific pharmacophore requirements of an antagonist that could effectively inhibit all or most of the different mutant ERs. To address this, we screened various chemotypes for blocking mutant ER-mediated transcriptional signaling and identified RU58668 as a model compound that contains structural elements that support potent ligand-induced inhibition of mutant ERs. We designed and synthesized a focused library of novel antagonists and probed how small and large perturbations in different ligand structural regions influenced inhibitory activity on individual mutant ERs in breast cancer cells. Effective inhibition derives from both nonpolar and moderately polar motifs in a multifunctional side chain of the antagonists, with the nature of the ligand core making important contributions by increasing the potency of ligands possessing similar types of side chains. Some of our new antagonists potently blocked the transcriptional activity of the three most common mutant ERs (L536R, Y537S, D538G) and inhibited mutant ER -mediated cell proliferation. Supported by our molecular modeling, these studies provide new insights into the role of specific components, involving both the ligand core and multifunctional side chain, in suppressing wild-type and mutant ER -mediated transcription and breast cancer cell proliferation.
• FOXM1 INHIBITOR COMPOSITIONS AND METHODS OF USING THE SAME
  申请人：The Board of Trustees of the University of Illinois

  公开号：EP3774708A1

  公开（公告）日：2021-02-17
• ANTIESTROGEN COMPOUNDS
  申请人：SHARMA Abhishek

  公开号：US20210130320A1

  公开（公告）日：2021-05-06

  A genus of proteolysis-targeting chimeras (PROTACs)-type compounds/antiestrogens has now been found that act as selective estrogen receptor degraders (SERDs) and estrogen receptor antagonists by degrading and antagonizing ERa in breast cancer cells. The compounds are of the following genus: The compounds described herein exhibit anti-proliferative effects, and are potentially useful, alone or in combination with other therapies, for the treatment of breast cancer. In general, these compounds combine a tight binding ERa targeting ligand tethered to a recognition motif or degron. Once bound, the degron recruits destructive cellular components and the targeted receptor (i.e., ERa) is degraded (i.e., destroyed) or antagonized.